Modelling the regulation of thermal adaptation in Candida albicans, a major fungal pathogen of humans

Peer reviewedPublisher PD

Intrauterine deaths — an unsolved problem in Polish perinatology

Objectives: The Polish criteria for “intrauterine death” include fetal demise after 22 weeks of gestation, weighing > 500 g and body length at least 25 cm, when the gestational age is unknown. The rate of fetal death in Poland in 2015 is 3:10,000. In 2020, 1,231 stillbirths were registered. Material and methods: An analysis using 142,662 births in the period between 2015–2020 in 11 living in Poland. The first subgroup was admitted as patients > 22 to the beginning of the 30th week of pregnancy (n = 229), and the second from the 30th week of pregnancy inclusively (n = 179). In the case of women from both subgroups, there was a risk of preterm delivery close to hospitalization. Results: It was found that stillbirth in 41% of women in the first pregnancy. For the patient, stillbirth was also the first in his life. The average stillbirth weight was 1487 g, the average body length was 40 cm. Among fetuses up to 30 weeks, male fetuses are born more often, in subgroup II, the sex of the child was usually female. Most fetal deaths occur in mothers < 15 and > 45 years of age. Conclusions: According to the Polish results of the origin of full-term fetuses > 30 weeks of gestation for death in the concomitant antenatal, such as placental-umbilical and fetal hypoxia, acute intrapartum effects rarely, and moreover < 30 Hbd fetal growth restriction (FGR), occurring placental-umbilical, acute intrapartum often

A modeling perspective on Candida albicans' interactions with its human host

Ansätze der mathematischen Modellierung ermöglichen die Analyse der dynamischen Eigenschaften biologischer Systeme und den Einfluß spezifischer Funktionen. Das Ziel dieser Arbeit ist es verschiedene Aspekte der Interaktionen zwischen Wirt und Krankheitserregern zu analysieren. In Kapitel 3 diskutiere ich ein Modell der zellulären Antwort auf Hitzeschockstress im Pilz Candida albicans. Das Modell in Form von gewöhnlichen Differentialgleichungen erörtert mehrere Aspekte des Systems, wie z.B. die erworbene Thermotoleranz und eine perfekte Anpassung an die Beanspruchung durch die Temperaturwechsel. Im Rahmen der Interaktionen zwischen Wirt und Krankheitserreger ist die Studie relevant, da die Entwicklung von Fieber eine primäre Antwort des Organismus auf eine Pilzinvasion ist. Die Dynamik von C. albicans Virulenzfaktoren, wie z.B. der Übergang vom Hefe- zum Hyphenstadium, und die Abwehrmechanismen des Wirts bestimmen den Zustand des Pilzes, d.h. ob er als Kommensale oder Krankheitserreger vorkommt. Mit Hilfe einer agenten-basierten Modellierungstechnik, in Kapitel 4, untersuche ich die Auswirkungen potenzieller medikamentöser Behandlungen von Pilzpopulationen und ihre Effektivität. In Kapitel 5 analysiere ich die Dynamik der C. albicans Hefe- und Hyphenpopulationen unter der Annahme, das zwischen den Individuen beider Populationen paarweise Wechselwirkungen bestehen, die zusätzlich von Fresszellen und Ernährungsbedingungen beeinflusst werden. Das erste Modell basiert auf den Prinzipien der Spieltheorie. Aus dieser Studie lässt sich die Hypothese aufstellen, dass sich im Verlauf der Infektion die evolutionäre Spieldynamik von der Snowdrift Spieldynamik in Richtung Gefangendilemma verschiebt. Im zweiten Modell untersuche ich die Umschaltraten zwischen Hefen und Hyphen. Das Modell zeigt, dass in Pilzpopulationen die Ausprägung verschiedener Phänotypen der Grund für die erhöhte Überlebensfähigkeit der Population sein könnte.Mathematical modeling approaches facilitate the analysis of dynamic properties of mechanisms triggering specific functions of biological systems. Through this work I aim to shed light on various aspects of host-pathogen interactions. In Chapter 3, I discuss a model of heat shock stress response activated in the fungus Candida albicans. The model in form of ordinary differential equations reveals several features of the system, such as acquired thermotolerance and a perfect molecular adaptation to the thermal insult. The study is relevant in the context of host-pathogen interactions since development of fever is a primary host response to fungal invasion. The dynamics of C. albicans virulence factors, e.g., yeast to hypha transition, and defense mechanisms of the host determine the state of the fungi, i.e. whether to act as a commensal or as a foe. Through application of an agent-based modeling technique, in Chapter 4, I investigate effects of potential drug treatments on fungal populations and their effectivity in the fungal clearance. In Chapter 5, I analyze the dynamics of candida yeast and hyphal populations assuming pairwise interactions influenced by phagocytic cells and nutritional conditions. The first model is based on game theory principles. From the study it can be hypothesized that during the course of infection the evolutionary game dynamics shift from Snowdrift game dynamics toward Prisoners’ dilemma. In the second model, I examine switching rates between yeast and hypha. The model reveals that phenotypic variations may occur in order to increase the fitness of the population

New localities of Corallorhiza trifida (Orchidaceae) in the Beskid Sądecki Mts and in the Bieszczady Zachodnie Mts

Three new localities of rare and threatened orchid species - Corallorhiza trifida were found in the Beskid Sądecki and in the Western Bieszczady Mts. Information about plant communities in which the species was recorded and protection issues are presented

Assessing the advantage of morphological changes in Candida albicans: a game theoretical study

A range of attributes determines the virulence of human pathogens. During interactions with their hosts, pathogenic microbes often undergo transitions between distinct stages, and the ability to switch between these can be directly related to the disease process. Understanding the mechanisms and dynamics of these transitions is a key factor in understanding and combating infectious diseases. The human fungal pathogen Candida albicans exhibits different morphotypes at different stages during the course of infection (candidiasis). For example, hyphae are considered to be the invasive form, which causes tissue damage, while yeast cells are predominant in the commensal stage. Here, we described interactions of C. albicans with its human host in a game theoretic model. In the game, players are fungal cells. Each fungal cell can adopt one of the two strategies: to exist as a yeast or hyphal cell. We characterized the ranges of model parameters in which the coexistence of both yeast and hyphal forms is plausible. Stability analysis of the system showed that, in theory, a reduced ability of the host to specifically recognize yeast and hyphal cells can result in bi-stability of the microbial populations’ profile. Inspired by the model analysis we reasoned that the types of microbial interactions can change during invasive candidiasis. We found that positive cooperation among fungal cells occurs in mild infections and an enhanced tendency to invade the host is associated with negative cooperation. The model can easily be extended to multi-player systems with direct application to identifying individuals that enhance either positive or negative cooperation. Results of the modelling approach have potential application in developing treatment strategies

Integrating economic and psychological insights in binary choice models with social interactions

We investigate a class of binary choice models with social interactions. We propose a unifying perspective that integrates economic models using a utility function and psychological models using an impact function. A general approach for analyzing the equilibrium structure of these models within mean-field approximation is developed. It is shown that within a mean-field approach both the utility function and the impact function models are equivalent to threshold models. The interplay between heterogeneity and randomness in model formulation is discussed. A general framework is applied in a number of examples leading to some well-known models but also showing the possibility of more complex dynamics related to multiple equilibria. Our synthesis can provide a basis for many practical applications extending the scope of binary choice models.

Impact of sequential heat shocks.

<p>The model was used to simulate sequential 30 minute heat shocks of 30°C–42°C separated either by 20 or 120 minutes. Outcomes were then tested experimentally by determining Hsf1 phosphorylation levels. (A) Representations of the thermal transitions with the 20 minute recovery period. (B) Model simulations of Hsf1 phosphorylation for a 20 minute recovery period between heat shocks: solid black line simulates Hsf1 phosphorylation in cells that have seen a prior heat shock, dashed black line simulates Hsf1 phosphorylation in control cells that have had no prior heat shock. (C) These predictions were tested experimentally by moving exponentially growing cells from 30°C to 42°C for 30 minutes. Cells were then placed back at 30°C for 20 minutes before they received a second heat shock at 42°C. Control cells only received the second heat shock with no prior heat shock. Proteins were extracted and subjected to western blotting to measure Hsf1 phosphorylation (upper panel). The lower panel shows lambda phosphatase controls (λ Ppase) that confirm the Hsf1 phosphorylation states shown in the upper panel. (D) Representations of the thermal transition with a 120 minute recovery period between heat shocks. (E) Model simulation of Hsf1 phosphorylation for a 120 minute recovery period between heat shocks: solid black line, predicted Hsf1 phosphorylation in cells that have seen a prior heat shock; dashed black line, predicted Hsf1 phosphorylation in control cells that have had no prior heat shock. (F) These predictions were tested experimentally by moving exponentially growing cells from 30°C to 42°C for 30 minutes. Cells were then placed back at 30°C for 120 minutes before they received a second heat shock at 42°C. Control cells only received the second heat shock with no prior heat shock. Protein extracts were subjected to western blotting to measure Hsf1 phosphorylation (upper panel). The lower panel includes lambda phosphatase controls (λ Ppase) that confirm the phosphorylation status of samples from the upper panel. (G) Further controls involving direct comparison of 20 and 120 minute memory samples to confirm the differential Hsf1 phosphorylation in these samples, and hence the loss of molecular memory after 120 minutes. (H) The loss of molecular memory is reflected in reduced cellular resistance to the second heat shock. Cell viabilities (CFUs) were measured 0 and 15 minutes after the imposition of the second 30°C–42°C heat shock: grey bars, cells that received a 20 minute interval between heat shocks; grey bars, cells that received a 120 minute interval between heat shocks (* p<0.05, students t-test). Data reflect the outcomes for at least two independent replicate experiments.</p

The impact of slow thermal upshifts.

<p>The model was used to simulate slow thermal transitions from 37°C–42°C over 20, 60, 90 or 180 minute periods after a 37°C heat shock for 30 minutes. (A) Representations of a subset of the thermal transitions examined, some of which might mimic fevers in patients. (B) Model simulations of Hsf1 phosphorylation levels during slow temperature transitions from 37°C–42°C: 0 minute transition, solid black line; 20 minute transition, dotted black line; 60 minute transition, dashed black line; 90 minute transition, solid grey line; 180 minute transition, dotted grey line.</p