Stochastic resonance in climate reddening increases the risk of cyclic ecosystem extinction via phase-tipping.

Human activity is leading to changes in the mean and variability of climatic parameters in most locations around the world. The changing mean has received considerable attention from scientists and climate policy makers. However, recent work indicates that the changing variability, that is, the amplitude and the temporal autocorrelation of deviations from the mean, may have greater and more imminent impact on ecosystems. In this paper, we demonstrate that changes in climate variability alone could drive cyclic predator-prey ecosystems to extinction via so-called phase-tipping (P-tipping), a new type of instability that occurs only from certain phases of the predator-prey cycle. We construct a mathematical model of a variable climate and couple it to two self-oscillating paradigmatic predator-prey models. Most importantly, we combine realistic parameter values for the Canada lynx and snowshoe hare with actual climate data from the boreal forest. In this way, we demonstrate that critically important species in the boreal forest have increased likelihood of P-tipping to extinction under predicted changes in climate variability, and are most vulnerable during stages of the cycle when the predator population is near its maximum. Furthermore, our analysis reveals that stochastic resonance is the underlying mechanism for the increased likelihood of P-tipping to extinction.

A metapopulation network model for the spreading of SARS-CoV-2: Case study for Ireland.

We present preliminary results on an all-Ireland network modelling approach to simulate the spreading the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2), commonly known as the coronavirus. In the model, nodes correspond to locations or communities that are connected by links indicating travel and commuting between different locations. While this proposed modelling framework can be applied on all levels of spatial granularity and different countries, we consider Ireland as a case study. The network comprises 3440 electoral divisions (EDs) of the Republic of Ireland and 890 superoutput areas (SOAs) for Northern Ireland, which corresponds to local administrative units below the NUTS 3 regions. The local dynamics within each node follows a phenomenological SIRX compartmental model including classes of Susceptibles, Infected, Recovered and Quarantined (X) inspired from Science 368, 742 (2020). For better comparison to empirical data, we extended that model by a class of Deaths. We consider various scenarios including the 5-phase roadmap for Ireland. In addition, as proof of concept, we investigate the effect of dynamic interventions that aim to keep the number of infected below a given threshold. This is achieved by dynamically adjusting containment measures on a national scale, which could also be implemented at a regional (county) or local (ED/SOA) level. We find that - in principle - dynamic interventions are capable to limit the impact of future waves of outbreaks, but on the downside, in the absence of a vaccine, such a strategy can last several years until herd immunity is reached.

Phase tipping: how cyclic ecosystems respond to contemporary climate.

We identify the phase of a cycle as a new critical factor for tipping points (critical transitions) in cyclic systems subject to time-varying external conditions. As an example, we consider how contemporary climate variability induces tipping from a predator-prey cycle to extinction in two paradigmatic predator-prey models with an Allee effect. Our analysis of these examples uncovers a counterintuitive behaviour, which we call phase tipping or P-tipping, where tipping to extinction occurs only from certain phases of the cycle. To explain this behaviour, we combine global dynamics with set theory and introduce the concept of partial basin instability for attracting limit cycles. This concept provides a general framework to analyse and identify easily testable criteria for the occurrence of phase tipping in externally forced systems, and can be extended to more complicated attractors.

Covid-19 Estimating the burden of symptomatic disease in the community and the impact of public health measures on physical, mental and social wellbeing: a study protocol.

Introduction: Covid-19 was declared a pandemic in March 2020. Since then, governments have implemented unprecedented public health measures to contain the virus. This study will provide evidence to inform responses to the pandemic by: i) estimating population prevalence and trends of self-reported symptoms of Covid-19 and the proportions of symptomatic individuals and household contacts testing positive for Covid-19; ii) describing acceptance and compliance with physical-distancing measures, explore effects of public health measures on physical, mental and social wellbeing; iii) developing a mathematical network model to inform decisions on the optimal levels of physical distancing measures. Methods: Two cross-sectional nationally-representative telephone surveys will be conducted in Ireland using random digit-dialling, with response rates estimates based on proportion of non-operational and non-answering numbers. The first survey with four waves in May and June will address adherence to social distancing measures and whether the respondent or other household members are or have been unwell during the preceding two weeks with one or more symptoms of Covid-19. The second survey with three waves in June, July and September will address knowledge, attitudes, and compliance towards physical-distancing measures and physical, mental and social wellbeing. The mathematical network model will be developed for all-Ireland (on various levels of spatial granularity including the scale of counties and electoral divisions) based on outputs from both cross-sectional surveys and relevant publicly available data to inform decisions on optimal levels and duration of physical distancing measures. Discussion: This study will contribute to our understanding of the impact and sustainability of public health measures of the Covid-19 pandemic. Findings will have long-lasting benefits, informing decision-making on the best levels, and duration of physical-distancing measures, balancing a range of factors including capacity of the health service with the effects on individuals' wellbeing and economic disruption. Findings will be shared with key policy-makers.

When very slow is too fast - collapse of a predator-prey system.

Critical transitions or regime shifts are sudden and unexpected changes in the state of an ecosystem, that are usually associated with dangerous levels of environmental change. However, recent studies show that critical transitions can also be triggered by dangerous rates of environmental change. In contrast to classical regime shifts, such rate-induced critical transitions do not involve any obvious loss of stability, or a bifurcation, and thus cannot be explained by the linear stability analysis. In this work, we demonstrate that the well-known Rosenzweig-MacArthur predator-prey model can undergo a rate-induced critical transition in response to a continuous decline in the habitat quality, resulting in a collapse of the predator and prey populations. Rather surprisingly, the collapse occurs even if the environmental change is slower than the slowest process in the model. To explain this counterintuitive phenomenon, we combine methods from geometric singular perturbation theory with the concept of a moving equilibrium, and study critical rates of environmental change with dependence on the initial state and the system parameters. Moreover, for a fixed rate of environmental change, we determine the set of initial states that undergo a rate-induced population collapse. Our results suggest that ecosystems may be more sensitive to how fast environmental conditions change than previously assumed. In particular, unexpected critical transitions with dramatic ecological consequences can be triggered by environmental changes that (i) do not exceed any dangerous levels, and (ii) are slower than the natural timescales of the ecosystem. This poses an interesting research question whether regime shifts observed in the natural world are predominantly rate-induced or bifurcation-induced.

Lipid-DNAs as Solubilizers of mTHPC.

Hydrophobic drug candidates require innovative formulation agents. We designed and synthesized lipid-DNA polymers containing varying numbers of hydrophobic alkyl chains. The hydrophobicity of these amphiphiles is easily tunable by introducing a defined number of alkyl chain-modified nucleotides during standard solid-phase synthesis of DNA using an automated DNA synthesizer. We observed that the resulting self-assembled micelles solubilize the poorly water-soluble drug, meta-tetra-hydroxyphenyl-chlorin (mTHPC) used in photodynamic therapy (PDT) with high loading concentrations and loading capacities. A cell viability study showed that mTHPC-loaded micelles exhibit good biocompatibility without irradiation, and high PDT efficacy upon irradiation. Lipid-DNAs provide a novel class of drug-delivery vehicle, and hybridization of DNA offers a potentially facile route for further functionalization of the drug-delivery system with, for instance, targeting or imaging moieties.

Fine-tuning Nanocarriers Specifically toward Cargo: A Competitive Study on Solubilizing Related Photosensitizers for Photodynamic Therapy.

Tailor-made drug solubilizers are studied based on peptide-poly(ethylene glycol) conjugates, which exhibit peptide segments constituting binding motifs for the small-molecule drugs of interest to render them water-soluble. Suitable 7mer peptides are selected via combinatorial means by screening large one-bead-one-compound (OBOC) peptide libraries. The capability of the screening method to read out structural detail of the drugs is investigated by comparing three related photosensitizers (Chlorin E6 (Ce6), Pheophorbide A (Pba) and meta-tetra(hydroxyphenyl)chlorin (m-THPC), which are applicable for photodynamic cancer therapy. The screening procedure delivers de novo solubilizers that show the best solubilization efficiency for the drug the screening is performed with. While molecular recognition events between peptide and drug are not expected to be found, significant binding capacity differences of, e.g., the Ce6-solubilizer for Pba are suggesting selectivity in drug binding, even among structurally closely related drugs. Cyro-Electron microscopy revealed the formation of colloidal aggregates between drug moieties and peptide conjugates. Insights into relevant amino acids in the identified peptide sequences are gained by studying capacities of systematic point mutations (alanine scans), enabling understanding of drug-binding motifs. These reveal the importance of sequence positioning of appropriate H-bonding between polar functional groups of the peptide and the drugs, which agrees well with computational binding studies performed on drug/peptide model complexes.

Intradermal drug delivery by nanogel-peptide conjugates; specific and efficient transport of temoporfin.

Nanogels offer many unique features rendering them as very attractive candidates for drug delivery. However, for their applications the loading capacity and specific encapsulation, in particular for hydrophobic drugs, in a complex media are two critical factors. In this work, we report for the first time on the preparation of nanogel-peptide conjugates with the ability of specific encapsulation of temoporfin (m-THPC). The peptide was selected based on combinatorial means and it was conjugated to polyglycerol as the nanogel precursor. We observed that the loading capacity of nanogels improved 16 times upon peptide conjugation. Skin penetrations tests in barrier deficient skin showed that nanogel-peptide conjugates enhance the penetration of m-THPC in the viable skin layers efficiently. This study indicates that nanogel-peptide conjugates could be used as unique carriers with high loading capacity for hydrophobic compounds, which provides the basis for the design of advanced topical drug delivery systems.

Advancing Drug Formulation Additives toward Precision Additives with Release Mediating Peptide Interlayer.

Amphiphilic drug formulation additives based on palmitic acid-modified poly(ethylene glycol) (Pal-PEG) are combined with a tailored drug binding peptide that is positioned at the hydrophobic-hydrophilic interface. The peptide originates from combinatorial selection and enables precise modulation of the drug release profiles. While Pal provides a cost-effective reservoir for drug storage, the PEG realizes solubility and shielding. The precision additives reach high payloads close to 1:1, rendering a photosensitizer water-soluble and providing adjustable drug activation kinetics by fine-tuning the peptide interface layer.

Generalizing the Concept of Specific Compound Formulation Additives towards Non-Fluorescent Drugs: A Solubilization Study on Potential Anti-Alzheimer-Active Small-Molecule Compounds.

Tailor-made compound formulation additives enable the testing of potential drugs with undesirable pharmacological profiles. A combinatorial approach using Raman microscopy as the readout method is presented to select peptide sequences from large one-bead-one-compound libraries. The resulting peptide-PEG conjugates solubilize potential prophylactic and therapeutic anti-Alzheimer compounds and can be used as specific additives not only for fluorescent but also for non-fluorescent compounds.

Specific Drug Formulation Additives: Revealing the Impact of Architecture and Block Length Ratio.

Combining poly(ethylene glycol) (PEG) with sequence-defined peptides in PEG-peptide conjugates offers opportunities to realize next-generation drug formulation additives for overcoming undesired pharmacological profiles of difficult small molecule drugs. The tailored peptide segments provide sequence-specific, noncovalent drug binding, and the hydrophilic PEG block renders the complexes water soluble. On the basis of a peptide sequence known to bind the photosensitizer m-tetra(hydroxyphenyl)chlorin (m-THPC) for photodynamic cancer therapy, a set of different conjugate architectures is synthesized and studied. Variations in PEG block length and amplification of the peptidic binding domain of PEG-peptide conjugates are used to fine tune critical parameters for hosting m-THPC, such as drug payload capacities, aggregation sizes, and drug release and activation kinetics.

Combinatorial screening for specific drug solubilizers with switchable release profiles.

Polymer-block-peptide conjugates are tailored to render hydrophobic small molecule drugs water soluble. The combinatorial strategy selects for bioconjugates that exhibit sequence-specific solubilization and switchable release profiles of the cargo through incorporation of a disulfide linker moiety into the peptide-library design. While the study focused on the photosensitizer m-THPC and reductive carrier cleavage, the approach is generic and might be expanded toward a broad range of poorly soluble small-molecule drugs and other selective cleavage mechanisms to disassemble a peptide binding domain of the bioconjugate-based solubilizer.

ß- and γ-Amino Acids at α-Helical Interfaces: Toward the Formation of Highly Stable Foldameric Coiled Coils.

Since peptides are vital for cellular and pathogenic processes, much effort has been put into the design of unnatural oligomers that mimic natural peptide structures, also referred to as foldamers. However, to enable the specific application of foldamers, a thorough characterization of their interaction profiles in native protein environments is required. We report here the application of phage display for the identification of suitable helical environments for a sequence comprising an alternating set of ß- and γ-amino acids. In vitro selected sequences show that an increase in the hydrophobic surface area at the helical interface as well as the incorporation of a polar H-bond donor functionality can significantly improve interhelical interactions involving backbone-extended amino acids. Thus, our data provide insight into the principles of the rational design of foldameric inhibitors for protein-protein interactions.

Adapting to a changing environment: non-obvious thresholds in multi-scale systems.

Many natural and technological systems fail to adapt to changing external conditions and move to a different state if the conditions vary too fast. Such 'non-adiabatic' processes are ubiquitous, but little understood. We identify these processes with a new nonlinear phenomenon-an intricate threshold where a forced system fails to adiabatically follow a changing stable state. In systems with multiple time scales, we derive existence conditions that show such thresholds to be generic, but non-obvious, meaning they cannot be captured by traditional stability theory. Rather, the phenomenon can be analysed using concepts from modern singular perturbation theory: folded singularities and canard trajectories, including composite canards. Thus, non-obvious thresholds should explain the failure to adapt to a changing environment in a wide range of multi-scale systems including: tipping points in the climate system, regime shifts in ecosystems, excitability in nerve cells, adaptation failure in regulatory genes and adiabatic switching in technology.

An unusual interstrand H-bond stabilizes the heteroassembly of helical αßγ-chimeras with natural peptides.

The substitution of α-amino acids by homologated amino acids has a strong impact on the overall structure and topology of peptides, usually leading to a loss in thermal stability. Here, we report on the identification of an ideal core packing between an α-helical peptide and an αßγ-chimera via phage display. Selected peptides assemble with the chimeric sequence with thermal stabilities that are comparable to that of the parent bundle consisting purely of α-amino acids. With the help of MD simulations and mutational analysis this stability could be explained by the formation of an interhelical H-bond between the selected cysteine and a backbone carbonyl of the ß/γ-segment. Gained results can be directly applied in the design of biologically relevant peptides containing ß- and γ-amino acids.

Exploiting specific interactions toward next-generation polymeric drug transporters.

A generic method describes advanced tailoring of polymer drug carriers based on polymer-block-peptides. Combinatorial means are used to select suitable peptide segments to specifically complex small-molecule drugs. The resulting specific drug formulation agents render insoluble drugs water-soluble and enable precise adjustment of drug-release profiles beyond established block-copolymer carriers. While proof of principle is shown on chlorin as a partially approved drug for photodynamic cancer therapy, the concept is universal and applies to a broad spectrum of difficult drugs.

Tipping points in open systems: bifurcation, noise-induced and rate-dependent examples in the climate system.

Tipping points associated with bifurcations (B-tipping) or induced by noise (N-tipping) are recognized mechanisms that may potentially lead to sudden climate change. We focus here on a novel class of tipping points, where a sufficiently rapid change to an input or parameter of a system may cause the system to 'tip' or move away from a branch of attractors. Such rate-dependent tipping, or R-tipping, need not be associated with either bifurcations or noise. We present an example of all three types of tipping in a simple global energy balance model of the climate system, illustrating the possibility of dangerous rates of change even in the absence of noise and of bifurcations in the underlying quasi-static system.

Using chaos for remote sensing of laser radiation.

An idea is proposed for detecting a weak laser signal from a remote source in the presence of strong background noise. The scheme exploits dynamical nonlinearities arising from heterodyning signal and reference fields inside an active reference laser cavity. This paper shows that for certain reference laser configurations, the resulting bifurcations in the reference laser may be used as warning of irradiation by a laser source.

Stochastic bifurcation in noise-driven lasers and Hopf oscillators.

This paper considers nonlinear dynamics in an ensemble of uncoupled lasers, each being a limit-cycle oscillator, which are driven by the same external white Gaussian noise. As the external-noise strength increases, there is an onset of synchronization and then subsequent loss of synchrony. Local analysis of the laser equations shows that synchronization becomes unstable via stochastic bifurcation to chaos, defined as a passing of the largest Lyapunov exponent through zero. The locus of this bifurcation is calculated in the three-dimensional parameter space defined by the Hopf parameter, amount of amplitude-phase coupling, and external-noise strength. Numerical comparison between the laser system and the normal form of Hopf bifurcation uncovers a square-root law for this stochastic bifurcation as well as strong enhancement in noise-induced chaos due to the laser's relaxation oscillation.