Chronic SSRI Treatment, but Not Norepinephrine Reuptake Inhibitor Treatment, Increases Neurogenesis in Juvenile Rats.

There has been growing recognition that major depressive disorder is a serious medical disorder that also affects children. This has been accompanied by an increased use of antidepressant drugs in adolescents; however, not all classes of antidepressants are effective in children and adolescents. There is an increasing need to understand the differences in antidepressant action in different developmental stages. There are some data indicating that the behavioral effect of chronic antidepressant treatment in adult rodents is dependent on hippocampal neurogenesis; however, it is not known which classes of antidepressant drugs induce hippocampal neurogenesis in adolescent rodents. Three classes of antidepressant drugs were tested in two age groups of Sprague Dawley rats, pre-adolescent (postnatal days 11-24) and adolescent (postnatal days 21-34): monoamine oxidase inhibitors (MAOIs); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); and tricyclic antidepressants (TCAs). To address which classes of antidepressant drugs might alter the rate of mitogenesis in neural progenitor cells in an adolescent rodent model, adolescent Sprague Dawley rats were treated with the thymidine analog 5-bromo-deoxy-2'-uridine (BrdU) on postnatal days 21 and 22 and antidepressant drugs or vehicle for 14 days (postnatal days 21-34). To address which classes of antidepressant drugs might alter the rate of neurogenesis, postnatal day-21 Sprague Dawley rats were treated with antidepressant drugs or vehicle for 14 days (postnatal days 21-34) and BrdU on postnatal days 33 and 34. In both experimental paradigms, BrdU-positive cells in the subgranular zone and the granule cell layer were counted. Newborn neurons were identified in the neurogenic paradigm by identifying cells expressing both the neuronal specific marker NeuN and BrdU using confocal microscopy. Only the SSRI fluoxetine significantly altered the basal mitogenic and neurogenic rates in adolescent rats. Treatment with the monoamine oxidase inhibitor (MAOI) tranylcypromine (TCP) and the TCA desipramine did not alter the rate of hippocampal neurogenesis in the adolescent rats. This is consistent with human clinical observations, where only SSRIs have efficacy for treatment of depression in patients under the age of 18. In pre-adolescent rats, postnatal days 11-24, none of the drugs tested significantly altered the basal mitogenic or neurogenic rates. All of the classes of antidepressant drugs are known to induce hippocampal neurogenesis in adult rats. The mechanisms of action underlying this developmental difference in antidepressant drug action between juveniles and adults are not known.

Phenotypic plasticity as a cause and consequence of population dynamics.

Predicting complex species-environment interactions is crucial for guiding conservation and mitigation strategies in a dynamically changing world. Phenotypic plasticity is a mechanism of trait variation that determines how individuals and populations adapt to changing and novel environments. For individuals, the effects of phenotypic plasticity can be quantified by measuring environment-trait relationships, but it is often difficult to predict how phenotypic plasticity affects populations. The assumption that environment-trait relationships validated for individuals indicate how populations respond to environmental change is commonly made without sufficient justification. Here we derive a novel general mathematical framework linking trait variation due to phenotypic plasticity to population dynamics. Applying the framework to the classical example of Nicholson's blowflies, we show how seemingly sensible predictions made from environment-trait relationships do not generalise to population responses. As a consequence, trait-based analyses that do not incorporate population feedbacks risk mischaracterising the effect of environmental change on populations.

A process-based, stage-structured model of potato cyst nematode population dynamics: Effects of temperature and resistance.

Potato cyst nematodes (PCN) are responsible for large losses in potato yields in many of the world's potato-growing regions. As soil temperatures increase due to climate change, there is potential for faster growth rates of PCN, allowing development of multiple generations in a growing season. We develop a process-based temperature-dependent model representing the life cycle of Globodera pallida, comprising juvenile, adult and cyst/diapause stages. To incorporate variability in the amount of time spent in each stage caused by genetic/environmental variation, the model is based on a mix of ordinary differential equations (ODEs) with sub-stages, and delay differential equations (DDEs). The effect of climate change is incorporated through the influence of soil temperature on the rate of development and survival in the hatching and juvenile stages. The level of the plant resistance to PCN is incorporated via the proportion of juveniles which become adults. After comparing the model with field data we run simulations to explore the effects of temperature and resistance on PCN populations. We find that with higher temperatures and longer growing seasons multiple generations of PCN can develop within a season, provided any required diapause period is short. Despite this, we show that growing resistant potatoes is a very effective control strategy and planting potatoes with even moderate levels of resistance can counter the effects of climate change.

Defining the molecular evolution of extrauterine high grade serous carcinoma.

OBJECTIVE: High grade serous carcinoma (HGSC) is the most common and most aggressive, subtype of epithelial ovarian cancer. It presents as advanced stage disease with poor prognosis. Recent pathological evidence strongly suggests HGSC arises from the fallopian tube via the precursor lesion; serous tubal intraepithelial carcinoma (STIC). However, further definition of the molecular evolution of HGSC has major implications for both clinical management and research. This study aims to more clearly define the molecular pathogenesis of HGSC. METHODS: Six cases of HGSC were identified at the Northern Ireland Gynaecological Cancer Centre (NIGCC) that each contained ovarian HGSC (HGSC), omental HGSC (OMT), STIC, normal fallopian tube epithelium (FTE) and normal ovarian surface epithelium (OSE). The relevant formalin-fixed paraffin embedded (FFPE) tissue samples were retrieved from the pathology archive via the Northern Ireland Biobank following attaining ethical approval (NIB11:005). Full microarray-based gene expression profiling was performed on the cohort. The resulting data was analysed bioinformatically and the results were validated in a HGSC-specific in-vitro model. RESULTS: The carcinogenesis of HGSC was investigated and showed the molecular profile of HGSC to be more closely related to normal FTE than OSE. STIC lesions also clustered closely with HGSC, indicating a common molecular origin. CONCLUSION: This study provides strong evidence suggesting that extrauterine HGSC arises from the fimbria of the distal fallopian tube. Furthermore, several potential pathways were identified which could be targeted by novel therapies for HGSC. These findings have significant translational relevance for both primary prevention and clinical management of the disease.

Role of vector phenotypic plasticity in disease transmission as illustrated by the spread of dengue virus by Aedes albopictus.

The incidence of vector-borne disease is on the rise globally, with burdens increasing in endemic countries and outbreaks occurring in new locations. Effective mitigation and intervention strategies require models that accurately predict both spatial and temporal changes in disease dynamics, but this remains challenging due to the complex and interactive relationships between environmental variation and the vector traits that govern the transmission of vector-borne diseases. Predictions of disease risk in the literature typically assume that vector traits vary instantaneously and independently of population density, and therefore do not capture the delayed response of these same traits to past biotic and abiotic environments. We argue here that to produce accurate predictions of disease risk it is necessary to account for environmentally driven and delayed instances of phenotypic plasticity. To show this, we develop a stage and phenotypically structured model for the invasive mosquito vector, Aedes albopictus, and dengue, the second most prevalent human vector-borne disease worldwide. We find that environmental variation drives a dynamic phenotypic structure in the mosquito population, which accurately predicts global patterns of mosquito trait-abundance dynamics. In turn, this interacts with disease transmission to capture historic dengue outbreaks. By comparing the model to a suite of simpler models, we reveal that it is the delayed phenotypic structure that is critical for accurate prediction. Consequently, the incorporation of vector trait relationships into transmission models is critical to improvement of early warning systems that inform mitigation and control strategies.

The Immune Response in the Uteri and Placentae of Chlamydia abortus-Infected Ewes and Its Association with Pregnancy Outcomes.

The enzootic abortion of ewes, caused by the bacterium Chlamydia abortus (C. abortus), is one of the main causes of abortion in sheep. There are multiple contributory factors, including chlamydial growth, host immune response, and hormonal balance, that result in different pregnancy outcomes, such as abortion, the birth of weak lambs that may die, or healthy lambs. This study aimed to determine the relationship between phenotypical patterns of immune cell infiltration and different pregnancy outcomes in twin-bearing sheep (both lambs born dead; one alive and one dead; both alive) when experimentally infected with C. abortus. Both the sheep uteri and placentae were collected after parturition. All samples were analysed for specific immune cell features, including cell surface antigens and the T-regulatory (Treg) cell-associated transcription factor and cytokines, by immunohistochemistry and in situ hybridisation. Some of these immunological antigens were evaluated in ovine reproductive tissues for the first time. Differential patterns of T helper/Treg cells revealed significant group effects in the placentae. It suggests the potential role that the balance of lymphocyte subsets may play in affecting different pregnancy outcomes in C. abortus-infected sheep. The present study provides novel detailed information about the immune responses observed at the maternofoetal interface in sheep at the time of pre-term abortion or lambing.

Efficacy of Phase I and Phase II Coxiella burnetii Bacterin Vaccines in a Pregnant Ewe Challenge Model.

The bacterium Coxiella burnetii can cause the disease Q-fever in a wide range of animal hosts. Ruminants, including sheep, are thought to play a pivotal role in the transmission of C. burnetii to humans; however, the only existing livestock vaccine, namely, Coxevac® (Ceva Animal Health Ltd., Libourne, France), a killed bacterin vaccine based on phase I C. burnetii strain Nine-Mile, is only approved for use in goats and cattle. In this study, a pregnant ewe challenge model was used to determine the protective effects of Coxevac® and an experimental bacterin vaccine based on phase II C. burnetii against C. burnetii challenge. Prior to mating, ewes (n = 20 per group) were vaccinated subcutaneously with either Coxevac®, the phase II vaccine, or were unvaccinated. A subset of pregnant ewes (n = 6) from each group was then challenged 151 days later (~100 days of gestation) with 106 infectious mouse doses of C. burnetii, Nine-Mile strain RSA493. Both vaccines provided protection against C. burnetii challenge as measured by reductions in bacterial shedding in faeces, milk and vaginal mucus, and reduced abnormal pregnancies, compared to unvaccinated controls. This work highlights that the phase I vaccine Coxevac® can protect ewes against C. burnetii infection. Furthermore, the phase II vaccine provided comparable levels of protection and may offer a safer and cost-effective alternative to the currently licensed vaccine.

Efficacy of high-throughput transthoracic ultrasonographic screening for on-farm detection of ovine pulmonary adenocarcinoma.

BACKGROUND: The aim of this study was to evaluate the efficacy of high-throughput on-farm transthoracic ultrasound (TUS) to screen for ovine pulmonary adenocarcinoma (OPA), an infectious ovine disease of increasing concern. No other routine diagnosis of preclinical OPA is available, or any vaccine or treatment. METHODS: More than 80,000 rapid TUS scans were applied on farms with a history of OPA. The TUS results from a convenience sample of 171 TUS-negative and 269 TUS-positive sheep were compared with postmortem histology/immunohistochemistry results, the 'gold standard' reference test for OPA diagnosis. These results, together with new data on within-flock prevalence, allowed estimation of the efficacy of rapid TUS screening to identify OPA (defined as tumours of larger than 1 cm) on-farm. RESULTS: The TUS screening had an estimated specificity of 0.998 (95% confidence interval [CI]: 0.998-0.999) and an estimated sensitivity of between 0.76 (95% CI: 0.72-0.79) and 0.99 (95% CI: 0.97-0.99) depending on the presumed false-negative rate applied to the calculation. CONCLUSION: High-throughput TUS should be considered for screening to identify individual sheep with OPA and has potential application to indicate flocks at low risk of OPA. However, lower efficacy is likely if conducted by less experienced persons.

Exact Bayesian inference of epidemiological parameters from mortality data: application to African swine fever virus.

Pathogens such as African swine fever virus (ASFV) are an increasing threat to global livestock production with implications for economic well-being and food security. Quantification of epidemiological parameters, such as transmission rates and latent and infectious periods, is critical to inform efficient disease control. Parameter estimation for livestock disease systems is often reliant upon transmission experiments, which provide valuable insights in the epidemiology of disease but which may also be unrepresentative of at-risk populations and incur economic and animal welfare costs. Routinely collected mortality data are a potential source of readily available and representative information regarding disease transmission early in outbreaks. We develop methodology to conduct exact Bayesian parameter inference from mortality data using reversible jump Markov chain Monte Carlo incorporating multiple routes of transmission (e.g. within-farm secondary and background transmission from external sources). We use this methodology to infer epidemiological parameters for ASFV using data from outbreaks on nine farms in the Russian Federation. This approach improves inference on transmission rates in comparison with previous methods based on approximate Bayesian computation, allows better estimation of time of introduction and could readily be applied to other outbreaks or pathogens.

Patterns of mortality in domesticated ruminants in Ethiopia.

Background: Premature death of livestock is a problem in all ruminant production systems. While the number of premature ruminant deaths in a country is a reasonable indicator for the nation's health, few data sources exist in a country like Ethiopia that can be used to generate valid estimates. The present study aimed to establish if three different data sets, each with imperfect information on ruminant mortality, including abortions, could be combined into improved estimates of nationwide mortality in Ethiopia. Methods: We combined information from a recent survey of ruminant mortality with information from the Living Standards Measurement Study and the Disease Outbreak and Vaccination Reporting dataset. Generalized linear mixed and hurdle models were used for data analysis, with results summarized using predicted outcomes. Results: Analyses indicated that most herds experienced zero mortality and reproductive losses, with rare occasions of larger losses. Diseases causing deaths varied greatly both geographically and over time. There was little agreement between the different datasets. While the models aid the understanding of patterns of mortality and reproductive losses, the degree of variation observed limited the predictive scope. Conclusions: The models revealed some insight into why mortality rates are variable over time and are therefore less useful in measuring production or health status, and it is suggested that alternative measures of productivity, such as number of offspring raised to 1 year old per dam, would be more stable over time and likely more indicative.

Happy or healthy? How members of the public prioritise farm animal health and natural behaviours.

The importance given to minimising health issues and promoting natural behaviours is a polarising issue within farm animal welfare. It is predominantly thought that members of the public prioritise animals being able to behave naturally over other aspects of farm animal welfare, such as addressing health issues. However, public perspectives may be more multi-dimensional than is generally thought, with the importance given to these different elements of welfare dependent on the situation and state of the animals in question. To examine this, a factorial survey using vignettes, which experimentally manipulated the different levels of health (high health vs. low health) and natural behaviour provision (high behaviour vs. low behaviour), was completed by a sample (n = 810) representative of the UK population (on age, gender, ethnicity). Contrary to the predominant view, this study found animal health had the greatest effect on participants' judgements, explaining more of the variance in their assessments of animal welfare than any other factor. However, findings also indicated that participants considered animal welfare to be most positive when both health issues are minimised and natural behaviours are promoted. Attitudes to natural behaviours also varied more between participants, with females, individuals who do not (regularly) eat meat and those with a greater belief in animal mind giving greater priority to natural behaviours. In the context of public and private welfare standards seeking to meet public expectations, this study provides important insights into how public perspectives of animal welfare are more nuanced than previously thought, influenced by the context of the animal, the aspect of welfare in question and personal characteristics.

Intramammary Immunisation Provides Short Term Protection Against Mannheimia haemolytica Mastitis in Sheep.

Mastitis affects both dairy and meat/wool sheep industries with losses due to reductions in milk quality and quantity, increased treatment costs and restricted lamb growth. Effective vaccines would be important tools for mastitis control. However, the development of vaccines against mastitis has proved challenging due to the failure to target protective immunity to the mammary gland. In order to target responses to the mammary gland, this study tested whether local administration directly into the gland through the teat canal or in the udder skin confers protection against an intramammary infection. In this study, we tested a vaccine that confers protection against respiratory disease caused by Mannheimia haemolytica to determine if it also protects against intramammary infection by the same organism. No evidence of protection was observed in animals that received a subcutaneous immunisation in the udder skin, however, intramammary immunisation provided almost complete protection against an experimental challenge administered 7 days post immunisation but not if the challenge was delivered 14 days post immunisation. To investigate further the nature of this variation in response, the somatic cell count and concentration of cytokines Interleukin-1ß, Interleukin-10 and Interleukin-17A was determined in milk over the course of each study. Intramammary immunisation induced an inflammatory response within the mammary gland, characterised by increases in SCC and in the production of cytokines IL-1ß, IL-10, and IL-17A. This response was similar to that observed in un-vaccinated control animals post challenge. The SCC and cytokine levels had returned to levels comparable with un-vaccinated controls prior to challenge at both 7 and 14 days post immunisation. The transient nature of the protective effect is consistent with the priming of an innate antibacterial response within the mammary gland which provides protection against challenge at 7 days but is diminished by 14 days post-vaccination. Further studies are planned to determine the nature of the innate immune mechanisms associated with the protective effect described here to determine whether it may be exploited to improve ruminant udder health.

A novel approach for predicting risk of vector-borne disease establishment in marginal temperate environments under climate change: West Nile virus in the UK.

Vector-borne diseases (VBDs), such as dengue, Zika, West Nile virus (WNV) and tick-borne encephalitis, account for substantial human morbidity worldwide and have expanded their range into temperate regions in recent decades. Climate change has been proposed as a likely driver of past and future expansion, however, the complex ecology of host and vector populations and their interactions with each other, environmental variables and land-use changes makes understanding the likely impacts of climate change on VBDs challenging. We present an environmentally driven, stage-structured, host-vector mathematical modelling framework to address this challenge. We apply our framework to predict the risk of WNV outbreaks in current and future UK climates. WNV is a mosquito-borne arbovirus which has expanded its range in mainland Europe in recent years. We predict that, while risks will remain low in the coming two to three decades, the risk of WNV outbreaks in the UK will increase with projected temperature rises and outbreaks appear plausible in the latter half of this century. This risk will increase substantially if increased temperatures lead to increases in the length of the mosquito biting season or if European strains show higher replication at lower temperatures than North American strains.

Uncovering mechanisms behind mosquito seasonality by integrating mathematical models and daily empirical population data: Culex pipiens in the UK.

BACKGROUND: Many mosquito-borne diseases exhibit substantial seasonality, due to strong links between environmental variables and vector and pathogen life-cycles. Further, a range of density-dependent and density-independent biotic and abiotic processes affect the phenology of mosquito populations, with potentially large knock-on effects for vector dynamics and disease transmission. Whilst it is understood that density-independent and density-dependent processes affect seasonal population levels, it is not clear how these interact temporally to shape the population peaks and troughs. Due to this, the paucity of high-resolution data for validation, and the difficulty of parameterizing density-dependent processes, models of vector dynamics may poorly estimate abundances, which has knock-on effects for our ability predict vector-borne disease outbreaks. RESULTS: We present a rich dataset describing seasonal abundance patterns of each life stage of Culex pipiens, a widespread vector of West Nile virus, at a field site in southern England in 2015. Abundance of immature stages was measured three times per week, whilst adult traps were run four nights each week. This dataset is integrated with an existing delay-differential equation model predicting Cx. pipiens seasonal abundance to improve understanding of observed seasonal abundance patterns. At our field site, the outcome of our model fitting suggests interspecific predation on mosquito larvae and temperature-dependent larval mortality combine to act as the main sources of population regulation throughout the active season, whilst competition for resources is a relatively small source of larval mortality. CONCLUSIONS: The model suggests that density-independent mortality and interspecific predation interact to shape patterns of mosquito seasonal abundance in a permanent aquatic habitat and we propose that competition for resources is likely to be important where periods of high rainfall create transient habitats. Further, we highlight the importance of challenging population abundance models with data from across all life stages of the species of interest if reliable inferences are to be drawn from these models, particularly when considering mosquito control and vector-borne disease transmission.

Determination of the enantiomeric purity of nucleoside analogs related to d4T and acyclovir, new potential antiviral agents, using liquid chromatography on cellulose chiral stationary phases.

We reported a method of determination of enantiomeric purity of the new potential antiviral agents by direct analytical HPLC. Those agents are nucleoside analogs, having one chiral center. They are synthesized as a single enantiomer (R or S) by an asymmetric pathway. The chiral stationary phases chosen are silica-based cellulose tris-3,5-dimethylphenylcarbamate (Chiralcel OD-H), or tris-methylbenzoate (Chiralcel OJ). Resolution was achieved using normal-phase chromatography with a mobile phase consisting of n-hexane-alcohol (ethanol or 2-propanol) in various percentages. Furthermore the effects of structural features on retention, selectivity and resolution, as well as on the elution order were thoroughly studied. Differences in the lipophilicity of the compounds were also examined.

Electrospray tandem mass-spectrometric analysis of diastereo- and stereoisomeric pyrimidine nucleoside analogues based on the 1,3-dihydrobenzo[c]furan core.

Electrospray mass spectrometry and tandem mass spectrometry have aided the structural characterization of the diastereoisomeric cis- and trans-1-(3-benzoyloxymethyl-1,3-dihydrobenzo[c]furan-1-yl)thymines and the four enantiomerically pure stereoisomers of uracil analogues. Low-energy collision-induced dissociation MS/MS analysis of the various precursor molecular and cluster ions confirmed the characteristic fingerprint pattern obtained in the conventional electrospray spectra and allowed a convenient method for the characterization of novel 1,3-dihydrobenzo[c]furan nucleosides.