Resonance effects and outbreaks in ecological time series

Organismal response to environmental variability is an important aspect of ecological processes. We propose new mechanisms whereby environmental variability can cause cyclic population outbreaks due to the nonlinearity of the organismal response. We consider stage-structured populations that respond to variable environments with variable diapause or dormancy, and in which cyclic changes of the environment induce a resonance-like boost in the population size. If there is also a stochastic component of variation in the environment, the population outbreaks are magnified by the phenomenon of "stochastic resonance". The results show that large population fluctuations may not be due to extrinsic or intrinsic factors alone, but to a nonlinear interaction between the external environment and internal population processes. Indeed, in the presence of such nonlinearities even very small environmental fluctuations can cause massive fluctuations in population size. Our theoretical results may help to explain periodic population cycles and outbreak dynamics found in many infectious diseases and pest species. We also discuss the evolution of the response parameters that regulate diapause or dormancy and promote the outbreak dynamics in variable environments.     

Northern infant syndrome: a deficiency state?

A syndrome is described that affected 16 Indian and Inuit infants roughly 3 months old, most of whom were born in settlements in the Canadian Arctic. The infants presented with a clinical picture that included hepatitis, hemolytic anemia, rickets and respiratory distress, a combination that resembled a syndrome first described in malnourished infants at the turn of the century by von Jaksch and Luzet. The clinical course was self-limited, and all the infants survived without sequelae. The cause of the syndrome was not determined; no infectious agents were discovered. However, low levels of vitamins A, C, D and E were found in a few infants in whom assays were done. The implications of these findings and their relation to the possible cause of this "northern infant syndrome" are discussed.     

The role of parasites and pathogens in influencing generalised anxiety and predation-related fear in the mammalian central nervous system

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Behavioural and neurophysiological traits and responses associated with anxiety and predation-related fear have been well documented in rodent models. Certain parasites and pathogens which rely on predation for transmission appear able to manipulate these, often innate, traits to increase the likelihood of their life-cycle being completed. This can occur through a range of mechanisms, such as alteration of hormonal and neurotransmitter communication and/or direct interference with the neurons and brain regions that mediate behavioural expression. Whilst some post-infection behavioural changes may reflect 'general sickness' or a pathological by-product of infection, others may have a specific adaptive advantage to the parasite and be indicative of active manipulation of host behaviour. Here we review the key mechanisms by which anxiety and predation-related fears are controlled in mammals, before exploring evidence for how some infectious agents may manipulate these mechanisms. The protozoan Toxoplasma gondii, the causative agent of toxoplasmosis, is focused on as a prime example. Selective pressures appear to have allowed this parasite to evolve strategies to alter the behaviour in its natural intermediate rodent host. Latent infection has also been associated with a range of altered behavioural profiles, from subtle to severe, in other secondary host species including humans. In addition to enhancing our knowledge of the evolution of parasite manipulation in general, to further our understanding of how and when these potential changes to human host behaviour occur, and how we may prevent or manage them, it is imperative to elucidate the associated mechanisms involved.     

Converting cancer therapies into cures: lessons from infectious diseases

During the past decade, cancer drug development has shifted from a focus on cytotoxic chemotherapies to drugs that target specific molecular alterations in tumors. Although these drugs dramatically shrink tumors, the responses are temporary. Research is now focused on overcoming drug resistance, a frequent cause of treatment failure. Here we reflect on analogous challenges faced by researchers in infectious diseases. We compare and contrast the resistance mechanisms arising in cancer and infectious diseases and discuss how approaches for overcoming viral and bacterial infections, such as HIV and tuberculosis, are instructive for developing a more rational approach for cancer therapy. In particular, maximizing the effect of the initial treatment response, which often requires synergistic combination therapy, is foremost among these approaches. A remaining challenge in both fields is identifying drugs that eliminate drug-tolerant "persister" cells (infectious disease) or tumor-initiating/stem cells (cancer) to prevent late relapse and shorten treatment duration.     

Evolution of time-keeping mechanisms: early emergence and adaptation to photoperiod

Virtually all species have developed cellular oscillations and mechanisms that synchronize these cellular oscillations to environmental cycles. Such environmental cycles in biotic (e.g. food availability and predation risk) or abiotic (e.g. temperature and light) factors may occur on a daily, annual or tidal time scale. Internal timing mechanisms may facilitate behavioural or physiological adaptation to such changes in environmental conditions. These timing mechanisms commonly involve an internal molecular oscillator (a 'clock') that is synchronized ('entrained') to the environmental cycle by receptor mechanisms responding to relevant environmental signals ('Zeitgeber', i.e. German for time-giver). To understand the evolution of such timing mechanisms, we have to understand the mechanisms leading to selective advantage. Although major advances have been made in our understanding of the physiological and molecular mechanisms driving internal cycles (proximate questions), studies identifying mechanisms of natural selection on clock systems (ultimate questions) are rather limited. Here, we discuss the selective advantage of a circadian system and how its adaptation to day length variation may have a functional role in optimizing seasonal timing. We discuss various cases where selective advantages of circadian timing mechanisms have been shown and cases where temporarily loss of circadian timing may cause selective advantage. We suggest an explanation for why a circadian timing system has emerged in primitive life forms like cyanobacteria and we evaluate a possible molecular mechanism that enabled these bacteria to adapt to seasonal variation in day length. We further discuss how the role of the circadian system in photoperiodic time measurement may explain differential selection pressures on circadian period when species are exposed to changing climatic conditions (e.g. global warming) or when they expand their geographical range to different latitudes or altitudes.     

Effects of ovarian maturation and insemination on the length of intermoult in Thermobia domestica

ABSTRACT. A study of the individual variability in the length of intermoult periods allows correlations to be established between reproductive and moulting cycles in adult females of Thermobia domestica (Packard) (Thysanura, Lepismatidae). By keeping the females without or with males and by changing the day of insemination, it is shown that the intermoult periods vary with the rate of ovarian maturation from the beginning of each stadium. Females with slow oocyte growth are never inseminated, even in the presence of males; they have short intermoults. Females with rapid oocyte growth can be inseminated and the timing of insemination regulates the length of the intermoults. It appears that the variability in duration of the intermoult only concerns the first part of the stadium (postecdysial period of the reproductive cycle=period of intense vitellogenesis), whereas the second part of the stadium (pre-ecdysial period=previtellogenesis) has an almost constant length. The endocrine mechanisms involved are considered, taking into account the cyclic changes in hormonal levels already described in other papers.     

Some old concepts and new findings on hormonal control of insect morphogenesis

By means of the artificially induced heterochronic developmental deviations represented by local prothetelies and metathetelies it has been possible to investigate the individual developmental fates of ontogenetically different tissues, such as larval, pupal, and adult epidermal cells, in one and the same body and under the identical concentration of juvenile hormone (JH) in the haemolymph.In contrast to the widely accepted hormonal theories which claim that the kind of morphogenesis is determined by large, intermediate, and low titres of JH, the heterochronic character of the tissues never developed into a uniform population of homomorphic epidermal cells. Instead, in the presence of effective amounts of JH the heterochronic pattern has been fully preserved and carried on into the next developmental instar. Moreover, in the absence of the effective JH amounts the ontogenetically different tissues, such as larval and pupal epidermal cells, simultaneously undergo their respective morphogenetic developments, i.e. larval-pupal and pupal-adult morphogenesis in the same hormonal milieu. It is concluded that the selective factor in determination of the kind of morphogenetical changes is not an altered JH titre but the extant, previously attained degree of ontogenetic structural differentiation. It has been demonstrated that JH can temporarily and reversibly inhibit the morphogenetic progress at quite different ontogenetic levels but it cannot cause a ‘reversal of metamorphosis’ at any of these levels.Under specific experimental conditions the larval epidermal cells can undergo pupal and adult morphogenesis without secreting the pupal cuticle. However, the pupal morphogenetic interstage, whether with the cuticle or without the pupal cuticle, constitutes an obligatory developmental step. Further, it appears that an absence of JH may represent an important condition but not a real cause of insect metamorphosis, as presumed in some other hormonal concepts. Thus, chromosomal duplications or cellular divisions in the absence of JH have not committed the cells to morphogenesis unless provided by an additional stimulus of endogenous prothoracic gland hormone or exogenous ecdysterone. An important factor in understanding the hormonal control of insect morphogenesis is the critical timing of the respective morphogenetic steps. This corresponds closely with the duration of the pharate phases in insect development. Possible hormonal mechanisms concerned in the regulation of morphogenesis in endopterygote insects have been outlined.     

The vertebrate segmentation clock and its role in skeletal birth defects

The segmental structure of the vertebrate body plan is most evident in the axial skeleton. The regulated generation of somites, a process called somitogenesis, underlies the vertebrate body plan and is crucial for proper skeletal development. A genetic clock regulates this process, controlling the timing of somite development. Molecular evidence for the existence of the segmentation clock was first described in the expression of Notch signaling pathway members, several of which are expressed in a cyclic fashion in the presomitic mesoderm (PSM). The Wnt and fibroblast growth factor (FGF) pathways have also recently been linked to the segmentation clock, suggesting that a complex, interconnected network of three signaling pathways regulates the timing of somitogenesis. Mutations in genes that have been linked to the clock frequently cause abnormal segmentation in model organisms. Additionally, at least two human disorders, spondylocostal dysostosis (SCDO) and Alagille syndrome (AGS), are caused by mutations in Notch pathway genes and exhibit vertebral column defects, suggesting that mutations that disrupt segmentation clock function in humans can cause congenital skeletal defects. Thus, it is clear that the correct, cyclic function of the Notch pathway within the vertebrate segmentation clock is essential for proper somitogenesis. In the future, with a large number of additional cyclic genes recently identified, the complex interactions between the various signaling pathways making up the segmentation clock will be elucidated and refined.     

Oscillators entrained by food and the emergence of anticipatory timing behaviors

Circadian rhythms are adjusted to the external environment by the light-dark cycle via the suprachiasmatic nucleus, and to the internal environment of the body by multiple cues that derive from feeding/fasting. These cues determine the timing of sleep/wake cycles and all the activities associated with these states. We suggest that numerous sources of temporal information, including hormonal cues such as corticoids, insulin, and ghrelin, as well as conditioned learned responses determined by the temporal relationships between photic and feeding/fasting signals, can determine the timing of regularly recurring circadian responses. We further propose that these temporal signals can act additively to modulate the pattern of daily activity. Based on such reasoning, we describe the rationale and methodology for separating the influences of these diverse sources of temporal information. The evidence indicates that there are individual differences in sensitivity to internal and external signals that vary over circadian time, time since the previous meal, time until the next meal, or with duration of food deprivation. All of these cues are integrated in sites and circuits modulating physiology and behavior. Individuals detect changes in internal and external signals, interpret those changes as "hunger," and adjust their physiological responses and activity levels accordingly.     

Cystic fibrosis infections: treatment strategies and prospects

Pseudomonas aeruginosa and Burkholderia cepacia are the two major Gram-negative rods that colonize/infect the lungs of patients with cystic fibrosis (CF). These organisms may cause progressive respiratory failure, although occasionally more rapid infections result in the ' Cepacia ' syndrome. Many antibiotics have been used against Pseudomonas and Burkholderia , but once chronic colonization has been established, eradication of these organisms is rare. Drug therapy for CF patients is compromised by a number of bacterial factors that render the infectious agents resistant to antibiotics, including efflux pumps that remove antibiotics, lack of penetration of antibiotics into bacterial biofilms, and changes in the cell envelope that reduce the permeability of antibiotics. Any combination of these mechanisms increases the likelihood of bacterial survival. Therefore, combinations of antibiotics or of antibiotic and nonantibiotic compounds are currently being tested against Pseudomonas and Burkholderia . However, progress has been slow, with only occasional combinations showing promise for the eradication of persistent Gram-negative rods in the airways of CF patients. This review will summarize the current knowledge of CF infections and speculate on potential future pathways to treat these chronic infections.     

The ovarian cycle and control of ovulation

The ovarian cycle of primates is a sequence of events reflecting follicular growth and development, the ovulation of a mature oocyte and the formation of a functional corpus luteum. A typical cycle generally consists of three phases: (1) the follicular or proliferative phase, (2) ovulation and (3) the luteal or secretory phase. Within this general pattern exists considerable species variation in terms of cycle length, timing of ovulation, presence or absence of menstruation and influence of season.
Details of the basic physiological mechanisms controlling cyclic ovarian function in primates are known for only a few species. Concentrating on information derived from studies in women and in rhesus and marmoset monkeys, this paper examines some of the hormonal mechanisms underlying the primate ovarian cycle with particular reference to the factors controlling preovulatory follicular development during the follicular phase.     

De novo generation of prion strains

Prions are self-replicating proteins that can cause neurodegenerative disorders such as bovine spongiform encephalopathy (also known as mad cow disease). Aberrant conformations of prion proteins accumulate in the central nervous system, causing spongiform changes in the brain and eventually death. Since the inception of the prion hypothesis - which states that misfolded proteins are the infectious agents that cause these diseases - researchers have sought to generate infectious proteins from defined components in the laboratory with varying degrees of success. Here, we discuss several recent studies that have produced an array of novel prion strains in vitro that exhibit increasingly high titres of infectivity. These advances promise unprecedented insight into the structure of prions and the mechanisms by which they originate and propagate.     

Nanoimaging for prion related diseases

Misfolding and aggregation of prion proteins is linked to a number of neurodegenerative disorders such as Creutzfeldt-Jacob disease (CJD) and its variants, kuru, Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia. In prion diseases, infectious particles are proteins that propagate by transmitting a misfolded state of a protein, leading to the formation of aggregates and ultimately to neurodegeneration. Prion phenomenon is not restricted to humans. There is a number of prion-related diseases in a variety of mammals, including bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cattle. All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal. Prion proteins were also found in some fungi where they are responsible for heritable traits. Prion proteins in fungi are easily accessible and provide a powerful model for understanding the general principles of prion phenomenon and molecular mechanisms of mammalian prion diseases. Presently, several fundamental questions related to prions remain unanswered. For example, it is not clear how prions cause the disease. Other unknowns include the nature and structure of infectious agent and how prions replicate? Generally, the phenomenon of misfolding of prion protein into infectious conformations that have the ability to propagate their properties via aggregation is of significant interest. Despite the crucial importance of misfolding and aggregation, very little is currently known about the molecular mechanisms of these processes. While there is an apparent critical need to study molecular mechanisms underlying misfolding and aggregation, the detailed characterization of these single molecule processes is hindered by the limitation of conventional methods. Although some issues remain unresolved, much progress has been recently made primarily due to the application of nanoimaging tools. The use of nanoimaging methods shows great promise for understanding the molecular mechanisms of prion phenomenon, possibly leading toward early diagnosis and effective treatment of these devastating diseases. This review article summarizes recent reports which advanced our understanding of the prion phenomenon through the use of nanoimaging methods.     

A Perspective on Multiple Waves of Influenza Pandemics

Background

A striking characteristic of the past four influenza pandemic outbreaks in the United States has been the multiple waves of infections. However, the mechanisms responsible for the multiple waves of influenza or other acute infectious diseases are uncertain. Understanding these mechanisms could provide knowledge for health authorities to develop and implement prevention and control strategies.

Materials and Methods

We exhibit five distinct mechanisms, each of which can generate two waves of infections for an acute infectious disease. The first two mechanisms capture changes in virus transmissibility and behavioral changes. The third mechanism involves population heterogeneity (e.g., demography, geography), where each wave spreads through one sub-population. The fourth mechanism is virus mutation which causes delayed susceptibility of individuals. The fifth mechanism is waning immunity. Each mechanism is incorporated into separate mathematical models, and outbreaks are then simulated. We use the models to examine the effects of the initial number of infected individuals (e.g., border control at the beginning of the outbreak) and the timing of and amount of available vaccinations.

Results

Four models, individually or in any combination, reproduce the two waves of the 2009 H1N1 pandemic in the United States, both qualitatively and quantitatively. One model reproduces the two waves only qualitatively. All models indicate that significantly reducing or delaying the initial numbers of infected individuals would have little impact on the attack rate. Instead, this reduction or delay results in a single wave as opposed to two waves. Furthermore, four of these models also indicate that a vaccination program started earlier than October 2009 (when the H1N1 vaccine was initially distributed) could have eliminated the second wave of infection, while more vaccine available starting in October would not have eliminated the second wave.     

Telomere attrition due to infection

Background

Telomeres–the terminal caps of chromosomes–become shorter as individuals age, and there is much interest in determining what causes telomere attrition since this process may play a role in biological aging. The leading hypothesis is that telomere attrition is due to inflammation, exposure to infectious agents, and other types of oxidative stress, which damage telomeres and impair their repair mechanisms. Several lines of evidence support this hypothesis, including observational findings that people exposed to infectious diseases have shorter telomeres. Experimental tests are still needed, however, to distinguish whether infectious diseases actually cause telomere attrition or whether telomere attrition increases susceptibility to infection. Experiments are also needed to determine whether telomere erosion reduces longevity.

Methodology/Principal Findings

We experimentally tested whether repeated exposure to an infectious agent, Salmonella enterica, causes telomere attrition in wild-derived house mice (Mus musculus musculus). We repeatedly infected mice with a genetically diverse cocktail of five different S. enterica strains over seven months, and compared changes in telomere length with sham-infected sibling controls. We measured changes in telomere length of white blood cells (WBC) after five infections using a real-time PCR method. Our results show that repeated Salmonella infections cause telomere attrition in WBCs, and particularly for males, which appeared less disease resistant than females. Interestingly, we also found that individuals having long WBC telomeres at early age were relatively disease resistant during later life. Finally, we found evidence that more rapid telomere attrition increases mortality risk, although this trend was not significant.

Conclusions/Significance

Our results indicate that infectious diseases can cause telomere attrition, and support the idea that telomere length could provide a molecular biomarker for assessing exposure and ability to cope with infectious diseases.     

Hormonal and non-hormonal bases of maternal behavior: The role of experience and epigenetic mechanisms

This article is part of a Special Issue “Parental Care”. Though hormonal changes occurring throughout pregnancy and at the time of parturition have been demonstrated to prime the maternal brain and trigger the onset of mother–infant interactions, extended experience with neonates can induce similar behavioral interactions. Sensitization, a phenomenon in which rodents engage in parental responses to young following constant cohabitation with donor pups, was elegantly demonstrated by Rosenblatt (1967) to occur in females and males, independent of hormonal status. Study of the non-hormonal basis of maternal behavior has contributed significantly to our understanding of hormonal influences on the maternal brain and the cellular and molecular mechanisms that mediate maternal behavior. Here, we highlight our current understanding regarding both hormone-induced and experience-induced maternal responsivity and the mechanisms that may serve as a common pathway through which increases in maternal behavior are achieved. In particular, we describe the epigenetic changes that contribute to chromatin remodeling and how these molecular mechanisms may influence the neural substrates of the maternal brain. We also consider how individual differences in these systems emerge during development in response to maternal care. This research has broad implications for our understanding of the parental brain and the role of experience in the induction of neurobiological and behavior changes.     

Hormone-induced changes in pyruvate kinase activity in isolated hepatocytes II. Relation to the hormonal regulation of gluconeogenesis gluconeogenesis

1. 1. Incubation of isolated hepatocytes with glucagon (10⁻⁶ M) or dibutyryl cyclic AMP (0.1 mM) causes a decrease in pyruvate kinase activity of 50%, measured at suboptimal substrate (phosphoenolpyruvate) concentrations and 1 mM Mg_free²⁺. The magnitude of the decrease in activity is not influenced by the applied extracellular concentrations of lactate (1 and 5 mM), glucose (5 and 30 mM) or fructose (10 and 25 mM). With all three substrates comparable inhibition percentages are induced by glucagon or dibutyryl cyclic AMP.

2. 2. The extent of inhibition of pyruvate kinase induced by incubation of hepatocytes with glucagon or dibutytyl cyclic AMP is not influenced by the extracellular Ca²⁺ concentration nor by the presence of 2 mM EGTA. The reactivation of pyruvate kinase seems to be inhibited by a high concentration of extracellular Ca²⁺ (2.6 mM) as compared to a low concentration of extracellular Ca²⁺ (0.26 mM).

3. 3. Incubation of hepatocytes in a Na⁺-free, high K⁺-concentration medium does not influence the magnitude of the pyruvate kinase inhibition induced by dibutyryl cyclic AMP. However, the reactivation reaction is stimulated under these incubation conditions.

4. 4. Incubation of hepatocytes with dibutyryl cyclic GMP (0.1 mM) leads to a 25% decrease in pyruvate kinase activity. The magnitude of the inhibition by dibutyryl cyclic (GMP) is not influenced by the presence of pyruvate (1 mM) or glucose (5 mM and 30 mM).

5. 5. The relative insensitivity of the pyruvate kinase inhibition induced by glucagon, dibutyryl cyclic AMP and dibutyryl cyclic GMP to the extracellular environment leads to the conclusion that the hormonal regulation of pyruvate kinase is not the only site of hormonal regulation of glycolysis and gluconeogenesis. It is concluded that hormonal regulation of pyruvate kinase activity is exerted by changes in the degree of (de)phosphorylation of the enzyme reflecting acute hormonal control as well as by changes in the concentration of the allosteric activator fructose 1,6-diphosphate. The latter depends at least in part on the hormonal control of the phosphofructokinase-fructose-1,6-phosphatase cycle.

The oestrogen paradox: a hypothesis

Epidemiological and observational studies suggest that oestrogens, when used as hormonal therapy in post-menopausal women, can increase the risk of breast cancer if used long term. However, more recent data suggest that short-term use in sub-groups of post-menopausal women significantly decreases the risk of breast cancer. This beneficial effect is also observed when high-dose oestrogen is administered to post-menopausal women with breast cancer to cause tumour regression, a phenomenon which commonly occurs. We consider these divergent responses to oestrogen to represent a "paradox". Data from our own and other investigative groups suggest a hypothesis to explain this paradox. Deprivation of oestradiol in model systems causes cells to adapt and to undergo apoptosis in response to oestrogen. This occurs through the Fas/Fas ligand death receptor pathway and through alterations in apoptotic mechanisms mediated by mitochondria. This process of programmed cell death may explain the regression of established breast cancer with oestrogen administration and the diminution in the rate of new breast cancer diagnoses recently reported. Our hypothesis is based upon pathological data indicating the presence of a "reservoir" of undiagnosed breast cancer in the population of women who would be starting on oestrogens as menopausal hormonal therapy. The long-term increased risk of breast cancer may then reflect different mechanisms. Oestrogens can cause mutations through enhancement of the rate of cell division and concomitantly the error rate in DNA replication. In addition, oestrogens can be metabolised to directly genotoxic compounds. These carcinogenic processes take much longer, since a number of mutations must accumulate before resulting in breast cancer. These hypotheses regarding oestrogen-induced apoptosis in the short term and carcinogenesis in the long term now require rigorous verification but would serve to explain the "oestrogen paradox".