Search

We consider a stochastic SIR (susceptible $\rightarrow$ infective $\rightarrow$ removed) model in which the infectious periods are modulated by a collection of independent and identically distributed Feller processes. Each infected individual is associated with one of these processes, the trajectories of which determine the duration of his infectious period, his contamination rate, and his type of removal (e.g. death or immunization). We use a martingale approach to derive the distribution of the final epidemic size and severity for this model and provide some general examples. Next, we focus on a single infected individual facing a given number of susceptibles, and we determine the distribution of his outcome (number of contaminations, severity, type of removal). Using a discrete-time formulation of the model, we show that this distribution also provides us with an alternative, more stable method to compute the final epidemic outcome distribution.

In plants, small-interfering RNAs (siRNAs) are mainly produced from transposable elements (TEs) within the RNA-directed DNA methylation pathway (RdDM), which is particularly important during reproductive development in many plant species. However, there is limited understanding of the origins, dynamics and function of TE-derived siRNAs acting in different cellular and developmental contexts. Here, we used the RNaseIII-like protein RTL1 to suppress siRNA biogenesis specifically in Arabidopsis pollen, and found distinct siRNA subsets produced in the sperm and vegetative cell lineages via RNA polymerase IV (Pol IV). We show that gametophytic siRNAs produced in the vegetative cell reinforce RdDM in pollen and interploidy hybridization barriers in the seed, while siRNAs produced specifically in sperm cells do not impact the epigenome and are dispensable for the “triploid block”. These results demonstrate that active siRNA biogenesis in the two pollen cell types has contrasting roles in transposon silencing and transgenerational epigenetic inheritance.

The paper deals with the problem of possible ruin when providing insurance coverage for an epidemic. The model studied is an SIS type epidemic which generalizes the well-known logistic model. Contractually, the premiums are paid by susceptible people while the care costs are reimbursed to infected people via an annuity or a lump-sum benefit. Our goal is to determine the distribution of the main statistics of the ruin when it occurs during the epidemic. The case where the reserve alternates between normal and epidemic episodes is also discussed using a Brownian modeling of the reserve. Finally, some of the results are illustrated for two particular SIS epidemic models.

The paper discusses the risk of ruin in insurance coverage of an epidemic in a closed population. The model studied is an extended susceptible–infective–removed (SIR) epidemic model built by Lefèvre and Simon (Methodology Comput. Appl. Prob.22, 2020) as a block-structured Markov process. A fluid component is then introduced to describe the premium amounts received and the care costs reimbursed by the insurance. Our interest is in the risk of collapse of the corresponding reserves of the company. The use of matrix-analytic methods allows us to determine the distribution of ruin time, the probability of ruin, and the final amount of reserves. The case where the reserves are subjected to a Brownian noise is also studied. Finally, some of the results obtained are illustrated for two particular standard SIR epidemic models.

Biopolymers are ideal candidates for the development of hydrogels for tissue engineering applications. However, chemical modifications are required to further improve their mechanical properties, in particular to cross-link them for long-lasting applications or biofabrication. Herein, we developed a novel gelatin-based hydrogel precursor, “GelmSi”. Gelatin was chosen as starting material because of its biocompatibility and bioactivity, favouring cell adhesion and migration. Alkoxysilane moieties were introduced in a controlled manner on the lysine side chains of gelatin to obtain a hybrid precursor which reacts in physiological conditions, forming covalent siloxane bonds and allowing the formation of a three-dimensional chemical network. On the contrary to unmodified gelatin, siloxane covalent network dramatically increases the stiffness and the thermal stability of the resulting gelatin-based hydrogel, making it suitable for cell encapsulation and cell culture. The biorthogonality and versatility of the GelmSi hybrid hydrogel unlock a broad range of gelatin-based bioengineering applications.

We consider an SIR model for the spread of an epidemic in a closed and homogeneously mixing population, where the infectious periods are represented by an arbitrary absorbing Markov process. A version of this process starts whenever an infection occurs, and the contamination rate of the newly infected individual is a function of its state. When his process is absorbed, the individual becomes a removed case. We use a martingale approach to derive the distribution of the final epidemic size and severity for this class of models. Next, we examine some special cases. In particular, we focus on situations where the infection processes are Brownian motions and where they are Markov-modulated fluid flows. In the latter case, we use matrix-analytic methods to provide more explicit results. We conclude with some numerical illustrations.

Motivated by modelling epidemics like COVID-19, this paper proposes a generalized chain binomial process which integrates two types of infectives, those with symptoms and those without. Testing of infectives and vaccination of susceptibles are then incorporated as preventive protective measures. Our interest relates to the distribution of the state of the population at the end of infection and to the reproduction number \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$R_0$$\end{document}R0 with the associated extinction condition. The method uses the construction of a family of martingales and a branching approximation for large populations, respectively. A more general branching process for epidemics is also constructed and studied. Finally, some results obtained are illustrated by numerical examples.

The principles of heredity state that the two alleles carried by a heterozygote are equally transmitted to the progeny. However, genomic regions that escape this rule have been reported in many organisms. It is notably the case of genetic loci referred to as gamete killers, where one allele enhances its transmission by causing the death of the gametes that do not carry it. Gamete killers are of great interest, particularly to understand mechanisms of evolution and speciation. Although being common in plants, only a few, all in rice, have so far been deciphered to the causal genes. Here, we studied a pollen killer found in hybrids between two accessions of Arabidopsis thaliana. Exploring natural variation, we observed this pollen killer in many crosses within the species. Genetic analyses revealed that three genetically linked elements are necessary for pollen killer activity. Using mutants, we showed that this pollen killer works according to a poison-antidote model, where the poison kills pollen grains not producing the antidote. We identified the gene encoding the antidote, a chimeric protein addressed to mitochondria. De novo genomic sequencing in 12 natural variants with different behaviors regarding the pollen killer revealed a hyper variable locus, with important structural variations particularly in killer genotypes, where the antidote gene recently underwent duplications. Our results strongly suggest that the gene has newly evolved within A. thaliana. Finally, we identified in the protein sequence polymorphisms related to its antidote activity.

The ever increasing performance requirements of modern aero-engines necessitate the development of effective ways to improve efficiency and reduce losses. Casing temperature control is particularly critical from this point of view, since thermal expansion directly affects the blade tip clearance and thus the associated leakages. To limit the turbine tip flows, Active Clearance Control (ACC) systems have been implemented over the last decades. These systems are usually based upon impingement cooling, generated by a series of perforated manifolds enclosing the turbine casing. When dealing with aeroengine low pressure turbines, the current trend in increasing the engine by-pass ratio, so as to enhance the system propulsive efficiency, pushes the limits of ACC traditional design performance. The reduction of the pressure head at the ACC system inlet requires lower nozzle-to-target distances as well as denser impingement arrays to compensate the reduction of the jets’ Reynolds number. Literature correlations for the impingement heat transfer coefficient estimation are then out of their confidence range and also RANS numerical approaches appear not suitable for future ACC designs. In this work, methodologies for the development of accurate and reliable tools to determine the heat transfer characteristics of low pressure ACC systems are presented. More precisely, this paper describes a custom designed finite difference procedure capable of solving the inverse conduction problem on the target plate of a test sample. The methodology was successfully applied to an experimental setup for the measurement of the thermal loads on a target plate of a representative low pressure ACC impinging system. The experimental data is then used to validate a suitable numerical approach. Results show that RANS model is not able to mimic the experimental trends, while scale-resolving turbulence models provide a good reconstruction of the experimental evidences, thus allowing to obtain a correct interpretation of flow and thermal phenomena for ACC systems.

This paper relates to Schur-constant vectors in their usual continuous version. Our first goal is to highlight the existing links with L1 symmetric Dirichlet vectors and Archimedean copulas. This leads us to briefly review the main properties of these three dependency models. Several special cases, mostly classical, are also examined in this context. Next, a discrete time risk model is considered in which the successive claims amounts constitute a Schur-constant vector. A simple compact formula is obtained for the corresponding probabilities of ruin. Its application is illustrated by some numerical examples.

We consider a one-sided Markov-modulated Brownian motion perturbed by catastrophes that occur at some rates depending on the modulating process. When a catastrophe occurs, the level drops to zero f...

International audience; As three‐dimensional folding is prerequisite to biopolymer activity, complex functions may also be achieved through foldamer science. Because of the diversity of sizes, shapes and folding available with synthetic monomers, foldamer frameworks enable a numerous opportunities for designing new generations of catalysts. We herein demonstrate that heterocyclic γ‐peptide scaffolds represent a versatile platform for enamine catalysis. One central feature was to determine how the catalytic activity and the transfer of chiral information might be under the control of the conformational behaviours of the oligomer.

This paper proposes a block-structured Markov process to describe the spread of epidemics of Susceptible-Infected-Removed (SIR) type. Our purpose is to determine the distribution of the final state of the process and of some other interesting measures of the dimension of the epidemic. The followed modeling approach proves to be simple and systematic. Its flexibility is underlined by the presentation of several specific models that extend the classical general epidemic. Finally, two numerical examples illustrate some of the results obtained.

International audience; Pentatricopeptide repeat (PPR) proteins form a large family of proteins targeted to organelles, where they post-transcriptionally modulate gene expression through binding to specific RNA sequences. Among them, the mitochondria-targeted restorer-of-fertility (Rf) PPRs inhibit peculiar mitochondrial genes that are detrimental to male gametes and cause cytoplasmic male sterility (CMS). Here, we revealed three nuclear loci involved in CMS in a cross between two distant Arabidopsis thaliana strains, Sha and Cvi-0. We identified the causal gene at one of these loci as RFL24, a conserved gene encoding a PPR protein related to known Rf PPRs. By analysing fertile revertants obtained in a male sterile background, we demonstrate that RFL24 promotes pollen abortion, in contrast with the previously described Rf PPRs, which allow pollen to survive in the presence of a sterilizing cytoplasm. We show that the sterility caused by the RFL24 Cvi-0 allele results from higher expression of the gene during early pollen development. Finally, we predict a binding site for RFL24 upstream of two mitochondrial genes, the CMS gene and the important gene cob. These results suggest that the conservation of RFL24 is linked to a primary role of ensuring a proper functioning of mitochondria, and that it was subsequently diverted by the CMS gene to its benefit.

Antimicrobial peptides (AMPs) are amphipathic molecules displaying broad-spectrum bactericidal activity, providing opportunities to develop a new generation of antibiotics. However, their use is limited either by poor metabolic stability or by high hemolytic activity. We herein addressed the potential of thiazole-based γ-peptide oligomers named ATCs as tunable scaffolds to design polycationic AMP mimetics. Knowing the side chain distribution along the backbone, we rationally designed facially amphiphilic sequences with bactericidal effect in the micromolar range. Since no hemolytic activity was detected up to 100 μM, this class of compounds has shown the potential for therapeutic development.

International audience; The insertion of cyclic building blocks in oligoureas to stabilize or modulate the properties of the 12/14-helix was often fruitless. We herein propose a fully compatible highly constrained building block that could be incorporated into oligoureas to develop highly stable and functionnal oligoureas helices.

Celine Bouclier and Matthieu Simon contributed equally ; Amandine Hurbin and May C. Morris contributed equally.; International audience; CDK4/cyclin D kinase constitutes an attractive pharmacological target for development of anticancer therapeutics, in particular in KRAS-mutant lung cancer patients, who have a poor prognosis and no targeted therapy available yet. Although several ATP-competitive inhibitors of CDK4 have been developed for anticancer therapeutics, they suffer from limited specificity and efficacy. Methods: As an alternative to ATP-competitive inhibitors we have designed a stapled peptide to target the main interface between CDK4 and cyclin D, and have characterized its physico-chemical properties and affinity to bind cyclin D1. Results: We have validated a positive correlation between CDK4/cyclin D level and KRAS mutation in lung cancer patients. The stapled peptide enters cells rapidly and efficiently, and inhibits CDK4 kinase activity and proliferation in lung cancer cells. Its intrapulmonary administration in mice enables its retention in orthotopic lung tumours and complete inhibition of their growth when co-administered with Abemaciclib. Conclusion: The stapled peptide targeting the main interface between CDK4 and cyclin D provides promising therapeutic perspectives for patients with lung cancer.

Sugars play key roles in many molecular and cellular communication processes involving a family of proteins named lectins. The low affinity associated with sugar recognition is generally counterbalanced by the multivalent nature of the interaction. While many polyglycosylated architectures have been described, only a few studies focused on the impact of topology variations of the multivalent structures on the interaction with lectin proteins. One major interest of our group concerns the design of new highly predictable and stable molecular pseudo-peptide architectures for therapeutic applications. In such a context, we described a class of constrained heterocyclic γ-amino acids built around a thiazole ring, named ATCs. ATC oligomers are helical molecules resulting from the formation of a highly stable C9 hydrogen-bonding pattern. Following our program, we herein address the potential of ATC oligomers as tunable scaffolds for the development of original multivalent glycoclusters.

A block-structured transient Markov process is introduced to describe an epidemic spreading within two linked populations, of carriers and susceptibles. The epidemic terminates as soon as t...

We determine the stationary distribution of a one-sided Markov-Modulated Brownian Motion (MMBM) of which the behaviour is modified during the intervals between a visit to level zero and the next visit to a fixed positive level b. We use the semi-regenerative structure of the process, and we also use the fluid approximation for MMBMs introduced by Latouche and Nguyen in 2015. Finally, we show how the expressions can be simplified in some interesting special cases and we conclude by providing some numerical illustrations.

This paper studies the pricing of some multivariate European options, namely Exchange options and Quanto options, when the risky assets involved are modelled by Markov-Modulated Lvy Processes (MMLPs). Pricing formulae are based upon the characteristic exponents by using the well known FFT methodology. We study these pricing issues both under a risk neutral martingale measure and the historical measure. The dependence between the assets components is incorporated in the joint characteristic function of the MMLPs. As an example, we concentrate upon a regime-switching version of the model of Ballotta etal. (2015) in which the dependence structure is introduced in a flexible way. Several numerical examples are provided to illustrate our results.

In this paper we aim to apply simple actuarial methods to build an insurance plan protecting against an epidemic risk in a population. The studied model is an extended SIR epidemic in which the removal and infection rates may depend on the number of registered removals. The costs due to the epidemic are measured through the expected epidemic size and infectivity time. The premiums received during the epidemic outbreak are measured through the expected susceptibility time. Using martingale arguments, a method by recursion is developed to calculate the cost components and the corresponding premium levels in this extended epidemic model. Some numerical examples illustrate the effect of removals and the premium calculation in an insurance plan.

International audience; The 300 kDa cation-independent M6P receptor (CI-MPR) mediates ligand internalization and trafficking to the endolysosomal compartments. Because of its endocytotic nature, it has been recognized as a promising class of receptors for target component delivery. Its cellular uptake involves the simultaneous binding of two protein units resulting in the formation of receptor dimers. While many multivalent glycoconjugates have been reported to date, little is known about the topological requests to induce an effective recruitment of CI-MPRs. We herein describe the synthesis and cell uptake ability of a set of highly organized glycoclusters bearing one to three saccharide units. The spatial arrangement of carbohydrate ligands is ensured by a heterocyclic γ-peptide central core.

Film Cooling is a crucial technology for engine manufacturer to develop high-efficiency gas turbine engines by raising turbine entry temperature. A lot of cooling holes geometries have been studied in the past few years in tests, as well as numerical simulations. Shaped holes are nowadays a standard geometry for protecting the blades, given the performance improvement compared to cylindrical holes. Numerical correlation with physical tests is challenging due to the high sensitivity to thermal mixing and adequate boundary condition predictions. This paper is devoted to numerical simulation comparisons of the 777 shaped holes configuration of Pennsylvania State University, for an incompressible flow with a density ratio of 1.5, a blowing ratio of 1.5 and a free stream turbulence intensity of 0.5%. Two different simulations have been chosen: a state-of-the-art RANS simulation with k-e Realizable model computed with ANSYS Fluent and a high fidelity solver Lattice-Boltzmann Method computed with Simulia PowerFLOW. In order to improve the accuracy of numerical simulations against test results, this article deals with an aerothermal model of the complete test bench. This additional modeling allows to strongly improve thermal prediction and to understand initial discrepancies related to test bench environment. Results show that k-ε Realizable simulation provides a good prediction of average effectiveness, but local differences appear due to inherent RANS modeling limitations. On the other hand, LBM simulation provides excellent results for both aerodynamic and thermal quantities: tests results are very well reproduced.

Discovery after discovery, host-associated microbiota reveal a growing list of positive effects on host homeostasis by contributing to host nutrition, improving hosts' immune systems and protecting hosts against pathogens. In that context, a collection of oyster associated bacteria producing antibacterial compounds have been established to evaluate their role in non-host-derived immunity. Here, we described alterins, potent anti-Gram negative compounds produced by Pseudoalteromonas hCg-6 and hCg-42 isolated from different healthy oyster hemolymph. The strains hCg-6 and hCg-42 produce a set of at least seven antibacterial compounds, ranging from 926 to 982 Da structurally characterized as cyclolipopeptides (CLPs). Alterins share the same cationic heptapeptidic cycle connected via an amido bond to different hydrophobic hydrocarbon tails. Their MICs disclosed a potent antibacterial activity directed against Gram-negative bacteria including oyster and human pathogens that may confer a beneficial defense mechanism to the host but also represents an untapped source of new antibiotics. The alterins&rsquo, mechanisms of action have been deciphered: after binding to lipopolysaccharides (LPS), alterins provoke a membrane depolarization and permeabilization leading to bacterial lysis. As hCg-6 and hCg-42 produced a set of natural derivatives, the structure/activity relationship linked to the carbon tail is clarified. We showed that the hydrocarbon tail determines the LPS-binding properties of alterins and consequently their antibacterial activities. Its length and saturation seem to play a major role in this interaction.

In this paper we are concerned with a stochastic model for the spread of an epidemic in a closed homogeneously mixing population when an infective can go through several stages of infection before being removed. The transitions between stages are governed by either a Markov process or a semi-Markov process. An infective of any stage makes contacts amongst the population at the points of a Poisson process. Our main purpose is to derive the distribution of the final epidemic size and severity, as well as an approximation by branching, using simple matrix analytic methods. Some illustrations are given, including a model with treatment discussed by Gani (2006).

Enzymes are predominantly proteins able to effectively and selectively catalyze highly complex biochemical reactions in mild reaction conditions. Nevertheless, they are limited to the arsenal of reactions that have emerged during natural evolution in compliance with their intrinsic nature, three-dimensional structures and dynamics. They optimally work in physiological conditions for a limited range of reactions, and thus exhibit a low tolerance for solvent and temperature conditions. The de novo design of synthetic highly stable enzymes able to catalyze a broad range of chemical reactions in variable conditions is a great challenge, which requires the development of programmable and finely tunable artificial tools. Interestingly, over the last two decades, chemists developed protein secondary structure mimics to achieve some desirable features of proteins, which are able to interfere with the biological processes. Such non-natural oligomers, so called foldamers, can adopt highly stable and predictable architectures and have extensively demonstrated their attractiveness for widespread applications in fields from biomedical to material science. Foldamer science was more recently considered to provide original solutions to the de novo design of artificial enzymes. This review covers recent developments related to peptidomimetic foldamers with catalytic properties and the principles that have guided their design.

We consider the risk-neutral pricing of vanilla, digital and down-and-out call options when the underlying asset price evolves like the exponential of a Markov-modulated Brownian motion (MMBM) with two-sided phase-type jumps. The price of such options is intimately related to the first passage properties of the MMBM. To analyse these first passages, we randomize the time horizon using Erlang distributions with suitable parameters and apply matrix-analytic methods. This provides us with closed form approximations of the options prices, with a very high precision, as shown by several numerical illustrations. In particular, we consider an example in which the phase-type jump distribution is constructed in such a way that it mimics fat tails.

12/10-Helices constitute suitable templates that can be used to design original structures. Nevertheless, they often suffer from a weak stability in polar solvents because they exhibit a mixed hydrogen-bond network resulting in a small macrodipole. In this work, stable and functionalizable 12/10-helices were developed by alternating a highly constrained β2, 3, 3 -trisubstituted bicyclic amino acid (S)-1-aminobicyclo[2.2.2]octane-2-carboxylic acid ((S)-ABOC) and an acyclic substituted β-homologated proteinogenic amino acid (l-β3 -hAA). Based on NMR spectroscopic analysis, it was shown that such mixed β-peptides display well-defined right-handed 12/10-helices in polar, apolar, and chaotropic solvents; that are, CD3 OH, CDCl3 , and [D6 ]DMSO, respectively. The stability of the hydrogen bonds forming the C10 and C12 pseudocycles as well as the benefit provided by the use of the constrained bicyclic ABOC versus typical acyclic β-amino acids sequences when designing 12/10-helix were investigated using NH/ND NMR exchange experiments and DFT calculations in various solvents. These studies showed that the β3 -hAA/(S)-ABOC helix displayed a more stable hydrogen-bond network through specific stabilization of the C10 pseudocycles involving the bridgehead NH of the ABOC bicyclic scaffold.

Potent and selective antimicrobial cyclic pseudopeptides (ACPPs) mixing α- and aza-β

International audience; According to their restricted conformational freedom, heterocyclic -amino acids are usually considered to be related to Z-vinylogous -amino acids. In this context, oligomers alternating -amino acids and thiazole-based -amino acids (ATCs) were expected to fold into a canonical 12-helical shape as described for /-hybrid peptides composed of cis-/-unsaturated -amino acids. However, through a combination of X-ray crystallography, NMR spectroscopy, FTIR experiments, and DFT calculations, it was determined that the folding behavior of ATC-containing hybrid peptides is much more complex. The homochiral /(S)-ATC sequences were unable to adopt a stable conformation, whereas the heterochiral /(R)-ATC peptides displayed novel ribbon structures stabilized by unusual C-9/12-bifurcated hydrogen bonds. These ribbon structures could be considered as a succession of pre-organized / dipeptides and may provide the basis for designing original -helix mimics.

Different intracellular delivery systems of bioactive compounds have been developed, including cell-penetrating peptides. While usually non-toxic and biocompatible, these vectors share some of the general peptide drawbacks, notably low bioavailability and susceptibility to protease degradation that limit their use. Here, we investigated the conversion of short peptide sequences into poly-α-amino-γ-lactam (Agl-AA) foldamers that adopted a ribbon-like structure. We used this template to distribute critical cationic and/or hydrophobic groups on both sides of their backbones, leading to potent short cell-permeable foldamers with low positive charge content. The lead compound showed dramatically improved protease resistance and was able to efficiently deliver a biologically relevant cargo inside the cell. This study provided a simple strategy to convert short peptide sequences into efficient protease-resistant cell-penetrating foldamers.