Diffusible Signal Molecules Research Articles

Quorum Sensing Inhibitors: An Alternative Strategy to Win the Battle against Multidrug-Resistant (MDR) Bacteria.

Antibiotic resistance is a major problem and a major global health concern. In total, there are 16 million deaths yearly from infectious diseases, and at least 65% of infectious diseases are caused by microbial communities that proliferate through the formation of biofilms. Antibiotic overuse has resulted in the evolution of multidrug-resistant (MDR) microbial strains. As a result, there is now much more interest in non-antibiotic therapies for bacterial infections. Among these revolutionary, non-traditional medications is quorum sensing inhibitors (QSIs). Bacterial cell-to-cell communication is known as quorum sensing (QS), and it is mediated by tiny diffusible signaling molecules known as autoinducers (AIs). QS is dependent on the density of the bacterial population. QS is used by Gram-negative and Gram-positive bacteria to control a wide range of processes; in both scenarios, QS entails the synthesis, identification, and reaction to signaling chemicals, also known as auto-inducers. Since the usual processes regulated by QS are the expression of virulence factors and the creation of biofilms, QS is being investigated as an alternative solution to antibiotic resistance. Consequently, the use of QS-inhibiting agents, such as QSIs and quorum quenching (QQ) enzymes, to interfere with QS seems like a good strategy to prevent bacterial infections. This review sheds light on QS inhibition strategy and mechanisms and discusses how using this approach can aid in winning the battle against resistant bacteria.

Revealing the atomic and electronic mechanism of human manganese superoxide dismutase product inhibition

Human manganese superoxide dismutase (MnSOD) is a crucial oxidoreductase that maintains the vitality of mitochondria by converting superoxide (O2●−) to molecular oxygen (O2) and hydrogen peroxide (H2O2) with proton-coupled electron transfers (PCETs). Human MnSOD has evolved to be highly product inhibited to limit the formation of H2O2, a freely diffusible oxidant and signaling molecule. The product-inhibited complex is thought to be composed of a peroxide (O22−) or hydroperoxide (HO2−) species bound to Mn ion and formed from an unknown PCET mechanism. PCET mechanisms of proteins are typically not known due to difficulties in detecting the protonation states of specific residues that coincide with the electronic state of the redox center. To shed light on the mechanism, we combine neutron diffraction and X-ray absorption spectroscopy of the product-bound, trivalent, and divalent states of the enzyme to reveal the positions of all the atoms, including hydrogen, and the electronic configuration of the metal ion. The data identifies the product-inhibited complex, and a PCET mechanism of inhibition is constructed.

Dentification of novel potential anti-quorum sensing molecules against LasR of Pseudomonas aeruginosa using in silico approach

Quorum sensing (QS), commonly known as inter-and intracellular communication in bacteria, is accomplished by small, diffusible signaling molecules termed as autoinducers. Numerous virulence factors that are involved in pathogenesis are regulated by QS. It has come to attention as a result of the growing resistance of bacteria to conventional antibiotics, as it applies less to no selective pressure to limit the development of resistance among bacteria. For inhibitors, LasR, a transcription factor that regulates QS in Pseudomonas aeruginosa, is a promising therapeutic target. Hence, the objective of this study is to identify possible LasR inhibitors from natural substances. Virtually 2068 ZINC database compounds were tested against the LasR structure. Following the filtering of suitable compounds using Lipinski's rule and ADME criteria. Depending on binding energy, eight novel potential QS inhibitory agents were identified. To determine how inhibitors and targets bind, structures of LasR-ligand complexes were examined. It is important to note that all of the compounds are structurally distinct from 3-oxo-C12-HSL, a native autoinducer of LasR, which is essential for the activation of LasR dimer that regulates QS system in Pseudomonas aeruginosa. These inhibitors are natural in origin and hence can be very useful in treating Pseudomonas infection; however, we have to properly evaluate their effectiveness, safety, and mode of action, through in vivo and in vitro investigation.

Extending a synthetic Notch morphogen circuit model to construct 2D cell structures

Morphogenesis, the process of cells forming a defined shape, is central during embryonic development. Among other cues it involves diffusible signaling molecules, known as morphogens, and concentration-dependent cellular responses to these molecules. Recent advances in synthetic biology have enabled the isolated design and study of cellular systems that mimic morphogenesis. Here, we build on a system from Toda et al. (2020) that uses a synthetic Notch morphogen circuit to trigger and modulate gene expression. Following our vision of a model-based design of different cellular shapes and patterns, we present extensions of this framework based on the current synthetic Notch signaling capabilities described in the literature. We show first results of implementing morphogen-dependent proliferation as a particular example. The proliferation triggered by the morphogen modulates the steepness of the morphogen gradient, which directly translates to the signal readout. Furthermore, our modeling framework allows us to consider and design patterns in 2D that can be modulated by varying the size and location of the morphogen source and those of the interacting molecules, such as morphogen inhibitors. This bottom-up engineering approach opens up opportunities to better understand the underlying principles of morphogenesis and to design complex tissues with desired functions.

RsaM: a unique dominant regulator of AHL quorum sensing in bacteria.

Quorum sensing (QS) in proteobacteria is a mechanism to control gene expression orchestrated by the LuxI/LuxR protein family pair, which produces and responds to N-acyl homoserine lactone (AHL) diffusible signal molecules. QS is often regarded as a cell density response via the sensing of/response to the concentrations of AHLs, which are constantly basally produced by bacterial cells. The luxI/R systems, however, undergo supra-regulation in response to external stimuli and many regulators have been implicated in controlling QS in bacteria, although it remains unclear how most of these regulators and cues contribute to the QS response. One regulator, called RsaM, has been reported in a few proteobacterial species to have a stringent role in the control of AHL QS. RsaMs are small, in the range of 140-170 aa long, and are found in several genera, principally in Burkholderia and Acinetobacter. The gene encoding RsaM is always located as an independent transcriptional unit, situated adjacent to QS luxI and/or luxR loci. One of the most remarkable aspects of RsaM is its uniqueness; it does not fall into any of the known bacterial regulatory families and it possesses a distinct and novel fold that does not exhibit binding affinity for nucleic acids or AHLs. RsaM stands out as a distinctive regulator in bacteria, as it is likely to have an important ecological role, as well as unravelling a novel way of gene regulation in bacteria.

Unraveling the Diverse Profile of N-Acyl Homoserine Lactone Signals and Their Role in the Regulation of Biofilm Formation in Porphyra haitanensis-Associated Pseudoalteromonas galatheae.

N-acyl homoserine lactones (AHLs) are small, diffusible chemical signal molecules that serve as social interaction tools for bacteria, enabling them to synchronize their collective actions in a density-dependent manner through quorum sensing (QS). The QS activity from epiphytic bacteria of the red macroalgae Porphyra haitanensis, along with its involvement in biofilm formation and regulation, remains unexplored in prior scientific inquiries. Therefore, this study explores the AHL signal molecules produced by epiphytic bacteria. The bacterium isolated from the surface of P. haitanensis was identified as Pseudoalteromonas galatheae by 16s rRNA gene sequencing and screened for AHLs using two AHL reporter strains, Agrobacterium tumefaciens A136 and Chromobacterium violaceum CV026. The crystal violet assay was used for the biofilm-forming phenotype. The inferences revealed that P. galatheae produces four different types of AHL molecules, i.e., C4-HSL, C8-HSL, C18-HSL, and 3-oxo-C16-HSL, and it was observed that its biofilm formation phenotype is regulated by QS molecules. This is the first study providing insights into the QS activity, diverse AHL profile, and regulatory mechanisms that govern the biofilm formation phenotype of P. galatheae. These findings offer valuable insights for future investigations exploring the role of AHL producing epiphytes and biofilms in the life cycle of P. haitanensis.

Beyond Thresholds: Quorum‐Sensing as Quantitatively Varying Reaction Norms to Multiple Environmental Dimensions

AbstractMany types of bacteria engage in complex collective behaviors, often controlled by a form of cell‐cell communication mediated by diffusible signal molecules called quorum sensing (QS). Each individual produces and responds to these diffusible signaling molecules, inferring properties of their environment, and modulating the regulation of hundreds of downstream genes in response. A threshold concept is ingrained in the QS literature following the use of the legal ‘quorum’ analogy, where populations of bacteria are synchronously sub‐quorate below a threshold population size or synchronously quorate above a threshold population size. However, a growing body of literature highlights that QS can produce more nuanced, graded responses to environmental variation, implying there is no simple threshold ‘quorum’ on either the single cell or population scale. In this commentary, we discuss reaction norms as a tool to quantify and compare QS‐controlled behaviors in an environmental context.

Porphyromonas gingivalis diffusible signaling molecules enhance Fusobacterium nucleatum biofilm formation via gene expression modulation

ABSTRACT Background Periodontitis is caused by a dysbiotic shift in the dental plaque microbiome. Fusobacterium nucleatum is involved in the colonization of Porphyromonas gingivalis, which plays a key role in dysbiosis, via coaggregation and synergy with this microorganism. Aim We investigated the effect of diffusible signaling molecules from P. gingivalis ATCC 33277 on F. nucleatum TDC 100 to elucidate the synergistic mechanisms involved in dysbiosis. Methods The two species were cocultured separated with an 0.4-µm membrane in tryptic soy broth, and F. nucleatum gene expression profiles in coculture with P. gingivalis were compared with those in monoculture. Results RNA sequencing revealed 139 genes differentially expressed between the coculture and monoculture. The expression of 52 genes was upregulated, including the coaggregation ligand-coding gene. Eighty-seven genes were downregulated. Gene Ontology analysis indicated enrichment for the glycogen synthesis pathway and a decrease in de novo synthesis of purine and pyrimidine. Conclusion These results indicate that diffusible signaling molecules from P. gingivalis induce metabolic changes in F. nucleatum, including an increase in polysaccharide synthesis and reduction in de novo synthesis of purine and pyrimidine. The metabolic changes may accelerate biofilm formation by F. nucleatum with P. gingivalis. Further, the alterations may represent potential therapeutic targets for preventing dysbiosis.

Coupling Cell Communication and Optogenetics: Implementation of a Light-Inducible Intercellular System in Yeast.

Cell communication is a widespread mechanism in biology, allowing the transmission of information about environmental conditions. In order to understand how cell communication modulates relevant biological processes such as survival, division, differentiation, and apoptosis, different synthetic systems based on chemical induction have been successfully developed. In this work, we coupled cell communication and optogenetics in the budding yeast Saccharomyces cerevisiae. Our approach is based on two strains connected by the light-dependent production of α-factor pheromone in one cell type, which induces gene expression in the other type. After the individual characterization of the different variants of both strains, the optogenetic intercellular system was evaluated by combining the cells under contrasting illumination conditions. Using luciferase as a reporter gene, specific co-cultures at a 1:1 ratio displayed activation of the response upon constant blue light, which was not observed for the same cell mixtures grown in darkness. Then, the system was assessed at several dark/blue-light transitions, where the response level varies depending on the moment in which illumination was delivered. Furthermore, we observed that the amplitude of response can be tuned by modifying the initial ratio between both strains. Finally, the two-population system showed higher fold inductions in comparison with autonomous strains. Altogether, these results demonstrated that external light information is propagated through a diffusible signaling molecule to modulate gene expression in a synthetic system involving microbial cells, which will pave the road for studies allowing optogenetic control of population-level dynamics.

Evidence for Complex Interplay between Quorum Sensing and Antibiotic Resistance in Pseudomonas aeruginosa.

Quorum sensing (QS) is a cell-density-dependent, intercellular communication system mediated by small diffusible signaling molecules. QS regulates a range of bacterial behaviors, including biofilm formation, virulence, drug resistance mechanisms, and antibiotic tolerance. Enzymes capable of degrading signaling molecules can interfere in QS-a process termed as quorum quenching (QQ). Remarkably, previous work reported some cases where enzymatic interference in QS was synergistic to antibiotics against Pseudomonas aeruginosa. The premise of combination therapy is attractive to fight against multidrug-resistant bacteria, yet comprehensive studies are lacking. Here, we evaluate the effects of QS signal disruption on the antibiotic resistance profile of P. aeruginosa by testing 222 antibiotics and antibacterial compounds from 15 different classes. We found compelling evidence that QS signal disruption does indeed affect antibiotic resistance (40% of all tested compounds; 89/222), albeit not always synergistically (not synergistic for 19% of compounds; 43/222). For some tested antibiotics, such as sulfathiazole and trimethoprim, we were able to relate the changes in resistance caused by QS signal disruption to the modulation of the expression of key genes of the folate biosynthetic pathway. Moreover, using a P. aeruginosa-based Caenorhabditis elegans killing model, we confirmed that enzymatic QQ modulates the effects of antibiotics on P. aeruginosa's pathogenicity in vivo. Altogether, these results show that signal disruption has profound and complex effects on the antibiotic resistance profile of P. aeruginosa. This work suggests that combination therapy including QQ and antibiotics should be discussed not globally but, rather, in case-by-case studies. IMPORTANCE Quorum sensing (QS) is a cell-density-dependent communication system used by a wide range of bacteria to coordinate behaviors. Strategies pertaining to the interference in QS are appealing approaches to control microbial behaviors that depend on QS, including virulence and biofilms. Interference in QS was previously reported to be synergistic with antibiotics, yet no systematic assessment exists. Here, we evaluate the potential of combination treatments using the model opportunistic human pathogen Pseudomonas aeruginosa PA14. In this model, collected data demonstrate that QS largely modulates the antibiotic resistance profile of PA14 (for more than 40% of the tested drugs). However, the outcome of combination treatments is synergistic for only 19% of them. This research demonstrates the complex relationship between QS and antibiotic resistance and suggests that combination therapy including QS inhibitors and antibiotics should be discussed not globally but, rather, in case-by-case studies.

Antiactivators prevent self-sensing in Pseudomonas aeruginosa quorum sensing

Quorum sensing is described as a widespread cell density-dependent signaling mechanism in bacteria. Groups of cells coordinate gene expression by secreting and responding to diffusible signal molecules. Theory, however, predicts that individual cells may short-circuit this mechanism by directly responding to the signals they produce irrespective of cell density. In this study, we characterize this self-sensing effect in the acyl-homoserine lactone quorum sensing system of Pseudomonas aeruginosa. We show that antiactivators, a set of proteins known to affect signal sensitivity, function to prevent self-sensing. Measuring quorum-sensing gene expression in individual cells at very low densities, we find that successive deletion of antiactivator genes qteE and qslA produces a bimodal response pattern, in which increasing proportions of constitutively induced cells coexist with uninduced cells. Comparing responses of signal-proficient and -deficient cells in cocultures, we find that signal-proficient cells show a much higher response in the antiactivator mutant background but not in the wild-type background. Our results experimentally demonstrate the antiactivator-dependent transition from group- to self-sensing in the quorum-sensing circuitry of P. aeruginosa. Taken together, these findings extend our understanding of the functional capacity of quorum sensing. They highlight the functional significance of antiactivators in the maintenance of group-level signaling and experimentally prove long-standing theoretical predictions.

Azetidomonamide and Diazetidomonapyridone Metabolites Control Biofilm Formation and Pigment Synthesis in Pseudomonas aeruginosa.

Synthesis of azetidine-derived natural products by the opportunistic pathogen Pseudomonas aeruginosa is controlled by quorum sensing, a process involving the production and sensing of diffusible signal molecules that is decisive for virulence regulation. In this study, we engineered P. aeruginosa for the titratable expression of the biosynthetic aze gene cluster, which allowed the purification and identification of two new products, azetidomonamide C and diazetidomonapyridone. Diazetidomonapyridone was shown to have a highly unusual structure with two azetidine rings and an open-chain diimide moiety. Expression of aze genes strongly increased biofilm formation and production of phenazine and alkyl quinolone virulence factors. Further physiological studies revealed that all effects were mainly mediated by azetidomonamide A and diazetidomonapyridone, whereas azetidomonamides B and C had little or no phenotypic impact. The P450 monooxygenase AzeF which catalyzes a challenging, stereoselective hydroxylation of the azetidine ring converting azetidomonamide C into azetidomonamide A is therefore crucial for biological activity. Based on our findings, we propose this group of metabolites to constitute a new class of diffusible regulatory molecules with community-related effects in P. aeruginosa.

Quorum-sensing induced transitions between bistable steady-states for a cell-bulk ODE-PDE model with lux intracellular kinetics.

Intercellular signaling and communication are used by bacteria to regulate a variety of behaviors. In a type of cell-cell communication known as quorum sensing (QS), which is mediated by a diffusible signaling molecule called an autoinducer, bacteria can undergo sudden changes in their behavior at a colony-wide level when the density of cells exceeds a critical threshold. In mathematical models of QS behavior, these changes can include the switch-like emergence of intracellular oscillations through a Hopf bifurcation, or sudden transitions between bistable steady-states as a result of a saddle-node bifurcation of equilibria. As an example of this latter type of QS transition, we formulate and analyze a cell-bulk ODE-PDE model in a 2-D spatial domain that incorporates the prototypical LuxI/LuxR QS system for a collection of stationary bacterial cells, as modeled by small circular disks of a common radius with a cell membrane that is permeable only to the autoinducer. By using the method of matched asymptotic expansions, it is shown that the steady-state solutions for the cell-bulk model exhibit a saddle-node bifurcation structure. The linear stability of these branches of equilibria are determined from the analysis of a nonlinear matrix eigenvalue problem, called the globally coupled eigenvalue problem. The key role on QS behavior of a bulk degradation of the autoinducer field, which arises from either a Robin boundary condition on the domain boundary or from a constant bulk decay, is highlighted. With bulk degradation, it is shown analytically that the effect of coupling identical bacterial cells to the bulk autoinducer diffusion field is to create an effective bifurcation parameter that depends on the population of the colony, the bulk diffusivity, the membrane permeabilities, and the cell radius. QS transitions occur when this effective parameter passes through a saddle-node bifurcation point of the Lux ODE kinetics for an isolated cell. In the limit of a large but finite bulk diffusivity, it is shown that the cell-bulk system is well-approximated by a simpler ODE-DAE system. This reduced system, which is used to study the effect of cell location on QS behavior, is easily implemented for a large number of cells. Predictions from the asymptotic theory for QS transitions between bistable states are favorably compared with full numerical solutions of the cell-bulk ODE-PDE system.

Pillars and Gaps of S-Nitrosylation-Dependent Epigenetic Regulation in Physiology and Cancer.

Nitric oxide (NO) is a diffusible signaling molecule produced by three isoforms of nitric oxide synthase, which release NO during the metabolism of the amino acid arginine. NO participates in pathophysiological responses of many different tissues, inducing concentration-dependent effect. Indeed, while low NO levels generally have protective effects, higher NO concentrations induce cytotoxic/cytostatic actions. In recent years, evidences have been accumulated unveiling S-nitrosylation as a major NO-dependent post-translational mechanism ruling gene expression. S-nitrosylation is a reversible, highly regulated phenomenon in which NO reacts with one or few specific cysteine residues of target proteins generating S-nitrosothiols. By inducing this chemical modification, NO might exert epigenetic regulation through direct effects on both DNA and histones as well as through indirect actions affecting the functions of transcription factors and transcriptional co-regulators. In this light, S-nitrosylation may also impact on cancer cell gene expression programs. Indeed, it affects different cell pathways and functions ranging from the impairment of DNA damage repair to the modulation of the activity of signal transduction molecules, oncogenes, tumor suppressors, and chromatin remodelers. Nitrosylation is therefore a versatile tool by which NO might control gene expression programs in health and disease.

Controlled spatial organization of bacterial growth reveals key role of cell filamentation preceding Xylella fastidiosa biofilm formation

The morphological plasticity of bacteria to form filamentous cells commonly represents an adaptive strategy induced by stresses. In contrast, for diverse human and plant pathogens, filamentous cells have been recently observed during biofilm formation, but their functions and triggering mechanisms remain unclear. To experimentally identify the underlying function and hypothesized cell communication triggers of such cell morphogenesis, spatially controlled cell patterning is pivotal. Here, we demonstrate highly selective cell adhesion of the biofilm-forming phytopathogen Xylella fastidiosa to gold-patterned SiO2 substrates with well-defined geometries and dimensions. The consequent control of both cell density and distances between cell clusters demonstrated that filamentous cell formation depends on cell cluster density, and their ability to interconnect neighboring cell clusters is distance-dependent. This process allows the creation of large interconnected cell clusters that form the structural framework for macroscale biofilms. The addition of diffusible signaling molecules from supernatant extracts provides evidence that cell filamentation is induced by quorum sensing. These findings and our innovative platform could facilitate therapeutic developments targeting biofilm formation mechanisms of X. fastidiosa and other pathogens.

Bacterial signalling mechanism: An innovative microbial intervention with multifaceted applications in microbial electrochemical technologies: A review

Microbial electrochemical technologies (METs) are a set of inventive tools that generate value-added by-products with concomitant wastewater remediation. However, due to the bottlenecks, like higher fabrication cost and inferior yield of resources, these inventive METs are still devoid of successful field-scale implementation. In this regard, application of quorum sensing (QS) mechanism to improve the power generation of the METs has gained adequate attention. The QS is an intercellular signalling mechanism that controls the bacterial social network in its vicinity via the synthesis of diffusible signal molecules labelled as auto inducers, thus ameliorating yield of valuables produced through METs. This state-of-the-art review elucidates different types of QS molecules and their working mechanism with the special focus on the widespread application of QS in the field of METs for their performance enhancement. Thus, this review intends to guide the researchers in rendering scalability to METs by integrating innovative QS mechanisms into them.

Microrna Regulation of Nodule Zone-Specific Gene Expression In Soybean

Microrna Regulation of Nodule Zone-Specific Gene Expression In Soybean

Interplay of two transcription factors for recruitment of the chromatin remodeling complex modulates fungal nitrosative stress response

Nitric oxide (NO) is a diffusible signaling molecule that modulates animal and plant immune responses. In addition, reactive nitrogen species derived from NO can display antimicrobial activities by reacting with microbial cellular components, leading to nitrosative stress (NS) in pathogens. Here, we identify FgAreB as a regulator of the NS response in Fusarium graminearum, a fungal pathogen of cereal crops. FgAreB serves as a pioneer transcription factor for recruitment of the chromatin-remodeling complex SWI/SNF at the promoters of genes involved in the NS response, thus promoting their transcription. FgAreB plays important roles in fungal infection and growth. Furthermore, we show that a transcription repressor (FgIxr1) competes with the SWI/SNF complex for FgAreB binding, and negatively regulates the NS response. NS, in turn, promotes the degradation of FgIxr1, thus enhancing the recruitment of the SWI/SNF complex by FgAreB.

Oxygen sensing, mitochondrial biology and experimental therapeutics for pulmonary hypertension and cancer

The homeostatic oxygen sensing system (HOSS) optimizes systemic oxygen delivery. Specialized tissues utilize a conserved mitochondrial sensor, often involving NDUFS2 in complex I of the mitochondrial electron transport chain, as a site of pO2-responsive production of reactive oxygen species (ROS). These ROS are converted to a diffusible signaling molecule, hydrogen peroxide (H2O2), by superoxide dismutase (SOD2). H2O2 exits the mitochondria and regulates ion channels and enzymes, altering plasma membrane potential, intracellular Ca2+ and Ca2+-sensitization and controlling acute, adaptive, responses to hypoxia that involve changes in ventilation, vascular tone and neurotransmitter release. Subversion of this O2-sensing pathway creates a pseudohypoxic state that promotes disease progression in pulmonary arterial hypertension (PAH) and cancer. Pseudohypoxia is a state in which biochemical changes, normally associated with hypoxia, occur despite normal pO2. Epigenetic silencing of SOD2 by DNA methylation alters H2O2 production, activating hypoxia-inducible factor 1α, thereby disrupting mitochondrial metabolism and dynamics, accelerating cell proliferation and inhibiting apoptosis. Other epigenetic mechanisms, including dysregulation of microRNAs (miR), increase pyruvate dehydrogenase kinase and pyruvate kinase muscle isoform 2 expression in both diseases, favoring uncoupled aerobic glycolysis. This Warburg metabolic shift also accelerates cell proliferation and impairs apoptosis. Disordered mitochondrial dynamics, usually increased mitotic fission and impaired fusion, promotes disease progression in PAH and cancer. Epigenetic upregulation of dynamin-related protein 1 (Drp1) and its binding partners, MiD49 and MiD51, contributes to the pathogenesis of PAH and cancer. Finally, dysregulation of intramitochondrial Ca2+, resulting from impaired mitochondrial calcium uniporter complex (MCUC) function, links abnormal mitochondrial metabolism and dynamics. MiR-mediated decreases in MCUC function reduce intramitochondrial Ca2+, promoting Warburg metabolism, whilst increasing cytosolic Ca2+, promoting fission. Epigenetically disordered mitochondrial O2-sensing, metabolism, dynamics, and Ca2+ homeostasis offer new therapeutic targets for PAH and cancer. Promoting glucose oxidation, restoring the fission/fusion balance, and restoring mitochondrial calcium regulation are promising experimental therapeutic strategies.

Dynamics of diffusive cell signaling relays.

In biological contexts as diverse as development, apoptosis, and synthetic microbial consortia, collections of cells or subcellular components have been shown to overcome the slow signaling speed of simple diffusion by utilizing diffusive relays, in which the presence of one type of diffusible signaling molecule triggers participation in the emission of the same type of molecule. This collective effect gives rise to fast-traveling diffusive waves. Here, in the context of cell signaling, we show that system dimensionality - the shape of the extracellular medium and the distribution of cells within it - can dramatically affect the wave dynamics, but that these dynamics are insensitive to details of cellular activation. As an example, we show that neutrophil swarming experiments exhibit dynamical signatures consistent with the proposed signaling motif. We further show that cell signaling relays generate much steeper concentration profiles than does simple diffusion, which may facilitate neutrophil chemotaxis.