Robust Control of Evolutionary Dynamics

The application of principles from evolutionary biology has long been used to gain new insights into the progression and clinical control of both infectious diseases and neoplasms. This iterative evolutionary process consists of expansion, diversification and selection within an adaptive landscape - species are subject to random genetic or epigenetic alterations that result in variations; genetic information is inherited through asexual reproduction and strong selective pressures such as therapeutic intervention can lead to the adaptation and expansion of resistant variants. These principles lie at the center of modern evolutionary synthesis and constitute the primary reasons for the development of resistance and therapeutic failure, but also provide a framework that allows for more effective control.

A model system for studying the evolution of resistance and control of therapeutic failure is the treatment of chronic HIV-1 infection by broadly neutralizing antibody (bNAb) therapy. A relatively recent discovery is that a minority of HIV-infected individuals can produce broadly neutralizing antibodies, that is, antibodies that inhibit infection by many strains of HIV. Passive transfer of human antibodies for the prevention and treatment of HIV-1 infection is increasingly being considered as an alternative to a conventional vaccine. However, recent evolution studies have uncovered that antibody treatment can exert selective pressure on virus that results in the rapid evolution of resistance. In certain cases, complete resistance to an antibody is conferred with a single amino acid substitution on the viral envelope of HIV.

The challenges in uncovering resistance mechanisms and designing effective combination strategies to control evolutionary processes and prevent therapeutic failure apply more broadly. We are motivated by two questions: Can we predict the evolution to resistance by characterizing genetic alterations that contribute to modified phenotypic fitness? Given an evolutionary landscape and a set of candidate therapies, can we computationally synthesize treatment strategies that control evolution to resistance?

To address the first question, we propose a mathematical framework to reason about evolutionary dynamics of HIV from computationally derived Gibbs energy fitness landscapes -- expanding the theoretical concept of an evolutionary landscape originally conceived by Sewall Wright to a computable, quantifiable, multidimensional, structurally defined fitness surface upon which to study complex HIV evolutionary outcomes.

To design combination treatment strategies that control evolution to resistance, we propose a methodology that solves for optimal combinations and concentrations of candidate therapies, and allows for the ability to quantifiably explore tradeoffs in treatment design, such as limiting the number of candidate therapies in the combination, dosage constraints and robustness to error. Our algorithm is based on the application of recent results in optimal control to an HIV evolutionary dynamics model and is constructed from experimentally derived antibody resistant phenotypes and their single antibody pharmacodynamics. This method represents a first step towards integrating principled engineering techniques with an experimentally based mathematical model in the rational design of combination treatment strategies and offers predictive understanding of the effects of combination therapies of evolutionary dynamics and resistance of HIV. Preliminary in vitro studies suggest that the combination antibody therapies predicted by our algorithm can neutralize heterogeneous viral populations despite containing resistant mutations.

The fish populations of the River Avon, Hampshire, downstream of Salisbury, in 1987

The objective of this study is to describe the present statu s of the coarse fish populations of the River Avon, Hampshire. The study arose from a widespread concern among anglers and riparian owners that fish numbers had decreased since the early 1970's, and from a scarcity of accurate information on population densities on which to assess this complaint. It was realised at the outset that, without such information from earlier years, the survey would not reveal the extent of any decline in the fisheries. The result s of the survey are compared with available data from other rivers , chiefly the nearby R. Frome and R. Stour. They may be used to assess any futur e changes in population densities and growth rates, and to indicate promising areas for future research. The data were collected from a quantitative survey of twelve river sections along the fifty kilometres of river between Salisbury and Sopley, and a qualitative survey of three weir pools within the same area from 14 September to 9 October, 1987.

Clonación, expresión y purificación de la proteína estructural VP4 de la cápside del Virus del triatoma (TrV; Dicistroviridae: Cripaviridae)

Triatoma virus (TrV) es un virus patógeno de Triatoma infestans y otros insectos hematófagos , que son los vectores principales de la enfermedad del Chagas (tripanosomiasis americana) . Esta enfermedad es un grave problema sanitario en muchos países de Latinoamérica , do nde es endé mic a y afecta alrededor de 8 millones de personas. El agente causante de dicha enfermedad es el protozoo parásito Tripanosoma cruzi , que infecta al insecto vector y este a su vez , infecta hospedadores vertebrados cuando se alimenta de su sangre [Rassi et al ., 2010] . Al aumentar el movimiento migracional de las personas , la enfermedad ha logrado exte nde rse a otras regiones y convertirse en un problema de salud en z o nas originariamen te no endémicas [ Gascon et a l ., 2010 ] . Debido a esto se ha propuesto el uso de TrV como agente de control biológico frente a los vectores de la enfermedad del Chagas

Estrategia para bloquear la entrada del virus de la Hepatitis C (HCV) en hepatocitos primarios

En esta memoria se presenta una propuesta para desarrollar un proyecto de investigación que permita establecer la eficacia de una estrategia original para evitar la entrada del virus de la hepatitis C (HCV) en las células hepáticas. Se propone la utilización combinada de dos anticuerpos contra dos factores esenciales para la entrada HCV en las células hepáticas, como son las moléculas CD81 y SR-BI. La eficacia para reducir la capacidad infectiva del HCV de bloquear individualmente cada una de estas moléculas ha sido previamente demostrada, así que en este proyecto proponemos que un uso combinado de moléculas que bloqueen ambos receptores permitiría avanzar en la búsqueda de vacunas que eviten eficazmente la infección del HCV.

Variation in bacterial populations in time and space

Obtaining a reliable estimate of the bacterial population is one of the main problems facing the bacterial ecologist. The author discusses the various methods available and concludes that the observed variability in bacterial populations depends on the sampling interval used.

The impact of Cow Green Reservoir on invertebrate populations in the River Tees

Cow Green is a new reservoir situated in Pennine moorland. It has an area of 312 ha, a capacity of 40 . 9 x 10 SUP-6 m SUP-3 and a maximum depth of 22 . 8 m. The function of the reservoir is to regulate flow in the River Tees to provide industrial Teesside with sufficient water during the dry spells. Invertebrate studies were carried out in the Tees to monitor changes resulting from the construction of the reservoir both in the flooded basin and below the dam. The overall effect of the reservoir on the Tees has been to increase the numbers and biomass of certain taxa, but generally not at the expense of previous fauna. Some of the positive effects, ie. increase in number and biomass, and maintenance of faunal diversity, may in part be attributable to the presence of the rapids and waterfall. Turbulence resulting from this rapid flow over heterogeneous bottom is sufficient to prevent clogging of interstitial spaces by silt and to maintain the variety of ecological niches necessary for a diverse fauna.

Effects of Cow Green Reservoir upon downstream fish populations

Post impoundment observations on the fish populations of the River Tees, downstream from the Cow Green Reservoir were made between 1971 and 1980. Both bullhead (Cottus gobio L.) and brown trout (Salmo trutta L.) population densities increased in the river after impoundment but changes in growth rate were small. Investigations into the stomach contents of the two species reflects the results of other work on increases of benthos in the river. Following regulation there was an increase in the quantity of Ephemerella ignita found in trout stomachs while in the bullhead, regulation caused an increase in the importance of Mollusca and a decrease in importance of Ephemeroptera and Plecoptera.

Undertreatment of human immunodeficiency virus in psychiatric inpatients: a cross-sectional study of seroprevalence and associated factors

Background: The aims of this study were to evaluate the prevalence of HIV and its associated demographic and clinical factors among psychiatric inpatients of a general hospital. Methods: This was a single-center, observational, cross-sectional study that included patients consecutively admitted to our unit aged 16 years or older and with no relevant cognitive problems. The patients were evaluated using a semistructured interview and an appropriate test for HIV infection. Results: Of the 637 patients who were screened, 546 (86%) who consented to participate were included in the analyses. Twenty-five (4.6%, 95% confidence interval [CI] 3.0-6.8) patients were HIV-positive. The prevalence was higher among patients with substance misuse (17.4%, 95% CI 9.7-28.8). All except one of the 25 patients knew of their seropositive condition prior to participation in the study. Only 14 (56%) of the 25 seropositive patients had previously received pharmacological treatment for their infection. According to the multiple logistic regression analysis, the likelihood of HIV infection was lower in patients with higher levels of education and higher among patients who were single, had history of intravenous drug use, and had an HIV-positive partner, particularly if they did not use condoms. Among the patients with HIV infection, 18 (72%) had a history of suicide attempts compared with 181 (34.7%) of the patients without HIV infection (relative risk 2.1, 95% CI 1.6-2.7; P<0.001). Conclusion: HIV infection is highly prevalent in patients admitted to a psychiatric unit, especially those with a diagnosis of substance misuse. Seropositive patients show very poor treatment adherence. The risk of suicide seems to be very high in this population. Implementing interventions to reduce the suicide risk and improve adherence to antiretroviral therapy and psychotropic medications seems crucial.

Modelling Lipid Competition Dynamics in Heterogeneous Protocell Populations

Recent experimental work in the field of synthetic protocell biology has shown that prebiotic vesicles are able to 'steal' lipids from each other. This phenomenon is driven purely by asymmetries in the physical state or composition of the vesicle membranes, and, when lipid resource is limited, translates directly into competition amongst the vesicles. Such a scenario is interesting from an origins of life perspective because a rudimentary form of cell-level selection emerges. To sharpen intuition about possible mechanisms underlying this behaviour, experimental work must be complemented with theoretical modelling. The aim of this paper is to provide a coarse-grain mathematical model of protocell lipid competition. Our model is capable of reproducing, often quantitatively, results from core experimental papers that reported distinct types vesicle competition. Additionally, we make some predictions untested in the lab, and develop a general numerical method for quickly solving the equilibrium point of a model vesicle population.

White spot syndrome virus (WSSV) transmission risk through infected cooked shrimp products assessed by polymerase chain reaction (PCR) and bio-inoculation studies

The aim of the study was to evaluate the resistance of white spot syndrome virus (WSSV) in shrimps (Penaeus monodon) to the process of cooking. The cooking was carried out at 1000C six different durations 5, 10, 15, 20, 25 and 30 min. The presence of WSSV was tested by single step and nested polymerase chain reaction (PCR). In the single step PCR, the primers 1s5 & 1a16 and IK1 & IK2 were used. While in the nested PCR, primers IK1 &IK2 – IK3 & IK4 were used for the detection of WSSV. WSSV was detected in the single step PCR with the primers 1s5 and 1a16 and the nested PCR with the primers IK1 and IK2 – IK3 & IK4 from the cooked shrimp samples. The cooked shrimps, which gave positive results for WSSV by PCR, were further confirmed for the viability of WSSV by conducting the bio-inoculation studies. Mortality (100%) was observed within 123 h of intra-muscular post injection (P.I) into the live healthy WSSV-free shrimps (P. monodon). These results show that the WSSV survive the cooking process and even infected cooked shrimp products may pose a transmission risk for WSSV to the native shrimp farming systems.

The juvenile salmonid populations of the River Lune catchment, 1981 to 1985

The aim of this study was to assess the status of the juvenile salmonid populations of the River Lune and its tributaries. There was special emphasis on juvenile salmon stocks in view of the implementation of a net limitation order in 1980. The number of licensed instruments were reduced as follows: (1) Drift, hang or whammel nets - from 12 to 10 (2) Draft or seine nets - from 3 to 1 (3) Heave or haaf nets - from 4 6 to 2 6 For the purpose of this report, the River Lune system has been divided into 13 subcatchments and these are examined with a view to detecting any trends in the data such as subcatchment productivity, partitioning between salmon and trout nursery streams, and whether the restrictions on salmon fishing had any discernible effects on juvenile salmon productivity. The effect of flow and instream obstructions on salmonid densities are also investigated as these have been shown to be important factors affecting abundance. Throughout the study period a programme of enhancement stocking took place primarily with salmon ova and fry. The possible impact of this on the results of the surveys has been assessed. The distribution and abundance of juvenile salmon was found to be relatively consistent in each of the 13 subcatchments studied over the 1981-1985 period.

A summary report on juvenile salmonid populations of the River Lune catchment, 1981 to 1991

This report summarises the fisheries electrofishing survey work undertaken on the River Lune, England, in the period 1981-85 and 1991. As part of a long term monitoring programme by the National Rivers Authority, juvenile surveys, with the emphasis on salmonids, have been carried out on the River Lune on a number of occasions since 1981. The latest survey in 1991 now gives the opportunity to assess what, if any, changes have occurred in the juvenile populations across the last 11 years and how future fisheries management may impact on the River Lune as a fishery. The areas of trout and salmon, fry and parr production will be considered in detail, as will adult trout populations. Water quality issues will be mentioned briefly as will habitat issues, where they are deemed to be important in affecting fish densities.

Simulation stochastique des structures démographiques. Application aux populations d'albacores, Thunnus albacares

A computer program has been written in order to generate a population of fishes following a Von Bertalanffy growth curve with a random Gaussian variability for birth dates and growth parameters K and L ∞. Standard deviations for these 3 parameters are chosen separately for each run. Fishing and natural mortalities are applied to this population. Using as an input parameters usually taken for yellowfin in the eastern Atlantic, the simulation suggests a standard deviation between 1 and 2 months for the birth dates in this population. It also indicates that increasing levels of fishing mortalities must produce a better agreement between age and length for the larger fish.

Note sur l'évolution des populations de Copépodes pélagiques de l'upwelling mauritanien (mars-avril 1972)

The evolution of a plankton copepod population in the Mauritania upwelling was studied by following a drogue for 9 days, from the point of upwelling till the water-mass dives under offshore waters. The Shannon index of specific diversity and the tropic structure allow separation into several stages in the studied succession. The upwelling brings near the shore a rather poor, highly diverse fauna, with a low filter-feeder rate. The phytoplanktonic development induces an increase in the copepod number. The filter-feeders become dominant and the diversity decreases. When the increase of copepod number stops, the diversity decreases and the omnivore and carnivore rate increases.

Genetic differentiation between Atlantic salmon populations in the Windermere catchment

Genetic analysis, using single locus probes for genomic DNA, revealed that the juvenile Atlantic salmon populations in the Rivers Leven, Rothay and Troutbeck were related but genetically distinct. This genetic differentiation is greater than might be expected (by comparison with other salmon populations in the UK) and it is recommended that no action is taken which might promote genetic exchange between the three rivers. Thus, future fisheries management practices should treat the salmon from each site as separate genetic stocks. It is unlikely that any attempts to encourage fish currently spawning in the River Leven (downstream of Windermere) to utilize the upper catchment will be successful. The faster growth rate of juvenile salmon in the River Leven, compared with the River Rothay, probably results from a difference in temperature between the inflowing streams and the main outflow of Windermere. Precocious sexual maturation of some male parr was found in all three populations but the incidence (13-33%) is well within the range reported for other waters. Because of their enhanced growth rate, it is likely that some of the precocious males in the River Leven were 0+ fish. A very high incidence of hybridization (>18%) between Atlantic salmon and brown/sea trout was found in Troutbeck but not in the other rivers. Mitochondrial DNA analysis of these hybrids revealed them to be the product of several, independent cross-fertilizations involving both sexes of both species. The implications of this finding are discussed in relation to the availability of suitable spawning sites in Troutbeck.