Pseudo-nullclines enable the analysis and prediction of signaling model dynamics.

A powerful method to qualitatively analyze a 2D system is the use of nullclines, curves which separate regions of the plane where the sign of the time derivatives is constant, with their intersections corresponding to steady states. As a quick way to sketch the phase portrait of the system, they can be sufficient to understand the qualitative dynamics at play without integrating the differential equations. While it cannot be extended straightforwardly for dimensions higher than 2, sometimes the phase portrait can still be projected onto a 2-dimensional subspace, with some curves becoming pseudo-nullclines. In this work, we study cell signaling models of dimension higher than 2 with behaviors such as oscillations and bistability. Pseudo-nullclines are defined and used to qualitatively analyze the dynamics involved. Our method applies when a system can be decomposed into 2 modules, mutually coupled through 2 scalar variables. At the same time, it helps track bifurcations in a quick and efficient manner, key for understanding the different behaviors. Our results are both consistent with the expected dynamics, and also lead to new responses like excitability. Further work could test the method for other regions of parameter space and determine how to extend it to three-module systems.

COVID vaccine evaluation of barriers and resources among families of children with diagnosed allergies.

Background: We aimed to determine vaccine hesitancy and the main barriers associated with the 2019 novel coronavirus, SARS-CoV-2 (COVID-19) vaccination among families of children diagnosed with food/drug/environmental allergies. Methods: Between May and June 2021, we approached 146 families seen at the outpatient allergy clinic at the Montreal Children's Hospital and a community allergy practice were invited to complete an anonymous online survey on COVID-19 and vaccination attitudes and behaviour. Uni and multivariable logistic regressions were compared to estimate factors associated with vaccine hesitancy. Results: Among all patients, 24.1% reported vaccine hesitancy. The large majority of parents (95.2%) believed that vaccines work. The most common barrier to vaccination was fear of adverse side effects (57.0%). One-third of participants (31.5%) reported that a history of food, venom and drug allergy was a contraindication for COVID-19 vaccination. Fifty-nine (60.8%) participants stated that the dissemination of additional information would increase their willingness to be vaccinated. Most (96.9%) parents reported that their children's vaccinations were up to date. Hesitant families were more likely to be parents of children aged 6-10 years, be of Asian descent, report that mRNA vaccines are riskier than traditional vaccines, and report that the vaccine should not be given if the child has a history of allergic reaction to vaccines. Conclusion: Vaccine hesitancy exists mainly among certain ethnic groups and families with young children. Allergies to food, venom and drug allergy are commonly perceived as contraindications for COVID-19 vaccination. Knowledge translation activities addressing parental concerns will help increase vaccination rates.

A nested bistable module within a negative feedback loop ensures different types of oscillations in signaling systems.

In this article, we consider a double phosphorylation cycle, a ubiquitous signaling component, having the ability to display bistability, a behavior strongly related to the existence of positive feedback loops. If this component is connected to other signaling elements, it very likely undergoes some sort of protein-protein interaction. In several cases, these interactions result in a non-explicit negative feedback effect, leading to interlinked positive and negative feedbacks. This combination was studied in the literature as a way to generate relaxation-type oscillations. Here, we show that the two feedbacks together ensure two types of oscillations, the relaxation-type ones and a smoother type of oscillations functioning in a very narrow range of frequencies, in such a way that outside that range, the amplitude of the oscillations is severely compromised. Even more, we show that the two feedbacks are essential for both oscillatory types to emerge, and it is their hierarchy what determines the type of oscillation at work. We used bifurcation analyses and amplitude vs. frequency curves to characterize and classify the oscillations. We also applied the same ideas to another simple model, with the goal of generalizing what we learned from signaling models. The results obtained display the wealth of oscillatory dynamics that exists in a system with a bistable module nested within a negative feedback loop, showing how to transition between different types of oscillations and other dynamical behaviors such as excitability. Our work provides a framework for the study of other oscillatory systems based on bistable modules, from simple two-component models to more complex examples like the MAPK cascade and experimental cases like cell cycle oscillators.

Publisher Correction: Integrated photonic guided metalens based on a pseudo-graded index distribution.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Integrated photonic guided metalens based on a pseudo-graded index distribution.

In this article, we report an integrated optical nanolens exhibiting a pseudo-graded index distribution in a guided configuration. This dielectric metalens relies on a permittivity distribution through dielectric strips of the core material, which is compatible with existing silicon photonic technology. We show in this paper that effective medium theory (EMT) inaccurately predicts the focal length of such devices, and we propose an efficient and accurate design approach based on 2D finite element method (FEM) mode calculations that are in good agreement with 3D FDTD simulations. The lens was fabricated on a 200 mm silicon on insulator pilot line, and fibre-to-fibre optical characterizations revealed an excellent transmission of 85% for TM polarization, in line with the simulated performance (90%). The proposed approach can be easily extended to width-variable strips, enabling the realization of all types of graded index devices, especially those derived from transformation optics.

Modeling the bioconversion of polysaccharides in a continuous reactor: A case study of the production of oligogalacturonates by Dickeya dadantii.

In the quest for a sustainable economy of the Earth's resources and for renewable sources of energy, a promising avenue is to exploit the vast quantity of polysaccharide molecules contained in green wastes. To that end, the decomposition of pectin appears to be an interesting target because this polymeric carbohydrate is abundant in many fruit pulps and soft vegetables. To quantitatively study this degradation process, here we designed a bioreactor that is continuously fed with de-esterified pectin (PGA). Thanks to the pectate lyases produced by bacteria cultivated in the vessel, the PGA is depolymerized into oligogalacturonates (UGA), which are continuously extracted from the tank. A mathematical model of our system predicted that the conversion efficiency of PGA into UGA increases in a range of coefficients of dilution until reaching an upper limit where the fraction of UGA that is extracted from the bioreactor is maximized. Results from experiments with a continuous reactor hosting a strain of the plant pathogenic bacterium Dickeya dadantii and in which the dilution coefficients were varied quantitatively validated the predictions of our model. A further theoretical analysis of the system enabled an a priori comparison of the efficiency of eight other pectate lyase-producing microorganisms with that of D. dadantii Our findings suggest that D. dadantii is the most efficient microorganism and therefore the best candidate for a practical implementation of our scheme for the bioproduction of UGA from PGA.

Neutropenia in kidney and liver transplant recipients: Risk factors and outcomes.

No studies have directly compared the key characteristics and outcomes of kidney (KTx) and liver transplantation (LTx) recipients with neutropenia. In this single-center, retrospective, cohort study, we enrolled all adult patients who received a KTx or LTx between 2000 and 2011. Neutropenia was defined as 2 consecutive absolute neutrophil count (ANC) values <1500/mm3 in patients without preexisting neutropenia. The first neutropenia episode occurring during the first year post-transplantation was analyzed. A total of 663 patients with KTx and 354 patients with LTx met the inclusion criteria. Incidence of neutropenia was 20% in KTx and 38% in LTx, respectively. High-risk CMV status and valganciclovir (VGCV) use were significant predictors of neutropenia for KTx recipients, but only VGCV use vs nonuse in LTx recipients. Neutropenia was associated with worse survival in KTx recipients (adjusted HR 1.95, 95% CI 1.18-3.22, P<.01), but not in LTx recipients (adjusted HR 0.75, 95% CI 0.52-1.10, P=.15). Sixteen acute rejection episodes were associated with preceding neutropenia in KTx recipients (HR 1.77, 95% CI 1.16-2.68, P=.007) and 24 acute rejection episodes in LTx recipients (HR 1.41, 95% CI 0.97-2.04, P=.07). Incidence of infection was similar in patients with and without neutropenia among KTx and LTx recipients.

Signaling cascades transmit information downstream and upstream but unlikely simultaneously.

BACKGROUND: Signal transduction is the process through which cells communicate with the external environment, interpret stimuli and respond to them. This mechanism is controlled by signaling cascades, which play the role of intracellular transmitter, being able to transmit biochemical information between cell membrane and nucleus. In theory as well as in practice, it has been shown that a perturbation can propagate upstream (and not only downstream) a cascade, by a mechanism known as retroactivity. This study aims to compare the conditions on biochemical parameters which favor one or the other direction of signaling in such a cascade. RESULTS: From a mathematical point of view, we show that the steady states of a cascade of arbitrary length n are described by an iterative map of second order, meaning that the cascade tiers are actually coupled three-by-three. We study the influence of the biochemical parameters in the control of the direction of transmission - upstream and/or downstream - along a signaling cascade. A numerical and statistical approach, based on the random scan of parameters describing a 3-tier signaling cascade, provides complementary findings to the analytical study. In particular, computing the likelihood of parameters with respect to various signaling regimes, we identify conditions on biochemical parameters which enhance a specific direction of propagation corresponding to forward or retro-signaling regimes. A compact graphical representation is designed to relay the gist of these conditions. CONCLUSIONS: The values of biochemical parameters such as kinetic rates, Michaelis-Menten constants, total concentrations of kinases and of phosphatases, determine the propensity of a cascade to favor or impede downstream or upstream signal transmission. We found that generally there is an opposition between parameter sets favoring forward and retro-signaling regimes. Therefore, on one hand our study supports the idea that in most cases, retroactive effects can be neglected when a cascade which is efficient in forward signaling, is perturbed by an external ligand inhibiting the activation at some tier of the cascade. This result is relevant for therapeutic methodologies based on kinase inhibition. On the other hand, our study highlights a less-known part of the parameter space where, although the forward signaling is inefficient, the cascade can interestingly act as a retro-signaling device.

Access to Functionalized Luminescent Multi-2,2':6',2″-terpyridine Ligands.

A one-pot synthesis of substituted multi-2,2':6',2″-terpyridines (multi-tpy) has been achieved using an acetylquaterpyridine precursor with various aryl aldehydes in basic media. This strategy enables ready access to functionalized tri-terpyridines. Utilizing a Suzuki-type cross-coupling, larger structures such as tetra- or even hexa-tpy were obtained from our tri-tpy precursor. These macromolecular units are ideal building blocks for the construction of transition-metal-based supramolecular assemblies.

Selective DNA purine base photooxidation by bis-terdentate iridium(III) polypyridyl and cyclometalated complexes.

Two bis-terdentate iridium(III) complexes with polypyridyl and cyclometalated ligands have been prepared and characterized. Their spectroscopic and electrochemical properties have been studied, and a photophysical scheme addressing their properties is proposed. Different types of excited states have been considered to account for the deactivation processes in each complex. Interestingly, in the presence of mono- or polynucleotides, a photoinduced electron-transfer process from a DNA purine base (i.e., guanine or adenine) to the excited complex is shown through luminescence quenching experiments. For the first time, this work reports evidence for selective DNA purine bases oxidation by excited iridium(III) bis-terdentate complexes.

Intrinsic feedbacks in MAPK signaling cascades lead to bistability and oscillations.

Previous studies have demonstrated that double phosphorylation of a protein can lead to bistability if some conditions are fulfilled. It was also shown that the signaling behavior of a covalent modification cycle can be quantitatively and, more importantly, qualitatively modified when this cycle is coupled to a signaling pathway as opposed to being isolated. This property was named retroactivity. These two results are studied together in this paper showing the existence of interesting phenomena--oscillations and bistability--in signaling cascades possessing at least one stage with a double-phosphorylation cycle as in MAPK cascades.

Retroactive signaling in short signaling pathways.

In biochemical signaling pathways without explicit feedback connections, the core signal transduction is usually described as a one-way communication, going from upstream to downstream in a feedforward chain or network of covalent modification cycles. In this paper we explore the possibility of a new type of signaling called retroactive signaling, offered by the recently demonstrated property of retroactivity in signaling cascades. The possibility of retroactive signaling is analysed in the simplest case of the stationary states of a bicyclic cascade of signaling cycles. In this case, we work out the conditions for which variables of the upstream cycle are affected by a change of the total amount of protein in the downstream cycle, or by a variation of the phosphatase deactivating the same protein. Particularly, we predict the characteristic ranges of the downstream protein, or of the downstream phosphatase, for which a retroactive effect can be observed on the upstream cycle variables. Next, we extend the possibility of retroactive signaling in short but nonlinear signaling pathways involving a few covalent modification cycles.

Dorsal spinal cord injury as a cause of recurrent asystole requiring permanent cardiac pacing.

Numerous unusual causes of atrioventricular block (AVB) with cardiac pacemaker implantation have been documented including cough, deglutition, or other vagally mediated mechanism. In spinal cord lesions, only high cervical spinal cord lesion has been reported as a cause of severe bradycardia. We report a case with not cervical but dorsal vertebral trauma and persistent paroxysmal AVB requiring cardiac pacemaker implantation.

Modelling the onset of virulence in pathogenic bacteria.

Bacterial virulence is a multifactorial process. In this chapter, we review some known mechanisms used by bacteria to trigger their production of virulence factors. We develop the idea that although the onset of virulence shows up an abrupt transition, the modelling of this dynamics can be classified in two qualitatively distinct infectious transitions which are respectively called "shift" or "switch." We review methods enabling one to determine the types of behaviour that can be exhibited by a given model and we consider applications in three cases of virulence factor regulation. We conclude that in most cases a "successful" infection would require that the onset of virulence follows an irreversible switch behaviour.

Efficient macrocyclization achieved via conformational control using intermolecular noncovalent π-cation/arene interactions.

Quinolinium salt 3 is an effective additive that acts as a conformation control element (CCE) to promote macrocyclization to form rigid cyclophanes via olefin metathesis or Glaser-Hay coupling, which do not cyclize in the absence of the additive. The additives are easily synthesized and highly modifiable and have solubility profiles which allow for simple recovery via filtration.

Toward a quantitative modeling of the synthesis of the pectate lyases, essential virulence factors in Dickeya dadantii.

A dynamic mathematical model has been developed and validated to describe the synthesis of pectate lyases (Pels), the major virulence factors in Dickeya dadantii. This work focuses on the simultaneous modeling of the metabolic degradation of pectin by Pel enzymes and the genetic regulation of pel genes by 2-keto-3-deoxygluconate (KDG), a catabolite product of pectin that inactivates KdgR, one of the main repressors of pel genes. This modeling scheme takes into account the fact that the system is composed of two time-varying compartments: the extracellular medium, where Pel enzymes cleave pectin into oligomers, and the bacterial cytoplasm where, after internalization, oligomers are converted to KDG. Using the quasi-stationary state approximations, the model consists of some nonlinear differential equations for which most of the parameters could be estimated from the literature or from independent experiments. The few remaining unknown parameters were obtained by fitting the model equations against a set of Pel activity data. Model predictions were verified by measuring the time courses of bacterial growth, Pel production, pel mRNA accumulation, and pectin consumption under various growth conditions. This work reveals that pectin is almost totally consumed before the burst of Pel production. This paradoxical behavior can be interpreted as an evolutionary strategy to control the diffusion process so that as soon as a small amount of pectin is detected by the bacteria in its surroundings, it anticipates more pectin to come. The model also predicts the possibility of bistable steady states in the presence of constant pectin compounds.

Macrophage interleukin-6 and tumour necrosis factor-alpha are induced by coronavirus fixation to Toll-like receptor 2/heparan sulphate receptors but not carcinoembryonic cell adhesion antigen 1a.

A rapid antiviral immune response may be related to viral interaction with the host cell leading to activation of macrophages via pattern recognition receptors (PPRs) or specific viral receptors. Carcinoembryonic cell adhesion antigen 1a (CEACAM1a) is the specific receptor for the mouse hepatitis virus (MHV), a coronavirus known to induce acute viral hepatitis in mice. The objective of this study was to understand the mechanisms responsible for the secretion of high-pathogenic MHV3-induced inflammatory cytokines. We report that the induction of the pro-inflammatory cytokines interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha in peritoneal macrophages does not depend on CEACAM1a, as demonstrated in cells isolated from Ceacam1a(-/-) mice. The induction of IL-6 and TNF-alpha production was related rather to the fixation of the spike (S) protein of MHV3 on Toll-like receptor 2 (TLR2) in regions enriched in heparan sulphate and did not rely on viral replication, as demonstrated with denatured S protein and UV-inactivated virus. High levels of IL-6 and TNF-alpha were produced in livers from infected C57BL/6 mice but not in livers from Tlr2(-/-) mice. The histopathological observations were correlated with the levels of those inflammatory cytokines. Depending on mouse strain, the viral fixation to heparan sulfate/TLR2 stimulated differently the p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB in the induction of IL-6 and TNF-alpha. These results suggest that TLR2 and heparan sulphate receptors can act as new viral PPRs involved in inflammatory responses.

A synergistic interferon-gamma production is induced by mouse hepatitis virus in interleukin-12 (IL-12)/IL-18-activated natural killer cells and modulated by carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1a receptor.

The production of interferon-gamma (IFN-gamma) by infiltrating natural killer (NK) cells in liver is involved in the control of mouse hepatitis virus (MHV) infection. The objectives of this study were to identify the mechanisms used by MHV type 3 to modulate the production of IFN-gamma by NK cells during the acute hepatitis in susceptible C57BL/6 mice. Ex vivo and in vitro experiments revealed that NK cells, expressing carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1a (the MHV receptor), can produce a higher level of IFN-gamma in the presence of both L2-MHV3 and interleukin-12 (IL-12)/IL-18. The synergistic production of IFN-gamma by NK cells depends on viral replication rather than viral fixation only, because it is inhibited or not induced in cells infected with ultraviolet-inactivated viruses and in cells from Ceacam1a(-/-) mice infected with virulent viruses. The synergistic IFN-gamma production involves the p38 mitogen-activated protein kinase (MAPK) rather than the extracellular signal-regulated kinase-1/2 MAPK signalling pathway. However, the signal triggered through the engagement of CEACAM1a decreases the production of IFN-gamma, when these molecules are cross-linked using specific monoclonal antibodies. These results suggest that control of acute hepatitis by IFN-gamma-producing NK cells may depend on both production of IL-12 and IL-18 in the liver environment and viral infection of NK cells.