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Background: Due to the lack of timely access to resources for critical care, strategic use of antiviral drugs is crucial for mitigating the impact of novel influenza viruses with pandemic potential in remote and isolated communities. We sought to evaluate the effect of antiviral treatment and prophylaxis of close contacts in a Canadian remote northern community. Methods: We used an agent-based, discrete-time simulation model for disease spread in a remote community, which was developed as an in-silico population using population census data. Relative and cumulative age-specific attack rates, and the total number of infections in simulated model scenarios were obtained. Results: We found that early initiation of antiviral treatment is more critical for lowering attack rates in a remote setting with a low population-average age compared to an urban population. Our results show that a significant reduction in the relative, age-specific attack rates due to increasing treatment coverage does not necessarily translate to a significant reduction in the overall arrack rate. When treatment coverage varies from low to moderate, targeted prophylaxis has a very limited impact in reducing attack rates and should be offered at a low level (below 10%) to avoid excessive waste of drugs. Conclusions: In contrast to previous work, for conservative treatment coverages, our results do not provide any convincing evidence for the implementation of targeted prophylaxis. The findings suggest that public health strategies in remote communities should focus on the wider availability (higher coverage) and timely distribution of antiviral drugs for treatment of clinically ill individuals. [ABSTRACT FROM AUTHOR]

In this study, a detailed characterization of Monocarboxylic Acid Transporter-1 (Mct1) in cytoplasmic vesicles of cultured rat brain microvascular endothelial cells shows them to be a diverse population of endosomes intrinsic to the regulation of the transporter by a brief 25 to 30 minute exposure to the membrane permeant cAMP analog, 8Br-cAMP. The vesicles are heterogeneous in size, mobility, internal pH, and co-localize with discreet markers of particular types of endosomes including early endosomes, clathrin coated vesicles, caveolar vesicles, trans-golgi, and lysosomes. The vesicular localization of Mct1 was not dependent on its N or C termini, however, the size and pH of Mct1 vesicles was increased by deletion of either terminus demonstrating a role for the termini in vesicular trafficking of Mct1. Using a novel BCECF-AM based assay developed in this study, 8Br-cAMP was shown to decrease the pH of Mct1 vesicles after 25 minutes. This result and method were confirmed in experiments with a ratiometric pH-sensitive EGFP-mCherry dual tagged Mct1 construct. Overall, the results indicate that cAMP signaling reduces the functionality of Mct1 in cerebrovascular endothelial cells by facilitating its entry into a highly dynamic vesicular trafficking pathway that appears to lead to the transporter's trafficking to autophagosomes and lysosomes. [ABSTRACT FROM AUTHOR]

Cisplatin, a commonly used chemotherapeutic, is associated with ototoxicity, renal toxicity and neurotoxicity, thus identifying means to increase the therapeutic index of cisplatin may allow for improved outcomes. A SNP (rs4343077) within EPS8, discovered through a genome wide association study of cisplatin-induced cytotoxicity and apoptosis in lymphoblastoid cell lines (LCLs), provided impetus to further study this gene. The purpose of this work was to evaluate the role of EPS8 in cellular susceptibility to cisplatin in cancerous and non-cancerous cells. We used EPS8 RNA interference to determine the effect of decreased EPS8 expression on LCL and A549 lung cancer cell sensitivity to cisplatin. EPS8 knockdown in LCLs resulted in a 7.9% increase in cisplatin-induced survival (P = 1.98×10−7) and an 8.7% decrease in apoptosis (P = 0.004) compared to control. In contrast, reduced EPS8 expression in lung cancer cells resulted in a 20.6% decrease in cisplatin-induced survival (P = 5.08×10−5). We then investigated an EPS8 inhibitor, mithramycin A, as a potential agent to increase the therapeutic index of cisplatin. Mithramycin A decreased EPS8 expression in LCLs resulting in decreased cellular sensitivity to cisplatin as evidenced by lower caspase 3/7 activation following cisplatin treatment (42.7%±6.8% relative to control P = 0.0002). In 5 non-small-cell lung carcinoma (NSCLC) cell lines, mithramycin A also resulted in decreased EPS8 expression. Adding mithramycin to 4 NSCLC cell lines and a bladder cancer cell line, resulted in increased sensitivity to cisplatin that was significantly more pronounced in tumor cell lines than in LCL lines (p<0.0001). An EGFR mutant NSCLC cell line (H1975) showed no significant change in sensitivity to cisplatin with the addition of mithramycin treatment. Therefore, an inhibitor of EPS8, such as mithramycin A, could improve cisplatin treatment by increasing sensitivity of tumor relative to normal cells. [ABSTRACT FROM AUTHOR]

Hypotheses that relate body size to energy use are of particular interest in community ecology and macroecology because of their potential to facilitate quantitative predictions about species interactions and to clarify complex ecological patterns. One prominent size-energy hypothesis, the energetic equivalence hypothesis, proposes that energy use from shared, limiting resources by populations or size classes of foragers will be independent of body size. Alternative hypotheses propose that energy use will increase with body size, decrease with body size, or peak at an intermediate body size. Despite extensive study, however, size-energy hypotheses remain controversial, due to a lack of directly-measured data on energy use, a tendency to confound distinct scaling relationships, and insufficient attention to the ecological contexts in which predicted relationships are likely to occur. Our goal, therefore, was to directly evaluate size-energy hypotheses while clarifying how results would differ with alternate methods and assumptions. We comprehensively tested size-energy hypotheses in a vertebrate frugivore guild in a tropical forest in Madagascar. Our test of size-energy hypotheses, which is the first to examine energy intake directly, was consistent with the energetic equivalence hypothesis. This finding corresponds with predictions of metabolic theory and models of energy distribution in ecological communities, which imply that body size does not confer an advantage in competition for energy among populations or size classes of foragers. This result was robust to different assumptions about energy regulation. Our results from direct energy measurement, however, contrasted with those obtained with conventional methods of indirect inference from size-density relationships, suggesting that size-density relationships do not provide an appropriate proxy for size-energy relationships as has commonly been assumed. Our research also provides insights into mechanisms underlying local size-energy relationships and has important implications for predicting species interactions and for understanding the structure and dynamics of ecological communities. [ABSTRACT FROM AUTHOR]

The recent development of lightweight GPS collars has enabled medium-to-small sized animals to be tracked via GPS telemetry. Evaluation of the performance and accuracy of GPS collars is largely confined to devices designed for large animals for deployment in natural environments. This study aimed to assess the performance of lightweight GPS collars within a suburban environment, which may be different from natural environments in a way that is relevant to satellite signal acquisition. We assessed the effects of vegetation complexity, sky availability (percentage of clear sky not obstructed by natural or artificial features of the environment), proximity to buildings, and satellite geometry on fix success rate (FSR) and location error (LE) for lightweight GPS collars within a suburban environment. Sky availability had the largest affect on FSR, while LE was influenced by sky availability, vegetation complexity, and HDOP (Horizontal Dilution of Precision). Despite the complexity and modified nature of suburban areas, values for FSR ( = 90.6%) and LE ( = 30.1 m) obtained within the suburban environment are comparable to those from previous evaluations of GPS collars designed for larger animals and within less built-up environments. Due to fine-scale patchiness of habitat within urban environments, it is recommended that resource selection methods that are not reliant on buffer sizes be utilised for selection studies. [ABSTRACT FROM AUTHOR]

CD8+ T cells are responsible for killing cells of the body that have become infected or oncogenically transformed. In order to do so, effector CD8+ T cells must recognize their cognate antigenic peptide bound to a MHC class I molecule that has been directly presented by the target cell. Due to the rapid nature of antigen presentation, it is believed that antigenic peptides are derived from a subset of newly synthesized proteins which are degraded almost immediately following synthesis and termed Defective Ribosomal Products or DRiPs. We have recently reported on a bioassay which can distinguish antigen presentation of DRiP substrates from other forms of rapidly degraded proteins and found that poly-ubiquitin chain disassembly may be necessary for efficient DRiP presentation. The AAA ATPase p97 protein is necessary for efficient cross-presentation of antigens on MHC class I molecules and plays an important role in extracting mis-folded proteins from the endoplasmic reticulum. Here, we find that genetic ablation or chemical inhibition of p97 does not diminish DRiP antigen presentation to any great extent nor does it alter the levels of MHC class I molecules on the cell surface, despite our observations that p97 inhibition increased the levels of poly-ubiquitinated proteins in the cell. These data demonstrate that inhibiting poly-ubiquitin chain disassembly alone is insufficient to abolish DRiP presentation. [ABSTRACT FROM AUTHOR]

Background: The Canadian National Antiviral Stockpile (NAS) contains treatment for 17.5% of Canadians. This assumes no concurrent intervention strategies and no wastage due to non-influenza respiratory infections. A dynamic model can provide a mechanism to consider complex scenarios to support decisions regarding the optimal NAS size under uncertainty. Methods: We developed a dynamic model for pandemic influenza in Canada that is structured by age and risk to calculate the demand for antivirals to treat persons with pandemic influenza under a wide-range of scenarios that incorporated transmission dynamics, disease severity, and intervention strategies. The anticipated per capita number of acute respiratory infections due to viruses other than influenza was estimated for the full pandemic period from surveys based on criteria to identify potential respiratory infections. Results: Our results demonstrate that up to two thirds of the population could develop respiratory symptoms as a result of infection with a pandemic strain. In the case of perfect antiviral allocation, up to 39.8% of the population could request antiviral treatment. As transmission dynamics, severity and timing of the emergence of a novel influenza strain are unknown, the sensitivity analysis produced considerable variation in potential demand (median: 11%, IQR: 2–21%). If the next pandemic strain emerges in late spring or summer and a vaccine is available before the anticipated fall wave, the median prediction was reduced to 6% and IQR to 0.7–14%. Under the strategy of offering empirical treatment to all patients with influenza like symptoms who present for care, demand could increase to between 65 and 144%. Conclusions: The demand for antivirals during a pandemic is uncertain. Unless an accurate, timely and cost-effective test is available to identify influenza cases, demand for antivirals from persons infected with other respiratory viruses will be substantial and have a significant impact on the NAS. [ABSTRACT FROM AUTHOR]

Invasive species are often favoured in fragmented, highly-modified, human-dominated landscapes such as urban areas. Because successful invasive urban adapters can occupy habitat that is quite different from that in their original range, effective management programmes for invasive species in urban areas require an understanding of distribution, habitat and resource requirements at a local scale that is tailored to the fine-scale heterogeneity typical of urban landscapes. The common brushtail possum (Trichosurus vulpecula) is one of New Zealand’s most destructive invasive pest species. As brushtail possums traditionally occupy forest habitat, control in New Zealand has focussed on rural and forest habitats, and forest fragments in cities. However, as successful urban adapters, possums may be occupying a wider range of habitats. Here we use site occupancy methods to determine the distribution of brushtail possums across five distinguishable urban habitat types during summer, which is when possums have the greatest impacts on breeding birds. We collected data on possum presence/absence and habitat characteristics, including possible sources of supplementary food (fruit trees, vegetable gardens, compost heaps), and the availability of forest fragments from 150 survey locations. Predictive distribution models constructed using the programme PRESENCE revealed that while occupancy rates were highest in forest fragments, possums were still present across a large proportion of residential habitat with occupancy decreasing as housing density increased and green cover decreased. The presence of supplementary food sources was important in predicting possum occupancy, which may reflect the high nutritional value of these food types. Additionally, occupancy decreased as the proportion of forest fragment decreased, indicating the importance of forest fragments in determining possum distribution. Control operations to protect native birds from possum predation in cities should include well-vegetated residential areas; these modified habitats not only support possums but provide a source for reinvasion of fragments. [ABSTRACT FROM AUTHOR]

Cognitive impairments are prominent sequelae of prolonged continuous seizures (status epilepticus; SE) in humans and animal models. While often associated with dendritic injury, the underlying mechanisms remain elusive. The mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated following SE. This pathway modulates learning and memory and is associated with regulation of neuronal, dendritic, and glial properties. Thus, in the present study we tested the hypothesis that SE-induced mTORC1 hyperactivation is a candidate mechanism underlying cognitive deficits and dendritic pathology seen following SE. We examined the effects of rapamycin, an mTORC1 inhibitor, on the early hippocampal-dependent spatial learning and memory deficits associated with an episode of pilocarpine-induced SE. Rapamycin-treated SE rats performed significantly better than the vehicle-treated rats in two spatial memory tasks, the Morris water maze and the novel object recognition test. At the molecular level, we found that the SE-induced increase in mTORC1 signaling was localized in neurons and microglia. Rapamycin decreased the SE-induced mTOR activation and attenuated microgliosis which was mostly localized within the CA1 area. These findings paralleled a reversal of the SE-induced decreases in dendritic Map2 and ion channels levels as well as improved dendritic branching and spine density in area CA1 following rapamycin treatment. Taken together, these findings suggest that mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with SE. [ABSTRACT FROM AUTHOR]

Fusion inhibitors are a class of antiretroviral drugs used to prevent entry of HIV into host cells. Many of the fusion inhibitors being developed, including the drug enfuvirtide, are peptides designed to competitively inhibit the viral fusion protein gp41. With the emergence of drug resistance, there is an increased need for effective and unique alternatives within this class of antivirals. One such alternative is a class of cyclic, cationic, antimicrobial peptides known as θ-defensins, which are produced by many non-human primates and exhibit broad-spectrum antiviral and antibacterial activity. Currently, the θ-defensin analog RC-101 is being developed as a microbicide due to its specific antiviral activity, lack of toxicity to cells and tissues, and safety in animals. Understanding potential RC-101 resistance, and how resistance to other fusion inhibitors affects RC-101 susceptibility, is critical for future development. In previous studies, we identified a mutant, R5-tropic virus that had evolved partial resistance to RC-101 during in vitro selection. Here, we report that a secondary mutation in gp41 was found to restore replicative fitness, membrane fusion, and the rate of viral entry, which were compromised by an initial mutation providing partial RC-101 resistance. Interestingly, we show that RC-101 is effective against two enfuvirtide-resistant mutants, demonstrating the clinical importance of RC-101 as a unique fusion inhibitor. These findings both expand our understanding of HIV drug-resistance to diverse peptide fusion inhibitors and emphasize the significance of compensatory gp41 mutations. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS), characterized by chronic inflammation, demyelination, and axonal damage, is a complicated neurological disease of the human central nervous system. Recent interest in adipose stromal/stem cell (ASCs) for the treatment of CNS diseases has promoted further investigation in order to identify the most suitable ASCs. To investigate whether MS affects the biologic properties of ASCs and whether autologous ASCs from MS-affected sources could serve as an effective source for stem cell therapy, cells were isolated from subcutaneous inguinal fat pads of mice with established experimental autoimmune encephalomyelitis (EAE), a murine model of MS. ASCs from EAE mice and their syngeneic wild-type mice were cultured, expanded, and characterized for their cell morphology, surface antigen expression, osteogenic and adipogenic differentiation, colony forming units, and inflammatory cytokine and chemokine levels in vitro. Furthermore, the therapeutic efficacy of the cells was assessed in vivo by transplantation into EAE mice. The results indicated that the ASCs from EAE mice displayed a normal phenotype, typical MSC surface antigen expression, and in vitro osteogenic and adipogenic differentiation capacity, while their osteogenic differentiation capacity was reduced in comparison with their unafflicted control mice. The ASCs from EAE mice also demonstrated increased expression of pro-inflammatory cytokines and chemokines, specifically an elevation in the expression of monocyte chemoattractant protein-1 and keratin chemoattractant. In vivo, infusion of wild type ASCs significantly ameliorate the disease course, autoimmune mediated demyelination and cell infiltration through the regulation of the inflammatory responses, however, mice treated with autologous ASCs showed no therapeutic improvement on the disease progression. [ABSTRACT FROM AUTHOR]

Background: Communicable disease outbreaks of novel or existing pathogens threaten human health around the globe. It would be desirable to rapidly characterize such outbreaks and develop accurate projections of their duration and cumulative size even when limited preliminary data are available. Here we develop a mathematical model to aid public health authorities in tracking the expansion and contraction of outbreaks with explicit representation of factors (other than population immunity) that may slow epidemic growth. Methodology: The Incidence Decay and Exponential Adjustment (IDEA) model is a parsimonious function that uses the basic reproduction number R0, along with a discounting factor to project the growth of outbreaks using only basic epidemiological information (e.g., daily incidence counts). Principal Findings: Compared to simulated data, IDEA provides highly accurate estimates of total size and duration for a given outbreak when R0 is low or moderate, and also identifies turning points or new waves. When tested with an outbreak of pandemic influenza A (H1N1), the model generates estimated incidence at the i+1th serial interval using data from the ith serial interval within an average of 20% of actual incidence. Conclusions and Significance: This model for communicable disease outbreaks provides rapid assessments of outbreak growth and public health interventions. Further evaluation in the context of real-world outbreaks will establish the utility of IDEA as a tool for front-line epidemiologists. [ABSTRACT FROM AUTHOR]

Johnes disease (JD), caused by Mycobacterium avium subsp paratuberculosis (MAP), occurs worldwide as chronic granulomatous enteritis of domestic and wild ruminants. To develop a cost effective vaccine, in a previous study we constructed an attenuated Salmonella strain that expressed a fusion product made up of partial fragments of MAP antigens (Ag85A, Ag85B and SOD) that imparted protection against challenge in a mouse model. In the current study we evaluated the differential immune response and protective efficacy of the Sal-Ag vaccine against challenge in a goat model as compared to the live attenuated vaccine MAP316F. PBMCs from goats vaccinated with Sal-Ag and challenged with MAP generated significantly lower levels of IFN-γ, following in vitro stimulation with either Antigen-mix or PPD jhonin, than PBMC from MAP316F vaccinated animals. Flow cytometric analysis showed the increase in IFN-γ correlated with a significantly higher level of proliferation of CD4, CD8 and γδT cells and an increased expression of CD25 and CD45R0 in MAP316F vaccinated animals as compared to control animals. Evaluation of a range of cytokines involved in Th1, Th2, Treg, and Th17 immune responses by quantitative PCR showed low levels of expression of Th1 (IFN-γ, IL-2, IL-12) and proinflammatory cytokines (IL-6, IL-8, IL-18, TNF-α) in the Sal-Ag immunized group. Significant levels of Th2 and anti-inflammatory cytokines transcripts (IL-4, IL-10, IL-13, TGF-β) were expressed but their level was low and with a pattern similar to the control group. Over all, Sal-Ag vaccine imparted partial protection that limited colonization in tissues of some animals upon challenge with wild type MAP but not to the level achieved with MAP316F. In conclusion, the data indicates that Sal-Ag vaccine induced only a low level of protective immunity that failed to limit the colonization of MAP in infected animals. Hence the Sal-Ag vaccine needs further refinement to increase its efficacy. [ABSTRACT FROM AUTHOR]

Respiratory infections stemming from influenza viruses and the Severe Acute Respiratory Syndrome corona virus (SARS-CoV) represent a serious public health threat as emerging pandemics. Despite efforts to identify the critical interactions of these viruses with host machinery, the key regulatory events that lead to disease pathology remain poorly targeted with therapeutics. Here we implement an integrated network interrogation approach, in which proteome and transcriptome datasets from infection of both viruses in human lung epithelial cells are utilized to predict regulatory genes involved in the host response. We take advantage of a novel “crowd-based” approach to identify and combine ranking metrics that isolate genes/proteins likely related to the pathogenicity of SARS-CoV and influenza virus. Subsequently, a multivariate regression model is used to compare predicted lung epithelial regulatory influences with data derived from other respiratory virus infection models. We predicted a small set of regulatory factors with conserved behavior for consideration as important components of viral pathogenesis that might also serve as therapeutic targets for intervention. Our results demonstrate the utility of integrating diverse ‘omic datasets to predict and prioritize regulatory features conserved across multiple pathogen infection models. [ABSTRACT FROM AUTHOR]

Delusions are the persistent and often bizarre beliefs that characterise psychosis. Previous studies have suggested that their emergence may be explained by disturbances in prediction error-dependent learning. Here we set up complementary studies in order to examine whether such a disturbance also modulates memory reconsolidation and hence explains their remarkable persistence. First, we quantified individual brain responses to prediction error in a causal learning task in 18 human subjects (8 female). Next, a placebo-controlled within-subjects study of the impact of ketamine was set up on the same individuals. We determined the influence of this NMDA receptor antagonist (previously shown to induce aberrant prediction error signal and lead to transient alterations in perception and belief) on the evolution of a fear memory over a 72 hour period: they initially underwent Pavlovian fear conditioning; 24 hours later, during ketamine or placebo administration, the conditioned stimulus (CS) was presented once, without reinforcement; memory strength was then tested again 24 hours later. Re-presentation of the CS under ketamine led to a stronger subsequent memory than under placebo. Moreover, the degree of strengthening correlated with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signal. This finding was partially replicated in an independent sample with an appetitive learning procedure (in 8 human subjects, 4 female). These results suggest a link between altered prediction error, memory strength and psychosis. They point to a core disruption that may explain not only the emergence of delusional beliefs but also their persistence. [ABSTRACT FROM AUTHOR]

Demography impacts the observed standing level of genetic diversity present in populations. Distinguishing the relative impacts of demography from selection requires a baseline of expressed gene variation in naturally occurring populations. Six nuclear genes were sequenced to estimate the patterns and levels of genetic diversity in natural Arabidopsis lyrata subsp. petraea populations that differ in demographic histories since the Pleistocene. As expected, northern European populations have genetic signatures of a strong population bottleneck likely due to glaciation during the Pleistocene. Levels of diversity in the northern populations are about half of that in central European populations. Bayesian estimates of historical population size changes indicate that central European populations also have signatures of population size change since the last glacial maxima, suggesting that these populations are not as stable as previously thought. Time since divergence amongst northern European populations is higher than amongst central European populations, suggesting that the northern European populations were established before the Pleistocene and survived glaciation in small separated refugia. Estimates of demography based on expressed genes are complementary to estimates based on microsatellites and transposable elements, elucidating temporal shifts in population dynamics and confirming the importance of marker selection for tests of demography. [ABSTRACT FROM AUTHOR]