Modelling the effect of temperature on the seasonal population dynamics of temperate mosquitoes.

Mosquito-borne diseases cause substantial mortality and morbidity worldwide. These impacts are widely predicted to increase as temperatures warm and extreme precipitation events become more frequent, since mosquito biology and disease ecology are strongly linked to environmental conditions. However, direct evidence linking environmental change to changes in mosquito-borne disease is rare, and the ecological mechanisms that may underpin such changes are poorly understood. Environmental drivers, such as temperature, can have non-linear, opposing impacts on the demographic rates of different mosquito life cycle stages. As such, model frameworks that can deal with fluctuations in temperature explicitly are required to predict seasonal mosquito abundance, on which the intensity and persistence of disease transmission under different environmental scenarios depends. We present a novel, temperature-dependent, delay-differential equation model, which incorporates diapause and the differential effects of temperature on the duration and mortality of each life stage and demonstrates the sensitivity of seasonal abundance patterns to inter- and intra-annual changes in temperature. Likely changes in seasonal abundance and exposure to mosquitoes under projected changes in UK temperatures are presented, showing an increase in peak vector abundance with warming that potentially increases the risk of disease outbreaks.

Effects of calcium intake on the cardiovascular system in postmenopausal women.

The use of calcium supplements for the prevention of complications of osteoporosis has significantly increased during the last years. The effects of calcium intake in postmenopausal women on cardiovascular parameters such as blood pressure, serum lipids and cardiovascular events are controversial. Even though transient beneficial effects of calcium supplementation have been reported, especially in women with low dietary calcium intake, their long-term outcomes are inconclusive. Only a very few studies investigating serum lipids in postmenopausal women have been described and these showed significant increases in high-density lipoprotein and high-density lipoprotein to low-density lipoprotein ratio. With regards to cardiovascular events in this population group adverse effects have been reported on the rates of myocardial infarction and stroke with increased calcium intake by some authors, however, others described no effects or even beneficial outcomes. We present a review of the current literature which provides a balanced summary of the possible beneficial and adverse effects of calcium intake in postmenopausal women on cardiovascular parameters. Taking into account the modest effect of calcium supplementation in reducing fracture rates, a reassessment of the role, benefits and adverse effects of calcium supplements should be conducted in postmenopausal women.

Evolution stabilises the synchronising dynamics of poikilotherm life cycles.

Temperature is the most significant factor controlling developmental timing of most temperate poikilotherms. In the face of climate change, a crucial question is how will poikilothermic organisms evolve when faced with changing thermal environments? In this paper, we integrate models for developmental timing and quantitative genetics. A simple model for determining developmental milestones (emergence times, egg hatch) is introduced, and the general quantitative genetic recursion for the mean value of developmental parameters presented. Evolutionary steps proportional to the difference between current median parameters and parameters currently selected for depend on the fitness, which is assumed to depend on emergence density. Asymptotic states of the joint model are determined, which turn out to be neutrally stable (marginal) fixed points in the developmental model by itself, and an associated stable emergence distribution is also described. An asymptotic convergence analysis is presented for idealized circumstances, indicating basic stability criteria. Numerical studies show that the stability analysis is quite conservative, with basins of attraction to the asymptotic states that are much larger than expected. It is shown that frequency-dependent selection drives oscillatory dynamics and that the asymptotic states balance the asymmetry of the emergence distribution and the fitness function.

Critical interplay between parasite differentiation, host immunity, and antigenic variation in trypanosome infections.

Increasing availability of pathogen genomic data offers new opportunities to understand the fundamental mechanisms of immune evasion and pathogen population dynamics during chronic infection. Motivated by the growing knowledge on the antigenic variation system of the sleeping sickness parasite, the African trypanosome, we introduce a mechanistic framework for modeling within-host infection dynamics. Our analysis focuses first on a single parasitemia peak and then on the dynamics of multiple peaks that rely on stochastic switching between groups of parasite variants. A major feature of trypanosome infections is the interaction between variant-specific host immunity and density-dependent parasite differentiation to transmission life stages. In this study, we investigate how the interplay between these two types of control depends on the modular structure of the parasite antigenic archive. Our model shows that the degree of synchronization in stochastic variant emergence determines the relative dominance of general over specific control within a single peak. A requirement for multiple-peak dynamics is a critical switch rate between blocks of antigenic variants, which implies constraints on variant surface glycoprotein (VSG) archive genetic diversification. Our study illustrates the importance of quantifying the links between parasite genetics and within-host dynamics and provides insights into the evolution of trypanosomes.

How parasitism affects critical patch-size in a host-parasitoid model: application to the forest tent caterpillar.

Habitat structure has broad impacts on many biological systems. In particular, habitat fragmentation can increase the probability of species extinction and on the other hand it can lead to population outbreaks in response to a decline in natural enemies. An extreme consequence of fragmentation is the isolation of small regions of suitable habitat surrounded by a large region of hostile matrix. This scenario can be interpreted as a critical patch-size problem, well studied in a continuous time framework, but relatively new to discrete time models. In this paper we present an integrodifference host-parasitoid model, discrete in time and continuous in space, to study how the critical habitat-size necessary for parasitoid survival changes in response to parasitoid life history traits, such as emergence time. We show that early emerging parasitoids may be able to persist in smaller habitats than late emerging species. The model predicts that these early emerging parasitoids lead to more severe host outbreaks. We hypothesise that promoting efficient late emerging parasitoids may be key in reducing outbreak severity, an approach requiring large continuous regions of suitable habitat. We parameterise the model for the host species of the forest tent caterpillar Malacosoma disstria Hbn., a pest insect for which fragmented landscape increases the severity of outbreaks. This host is known to have several parasitoids, due to paucity of data and as a first step in the modelling we consider a single generic parasitoid. The model findings are related to observations of the forest tent caterpillar offering insight into this host-parasitoid response to habitat structure.

Lipoprotein oxidation and its significance for atherosclerosis: a mathematical approach.

Atherosclerosis is a chronic disease which involves the build up of cholesterol and fatty deposits within the arterial wall. This results in the narrowing of the vessel lumen, which eventually restricts blood flow to vital organs such as the heart and lungs. These events may culminate in a heart attack or stroke, the commonest causes of death in the U.K. population. In this paper we study the early stages of atherosclerosis which include the build up of cholesterol within subendothelial cells to form what is known as a fatty streak, the earliest identifiable evidence of atherosclerosis. The deposition of cholesterol is believed to be a consequence of oxidation of circulating cholesterol-rich lipoproteins, in particular low density lipoproteins (LDLs). Via a mathematical model we investigate this process of oxidation within the context of an in vitro framework. We first recreate existing experimental results and then extend the model to investigate phenomenon not studied by current experimental protocols. We find that the model displays hysteresis which reveals some interesting insights into possible in vivo events. Mathematical analysis of this behaviour predicts that vitamin E supplementation is not as beneficial as high density lipoproteins (HDLs) and vitamin C. Furthermore, the scavenging of oxidants by HDL can provide an important first line of defence against LDL oxidation.

The role of nitric oxide in the formation of keloid and hypertrophic lesions.

Keloid and hypertrophic scars are a type of scarring pathology which is characterised by excess collagen deposition produced during the wound healing process. The mechanism by which this occurs is not understood and although hypertrophic scars can regress spontaneously, keloids do not, and currently no effective treatment exists. In this paper we hypothesise that nitric oxide, a free radical molecule synthesised by numerous mammalian cells, is involved in the formation of these scars. We suggest that the excess collagen production in keloid lesions can be attributed to higher than normal levels of nitric oxide, as the free radical is a known stimulus for fibroblast collagen synthesis. Furthermore, we propose that the basal epidermis is a source of this additional nitric oxide and we discuss this in relation to known histological characteristics of keloid and hypertrophic lesions.

A virally encoded chaperone specialized for folding of the major capsid protein of African swine fever virus.

It is generally believed that cellular chaperones facilitate the folding of virus capsid proteins, or that capsid proteins fold spontaneously. Here we show that p73, the major capsid protein of African swine fever virus (ASFV) failed to fold and aggregated when expressed alone in cells. This demonstrated that cellular chaperones were unable to aid the folding of p73 and suggested that ASFV may encode a chaperone. An 80-kDa protein encoded by ASFV, termed the capsid-associated protein (CAP) 80, bound to the newly synthesized capsid protein in infected cells. The 80-kDa protein was released following conformational maturation of p73 and dissociated before capsid assembly. Coexpression of the 80-kDa protein with p73 prevented aggregation and allowed the capsid protein to fold with kinetics identical to those seen in infected cells. CAP80 is, therefore, a virally encoded chaperone that facilitates capsid protein folding by masking domains exposed by the newly synthesized capsid protein, which are susceptible to aggregation, but cannot be accommodated by host chaperones. It is likely that these domains are ultimately buried when newly synthesized capsid proteins are added to the growing capsid shell.

Mathematical modelling of nitric oxide activity in wound healing can explain keloid and hypertrophic scarring.

Keloid and hypertrophic lesions are both types of scarring pathologies which arise as a consequence of excess collagen deposition during the wound healing process. The exact mechanism by which this occurs is not understood and currently no effective treatment exists. In this paper, we study the possible role of nitric oxide in excess scar formation. In recent years, the physiological role of this free radical in mammalian tissue has been extensively studied; in particular numerous groups have studied its role in wound healing. We describe a mathematical model which offers a possible explanation for keloid scarring in terms of the presence of higher than normal nitric oxide concentrations related to the fact that nitric oxide stimulates synthesis of collagen by fibroblasts. As a consequence of this, we put forward a suggestion for a treatment strategy involving the surgical excision of the keloid lesion combined with the application of a low-dose nitric oxide inhibitor. In addition, we show that a quasi-steady-state analysis of our model reveals a possible approach to distinguishing between hypertrophic and keloid lesions, a task which has to date proven to be clinically difficult. We also present an extended model which confirms these results in the context of a more complicated and biologically more realistic system. The fuller model demonstrates additional features of keloid and hypertrophic scarring which we were not able to consider in the basic model, and as a consequence further supports our hypothesis that nitric oxide activity could play a key role in keloid scarring.

Biochemical requirements of virus wrapping by the endoplasmic reticulum: involvement of ATP and endoplasmic reticulum calcium store during envelopment of African swine fever virus.

Enwrapment by membrane cisternae has emerged recently as a mechanism of envelopment for large enveloped DNA viruses, such as herpesviruses, poxviruses, and African swine fever (ASF) virus. For both ASF virus and the poxviruses, wrapping is a multistage process initiated by the recruitment of capsid proteins onto membrane cisternae of the endoplasmic reticulum (ER) or associated ER-Golgi intermediate membrane compartments. Capsid assembly induces progressive bending of membrane cisternae into the characteristic shape of viral particles, and envelopment provides virions with two membranes in one step. We have used biochemical assays for ASF virus capsid recruitment, assembly, and envelopment to define the cellular processes important for the enwrapment of viruses by membrane cisternae. Capsid assembly on the ER membrane, and envelopment by ER cisternae, were inhibited when cells were depleted of ATP or depleted of calcium by incubation with A23187 and EDTA or the ER calcium ATPase inhibitor, thapsigargin. Electron microscopy analysis showed that cells depleted of calcium were unable to assemble icosahedral particles. Instead, assembly sites contained crescent-shaped and bulbous structures and, in rare cases, empty closed five-sided particles. Interestingly, recruitment of the capsid protein from the cytosol onto the ER membrane did not require ATP or an intact ER calcium store. The results show that following recruitment of the virus capsid protein onto the ER membrane, subsequent stages of capsid assembly and enwrapment are dependent on ATP and are regulated by the calcium gradients present across the ER membrane cisternae.

The major structural protein of African swine fever virus, p73, is packaged into large structures, indicative of viral capsid or matrix precursors, on the endoplasmic reticulum.

African swine fever virus (ASFV) is a large enveloped DNA virus that shares the striking icosahedral symmetry of iridoviruses. To understand the mechanism of assembly of ASFV, we have been studying the biosynthesis and subcellular distribution of p73, the major structural protein of ASFV. Sucrose density sedimentation of lysates prepared from infected cells showed that newly synthesized p73 was incorporated into a complex with a size of 150 to 250 kDa. p73 synthesized by in vitro translation migrated at 70 kDa, suggesting that cellular and/or viral proteins are required for the formation of the 150- to 250-kDa complex. During a 2-h chase, approximately 50% of the newly synthesized pool of p73 bound to the endoplasmic reticulum (ER). During this period, the membrane-bound pool of p73, but not the cytosolic pool, formed large complexes of approximately 50,000 kDa. The complexes were formed via assembly intermediates, and the entire membrane-associated pool of p73 was incorporated into the 50,000-kDa complex within 2 h. The 50,000-kDa complexes containing p73 were also detected in virions secreted from cells. Immunoprecipitation of sucrose gradients with sera taken from hyperimmune pigs suggested that p73 was the major component of the 50,000-kDa complex. It is possible, therefore, that the complex contains between 600 and 700 copies of p73. The kinetics of complex formation and envelopment of p73 were similar, and complex formation and envelopment were both reversibly inhibited by cycloheximide, suggesting a functional link between complex assembly and ASFV envelopment. A protease protection assay detected 50,000-kDa complexes on the inside and outside of the membranes forming the viral envelope. The identification of a complex containing p73 beneath the envelope of ASFV suggests that p73 may be a component of the inner core shell or matrix of ASFV. The outer pool may represent p73 within the outer capsid layer of the virus. In summary, the data suggest that the assembly of the inner core matrix and outer capsid of ASFV takes place on the ER membrane during envelopment and that these structures are not preassembled in the cytosol.

Involvement of the endoplasmic reticulum in the assembly and envelopment of African swine fever virus.

African swine fever (ASF) virus is a large enveloped DNA virus assembled in the cytoplasm of cells. In this study, the membrane compartments involved in the envelopment of ASF virus were investigated. A monoclonal antibody recognizing p73, the major structural protein of ASF virus, was generated to analyze the binding of p73 to membranes during the assembly of the virus. Approximately 50% of the intracellular pool of p73 associated with membranes as a peripheral membrane protein. Binding was rapid and complete within 15 min of synthesis. Subcellular membrane fractionation showed that newly synthesized p73 molecules cosedimented with endoplasmic reticulum (ER) membranes and remained associated with the ER during a 2-h chase. A similar distribution on gradients was recorded for p17, a structural membrane protein of ASF virus. The results suggested that the ER was involved in the assembly of ASF virus. A protease protection assay demonstrated a time-dependent envelopment of the membrane bound, but not cytosolic, pool of p73. Envelopment of p73 took place 1 h after binding to membranes and was completed 1 h before the first detection of p73 in virions secreted from cells. Envelopment was unaffected by brefeldin A and monensin, drugs that block membrane transport between the ER and Golgi. Taken together the results provide evidence for the binding of ASF virus structural proteins to a specific membrane compartment and implicate a role for the ER in the assembly and envelopment of ASF virus.