ABSTRACTHypoxia-inducible factors (HIFs) are key regulators of intracellular oxygen homeostasis. The marked increase in HIFs activity in hypoxia as compared to normoxia, together with their transcriptional control of primary metabolic pathways, motivated the widespread view of HIFs as responsible for the cell’s metabolic adaptation to hypoxic stress. In this work, we suggest that this prevailing model of HIFs regulation is misleading. We propose an alternative model focused on understanding the dynamics of HIFs’ activity within its physiological context. Our model suggests that HIFs would not respond to but rather prevent the onset of hypoxic stress by regulating the traffic of electrons between catabolic substrates and oxygen. The explanatory power of our approach is patent in its interpretation of the Warburg effect, the tendency of tumor cells to favor anaerobic metabolism over respiration, even in fully aerobic conditions. This puzzling behavior is currently considered as an anomalous metabolic deviation. Our model predicts the Warburg effect as the expected homeostatic response of tumor cells to the abnormal increase in metabolic demand that characterizes malignant phenotypes. This alternative perspective prompts a redefinition of HIFs’ function and underscores the need to explicitly consider the cell’s metabolic activity in understanding its responses to changes in oxygen availability.

Metabolic overflow is defined by the excretion of partially oxidized byproducts, such as acetate, ethanol, and lactate, which could otherwise be used to produce energy. This behavior, widespread across diverse biological systems, is paradoxical because it suggests a seemingly wasteful use of resources that could instead be employed to maximize energy production. In this work, we investigate the ecological implications of metabolic overflow, using bacterial acetate metabolism as a model. We formulate a second-order generalization of the logistic growth equation, incorporating resource availability and acceleration dynamics to provide an explicit mechanistic link between metabolic overflow and ecological collapse. We demonstrate that acetate-mediated growth deceleration reduces the risk of overshoot and collapse, especially under conditions of resource oversupply. By inhibiting excessive proliferation, acetate overflow enhances the survival and stability of bacterial communities in fluctuating environments. In this context, acetate acts as a quorum-sensing signal, coordinating population-wide responses and enabling the active regulation of growth rates before resource exhaustion occurs. Our findings suggest that overflow metabolism is an adaptive strategy evolved to mitigate the risk of ecological collapse and stabilize microbial populations. These insights highlight the dual role of metabolic byproducts as both inhibitors of growth and regulators of population dynamics, with significant implications for microbial ecology and biotechnological applications. ### Competing Interest Statement The authors have declared no competing interest. MINECO, PID2022-138187OB-I00

This work is concerned with bone remodeling, an intriguing and efficient biological process that ensures the optimal compliance of the human skeleton by screening and replacing any single piece of it on a recursive basis. We propose here that a class of algorithms, which are simple enough to be implemented at an individual cell level, suffices to account for the two main features of such homeostatic process: thorough screening of the whole skeleton on the one hand and destruction and subsequent replacement of any single bone piece on the other. This last process is accomplished at a microscopic scale by special groups of cells, assembled for that purpose, called Bone Multicellular Units (BMUs). Moreover, it is shown that the algorithms proposed are robust, i.e, they remain functional in a wide range of biomechanical environments, thus allowing for different remodeling rates at different places.

In this work, we present a novel modeling framework for understanding the dynamics of homeostatic regulation. Inspired by engineering control theory, this framework incorporates unique features of biological systems. First, biological variables often play physiological roles, and taking this functional context into consideration is essential to fully understand the goals and constraints of homeostatic regulation. Second, biological signals are not abstract variables, but rather material molecules that may undergo complex turnover processes of synthesis and degradation. We suggest that the particular nature of biological signals may condition the type of information they can convey, and their potential role in shaping the dynamics and the ultimate purpose of homeostatic systems. We show that the dynamic interplay between regulated variables and control signals is a key determinant of biological homeostasis, challenging the necessity and the convenience of strictly extrapolating concepts from engineering control theory in modeling the dynamics of homeostatic systems. This work provides a simple, unified framework for studying biological regulation and identifies general principles that transcend molecular details of particular homeostatic mechanisms. We show how this approach can be naturally applied to apparently different regulatory systems, contributing to a deeper understanding of homeostasis as a fundamental process in living systems.

Insects damaging and penetrating plastic packaged materials has been reported since the 1950s. Radical innovation breakthroughs of plastic biodegradation have been initiated since the discovery of biodegradation of plastics by Tenebrio molitor larvae in 2015 followed by Galleria mellonella in 2017. Here we review updated studies on the insect-mediated biodegradation of plastics. Plastic biodegradation by insect larvae, mainly by some species of darkling beetles (Tenebrionidae) and pyralid moths (Pyralidae) is currently a highly active and potentially transformative area of research. Over the past eight years, publications have increased explosively, including discoveries of the ability of different insect species to biodegrade plastics, biodegradation performance, and the contribution of host and microbiomes, impacts of polymer types and their physic-chemical properties, and responsible enzymes secreted by the host and gut microbes. To date, almost all major plastics including polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC), polyethylene terephthalate (PET), polyurethane (PUR), and polystyrene (PS) can be biodegraded by T. molitor and ten other insect species representing the Tenebrionidae and Pyralidae families. The biodegradation processes are symbiotic reactions or performed by synergistic efforts of both host and gut-microbes to rapidly depolymerize and biodegrade plastics with hourly half-lives. The digestive ezymens and bioreagents screted by the insects play an essential role in plasatic biodegradation in certain species of Tenebrionidae and Pyralidae families. New research on the insect itself, gut microbiomes, transcriptomes, proteomes and metabolomes has evaluated the mechanisms of plastic biodegradation in insects. We conclude this review by discussing future research perspectives on insect-mediated biodegradation of plastics.

The regulation of red blood cell (RBC) homeostasis is widely assumed to rely on the control of cell production by erythropoietin (EPO) and the destruction of cells at a fixed, species-specific age. In this work, we show that such a regulatory mechanism would be a poor homeostatic solution to satisfy the changing needs of the body. Effective homeostatic control would require RBC lifespan to be variable and tightly regulated. We suggest that EPO may control RBC lifespan by determining CD47 expression in newly formed RBCs and SIRP-α expression in sinusoidal macrophages. EPO could also regulate the initiation and intensity of anti-RBC autoimmune responses that curtail RBC lifespan in some circumstances. These mechanisms would continuously modulate the rate of RBC destruction depending on oxygen availability. The control of RBC lifespan by EPO and autoimmunity emerges as a key mechanism in the homeostasis of RBCs.

ABSTRACT The regulation of red blood cell (RBC) homeostasis is widely assumed to rely on the control of cell production by erythropoietin (EPO) and the destruction of cells at a fixed, species-specific age. In this work, we show that such a regulatory mechanism is a poor homeostatic solution to satisfy the changing needs of the body. Effective homeostatic control requires RBC lifespan to be variable and tightly regulated. We show that EPO controls RBC lifespan by determining CD47 expression in newly formed RBCs and SIRP- α expression in sinusoidal macrophages. EPO also controls the initiation and intensity of anti-RBC autoimmune responses that curtail RBC lifespan in some circumstances. These mechanisms continuously modulate the rate of RBC destruction depending on oxygen availability. The finding of new homeostatic roles for EPO and autoimmunity critically challenges the current paradigm of RBC homeostasis and sets the grounds for a new approach to this field.

Microbiomes have been the focus of a substantial research effort in the last decades. The composition of microbial populations is normally determined by comparing DNA sequences sampled from those populations with the sequences stored in genomic databases. Therefore, the amount of information available in databanks should be expected to constrain the accuracy of microbiome analyses. Albeit normally ignored in microbiome studies, this constraint could severely compromise the reliability of microbiome data. To test this hypothesis, we generated virtual bacterial populations that exhibit the ecological structure of real-world microbiomes. Confronting the analyses of virtual microbiomes with their original composition revealed critical issues in the current approach to characterizing microbiomes, issues that were empirically confirmed by analyzing the microbiome of Galleria mellonella larvae. To reduce the uncertainty of microbiome data, the effort in the field must be channeled towards significantly increasing the amount of available genomic information and optimizing the use of this information.

The invention of fossil fuel–derived plastics changed and reshaped society for the better; however, their mass production has created an unprecedented accumulation of waste and an environmental crisis. Scientists are searching for better ways to reduce plastic waste than the current methods of mechanical recycling and incineration, which are only partial solutions. Biological means of breaking down plastics have been investigated as alternatives, with studies mostly focusing on using microorganisms to biologically degrade sturdy plastics like polyethylene (PE). Unfortunately, after a few decades of research, biodegradation by microorganisms has not provided the hoped-for results. Recent studies suggest that insects could provide a new avenue for investigation into biotechnological tools, with the discovery of enzymes that can oxidize untreated PE. But how can insects provide a solution that could potentially make a difference? And how can biotechnology revolutionize the plastic industry to stop ongoing/increasing contamination?

Plastic waste management is a pressing ecological, social, and economic challenge. The saliva of the lepidopteran Galleria mellonella larvae is capable of oxidizing and depolymerizing polyethylene in hours at room temperature. Here, we analyze by cryo–electron microscopy (cryo-EM) G. mellonella ’s saliva directly from the native source. The three-dimensional reconstructions reveal that the buccal secretion is mainly composed of four hexamerins belonging to the hemocyanin/phenoloxidase family, renamed Demetra, Cibeles, Ceres, and a previously unidentified factor termed Cora. Functional assays show that this factor, as its counterparts Demetra and Ceres, is also able to oxidize and degrade polyethylene. The cryo-EM data and the x-ray analysis from purified fractions show that they self-assemble primarily into three macromolecular complexes with striking structural differences that likely modulate their activity. Overall, these results establish the ground to further explore the hexamerins’ functionalities, their role in vivo, and their eventual biotechnological application.

One of the major environmental issues that modern civilizations are currently dealing with is the growing amount of plastic waste. Because of how they affect all forms of life, this waste is seen as a severe worldwide issue. Current methods for plastic waste disposal do not offer definitive solutions and often lead to the production of microplastics or secondary pollution. In recent years there has been a growing interest by the scientific community in the degradation of plastics by biological means, in particular the possibilities of using insects as a potential solution to the accumulation of this type of waste have been investigated. Among these, one of the most promising is undoubtedly the lepidopteran Galleria mellonella , which synthesizes the first ever discovered polyethylene degrading enzymes. In this review we propose an overview of plastic polymers production and common degradation methodologies, and analyses the current state of the art about the degradation carried out by this insect.

ABSTRACT Bacteria have evolved a variety of innate and adaptive immune strategies to fight bacteriophage (phage) infections. Innate defenses (unspecific mechanisms directed against any phage infecting the cell) range from the identification and cleavage of the viral DNA by restriction nucleases to the suicidal death of infected host cells, an extreme solution that prevents the spread of the infection throughout the population. Adaptive immunity, on the other hand, involves the creation of an immune memory that targets specific phages in case of reinfection. It is obvious that not every infection leads to the suicide of the host cell or to the formation of immune memory against the infecting phage, so what determines the outcome of an anti-phage response? In this work, we suggest that the dynamic aspects of phage infections are key to addressing this question. We show that the rates of viral DNA replication and cleavage define functional categories of phages that differ in their susceptibility to the immune strategies evolved by bacteria. From this viewpoint, the combined action of diverse bacterial defenses would be necessary to reduce the chances of phage immune evasion. This perspective allows us to formulate simple molecular mechanisms that could account for the decision of infected cells to undergo suicidal cell death or to incorporate new phages into the immune memory. This work highlights the importance of dynamics to understand bacterial immunity and formulates explicit hypotheses that could inspire a new and original empirical approach to the study of phage/bacteria interactions.

Plastic degradation by biological systems with re-utilization of the by-products could be a future solution to the global threat of plastic waste accumulation. Here, we report that the saliva of Galleria mellonella larvae (wax worms) is capable of oxidizing and depolymerizing polyethylene (PE), one of the most produced and sturdy polyolefin-derived plastics. This effect is achieved after a few hours' exposure at room temperature under physiological conditions (neutral pH). The wax worm saliva can overcome the bottleneck step in PE biodegradation, namely the initial oxidation step. Within the saliva, we identify two enzymes, belonging to the phenol oxidase family, that can reproduce the same effect. To the best of our knowledge, these enzymes are the first animal enzymes with this capability, opening the way to potential solutions for plastic waste management through bio-recycling/up-cycling.

Bacterial cells are equipped with a variety of immune strategies to fight bacteriophage infections. Such strategies include unspecific mechanisms directed against any phage infecting the cell, ranging from the identification and cleavage of the viral DNA by restriction nucleases (restriction-modification systems) to the suicidal death of infected host cells (abortive infection, Abi). In addition, CRISPR-Cas systems generate an immune memory that targets specific phages in case of reinfection. However, the timing and coordination of different antiviral systems in bacterial cells are poorly understood. Here, we use simple mathematical models of immune responses in individual bacterial cells to propose that the intracellular dynamics of phage infections are key to addressing these questions. Our models suggest that the rates of viral DNA replication and cleavage inside host cells define functional categories of phages that differ in their susceptibility to bacterial anti-phage mechanisms, which could give raise to alternative phage strategies to escape bacterial immunity. From this viewpoint, the combined action of diverse bacterial defenses would be necessary to reduce the chances of phage immune evasion. The decision of individual infected cells to undergo suicidal cell death or to incorporate new phage sequences into their immune memory would be determined by dynamic interactions between the host's immune mechanisms and the phage DNA. Our work highlights the importance of within-cell dynamics to understand bacterial immunity, and formulates hypotheses that may inspire future research in this area.

One of the most remarkable aspects of human homoeostasis is bone remodelling. This term denotes the continuous renewal of bone that takes place at a microscopic scale and ensures that our skeleton preserves its full mechanical compliance during our lives. We propose here that a renewal process of this type can be represented at an algorithmic level as the interplay of two different but related mechanisms. The first of them is a preliminary screening process, by means of which the whole skeleton is thoroughly and continuously explored. This is followed by a renovation process, whereby regions previously marked for renewal are first destroyed and then rebuilt, in such a way that global mechanical compliance is never compromised. In this work, we pay attention to the first of these two stages. In particular, we show that an efficient screening mechanism may arise out of simple local rules, which at the biological level are inspired by the possibility that individual bone cells compute signals from their nearest local neighbours. This is shown to be enough to put in place a process which thoroughly explores the region where such mechanism operates.

The protection induced by vaccines against infectious diseases such as malaria, dengue or hepatitis relies on a the creation of immune memory by T cells, key components of the human immune system. The induction of a strong T cell response leading to long lasting memory can be improved by using prime-boost (PB) vaccines, which consist in successive inoculations of appropriate vectors carrying target antigens that can be recognized by specific T cell clones. A problem faced by PB vaccines is the fact that T cell response is often biased towards a few clones that can identify only a small set of antigens, out of the many that could be displayed by the pathogen. This phenomenon, known as immunodominance, can significantly compromise the effectiveness of vaccination. In this work we will use mathematical modeling to better understand the role of T cell population dynamics in the onset of immunodominance in PB vaccines. In particular, we will use mathematical analysis and simulations to compare single-dose vaccines with PB ones, both for homologous (where the same antigen is used in every shot) and heterologous protocols (in which different antigens are used at each step).

A growing number of studies suggest that SARS-CoV-2 could interfere with homeostatic mechanisms in the lung but the implications of this possible interference have not been fully explored in the literature. In this work, we examine the consequences that can be drawn from this hypothesis according to currently available knowledge. We suggest that one such consequence is the potential disruption of normal ventilation and perfusion of lung regions that may be distant from the infection sites. Loss of ventilation might result in local alveolar hypoxia and contribute to hypoxemia, which in turn could trigger homeostatic responses that enhance blood oxygenation by redistributing pulmonary blood circulation. Sudden changes in perfusion might then lead to the development of hydrostatic edema and eventually to vascular remodeling and inflammation. Therefore, the immune response might not be the only source of the substantial inflammation observed in lung tissues of patients with severe COVID-19, as is often assumed in the literature. The balance between the homeostatic and the immune reaction in each patient could account for the observed heterogeneity of the clinical manifestations of COVID-19.

One of the early, profound insights regarding the biology of the neural crest was the observation of its contribution to the skeletal structures of the cranium and jaws. The critical nature of these structures made the comparative analysis of the cranial neural crest and its derived structures essential investigative aims toward our understanding of the development and evolution of vertebrates and vertebrate-specific structures. Though classically applied to a relatively wide range of taxa in the nineteenth and early twentieth centuries, the application of traditional methodologies for complex comparative developmental and anatomical analyses subsequently become more limited by their time-consuming nature, resource scarcity, and a greater emphasis on the genetic and molecular regulation of patterning and morphogenesis in a select number of tractable model organisms. Recently, however, this trend has been reversed, and the value of genetic and molecular-based questions applied to non-model (unconventional) vertebrate organisms has been re-appreciated. This is particularly true of comparative investigations of cranial neural crest biology. Herein, we present methodologies for the analysis of the cranial neural crest and its structural derivatives employable in modern investigations of both model and unconventional vertebrate organisms.