Vaccine delivery using nanoparticles

This is the final version of the article. Available from the publisher via the DOI in this record.Vaccination has had a major impact on the control of infectious diseases. However, there are still many infectious diseases for which the development of an effective vaccine has been elusive. In many cases the failure to devise vaccines is a consequence of the inability of vaccine candidates to evoke appropriate immune responses. This is especially true where cellular immunity is required for protective immunity and this problem is compounded by the move toward devising sub-unit vaccines. Over the past decade nanoscale size (<1000 nm) materials such as virus-like particles, liposomes, ISCOMs, polymeric, and non-degradable nanospheres have received attention as potential delivery vehicles for vaccine antigens which can both stabilize vaccine antigens and act as adjuvants. Importantly, some of these nanoparticles (NPs) are able to enter antigen-presenting cells by different pathways, thereby modulating the immune response to the antigen. This may be critical for the induction of protective Th1-type immune responses to intracellular pathogens. Their properties also make them suitable for the delivery of antigens at mucosal surfaces and for intradermal administration. In this review we compare the utilities of different NP systems for the delivery of sub-unit vaccines and evaluate the potential of these delivery systems for the development of new vaccines against a range of pathogens.This work was partly supported by grant number U54 AI057156 from the Western Regional Centre for Excellence, USA. The study performed in the laboratory of RWT was supported by NIH/NIAID grant U54 AI057156 from the Western Regional Center for Excellence. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIAID or NIH

Layered Community Support for Sustainable Dairy Farming

Environmental, community, and economic sustainability of dairy production has important support layers based on production system characteristics, farm size, locational variables, age, and grazing system amenities. Advanced pollution control technology is key to the sustainability of especially large confinement dairies. Grazing dairies are positively viewed, and nearly 70% of respondents are willing to pay a $0.50 premium for milk from grazed cows. Study findings, based on analysis of 600 telephone survey responses from 28 Pennsylvania counties, indicate strong support for dairy farm sustainability, especially when compared with industrial development, which points to critical opportunities for future Extension education programming

Reconstructing changes in macrophyte cover in lakes across the northeastern United States based on sedimentary diatom assemblages

Abstract Macrophytes are a critical component of lake ecosystems affecting nutrient and contaminant cycling, food web structure, and lake biodiversity. The long-term (decades to centuries) dynamics of macrophyte cover are, however, poorly understood and no quantitative estimates exist for pre-industrial (pre-1850) macrophyte cover in northeastern North America. Using a 215 lake dataset, we tested if surface sediment diatom assemblages significantly differed among lakes that have sparse (&lt;10% cover; group 1), moderate (10-40% cover; group 2) or extensive (&gt;40% cover; group 3) macrophyte cover. Analysis of similarity indicated that the diatom assemblages of these a priori groups of macrophyte cover were significantly different from one another (i.e., difference between: groups 1 and 3, R statistic = 0.31, P &lt; 0.001; groups 1 and 2, R statistic = 0.049, P &lt; 0.01; groups 3 and 2, R statistic = 0.112, P &lt; 0.001). We then developed an inference model for macrophyte cover from lakes classified as sparse or extensive cover (145 lakes) based on the surface sediment diatom assemblages, and applied this model using the top-bottom paleolimnological approach (i.e., comparison of recent sediments to pre-disturbance sediments). We used the second axis of our correspondence analysis, which significantly divided sparse and extensive macrophyte cover sites, as the independent variable in a logistic regression to predict macrophyte cover as either sparse or extensive. Cross validation, using 48 randomly chosen sites that were excluded from model development, indicated that our model accurately predicts macrophyte cover 79% of the time (r 2 = 0.32, P &lt; 0.001). When applied to the top and bottom sediment samples, our model predicted that 12.5% of natural lakes and 22.4% of reservoirs in the dataset have undergone a ! 30% change in macrophyte cover. For the sites with an inferred change in macrophyte cover, the majority of natural lakes (64.3%) increased in cover, while the majority of reservoirs (87.5%) decreased in macrophyte cover. This study demonstrates that surface sediment diatom assemblages from profundal zones differ in lakes based on their macrophyte cover and that diatoms are useful indicators for quantitatively reconstructing changes in macrophyte cover

Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

&lt;p&gt;Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.&lt;/p&gt; &lt;p&gt;Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.&lt;/p&gt; &lt;p&gt;Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.&lt;/p&gt

Geographical patterns in openland cover and hayfield mowing in the Upper Great Lakes region: implications for grassland bird conservation

Abstract Populations of many grassland bird species such as Grasshopper Sparrow (Ammodramus savannarum), Henslow&apos;s Sparrow (A. henslowii), and Bobolink (Dolichonyx oryzivorus) have experienced considerable declines over the last century. To foster multi-species grassland bird conservation in the Upper Great Lakes (UGL) states of Michigan, Minnesota, and Wisconsin, we quantified geographic patterns within three sub-regional zones (e.g., North, Central, and South) of the UGL. Patterns of interest included the distribution and abundance of openland cover type (including managed pasture-hayland), the distribution, phenology, habitat affinity, and longterm population trends of ten grassland bird species, and (in particular) the geographic patterns in hayfield mowing and the temporal changes in hayfield cover. Approximately 10, 38, and 53% of the UGL openland was proportioned in the North, Central, and South zones, respectively. The distribution of hayland also varied by zone: North, 17%; Central, 46%; and South, 37%. In the central portion of the UGL where the greatest area is devoted to hay production, alfalfa-more intensively managed than mixed-grass hay-predominates. Although we found significance differences (P \ 0.05) in hayfield mowing intensity between zones (with the majority of land under relatively low-intensity mowing found in the North Zone, particularly the Upper Peninsula of Michigan) no strong relationships were found between hayfield mowing patterns, other land cover-land use variables, and bird population trends at finer scales of study. Nonetheless, we suggest that the geographic patterns illustrated here provide useful information for grassland bird conservation planning across the UGL

Elongase Reactions as Control Points in Long-Chain Polyunsaturated Fatty Acid Synthesis

Extent: 9p.Background: Δ6-Desaturase (Fads2) is widely regarded as rate-limiting in the conversion of dietary α-linolenic acid (18:3n-3; ALA) to the long-chain omega-3 polyunsaturated fatty acid docosahexaenoic acid (22:6n-3; DHA). However, increasing dietary ALA or the direct Fads2 product, stearidonic acid (18:4n-3; SDA), increases tissue levels of eicosapentaenoic acid (20:5n-3; EPA) and docosapentaenoic acid (22:5n-3; DPA), but not DHA. These observations suggest that one or more control points must exist beyond ALA metabolism by Fads2. One possible control point is a second reaction involving Fads2 itself, since this enzyme catalyses desaturation of 24:5n-3 to 24:6n-3, as well as ALA to SDA. However, metabolism of EPA and DPA both require elongation reactions. This study examined the activities of two elongase enzymes as well as the second reaction of Fads2 in order to concentrate on the metabolism of EPA to DHA. Methodology/Principal Findings: The substrate selectivities, competitive substrate interactions and dose response curves of the rat elongases, Elovl2 and Elovl5 were determined after expression of the enzymes in yeast. The competitive substrate interactions for rat Fads2 were also examined. Rat Elovl2 was active with C20 and C22 polyunsaturated fatty acids and this single enzyme catalysed the sequential elongation reactions of EPA→DPA→24:5n-3. The second reaction DPA→24:5n-3 appeared to be saturated at substrate concentrations not saturating for the first reaction EPA→DPA. ALA dose-dependently inhibited Fads2 conversion of 24:5n-3 to 24:6n-3. Conclusions: The competition between ALA and 24:5n-3 for Fads2 may explain the decrease in DHA levels observed after certain intakes of dietary ALA have been exceeded. In addition, the apparent saturation of the second Elovl2 reaction, DPA→24:5n-3, provides further explanations for the accumulation of DPA when ALA, SDA or EPA is provided in the diet. This study suggests that Elovl2 will be critical in understanding if DHA synthesis can be increased by dietary means.Melissa K. Gregory, Robert A. Gibson, Rebecca J. Cook-Johnson, Leslie G. Cleland and Michael J. Jame

Two different types of malignant fibrous histiocytomas from pet dogs

We describe 2 cases of malignant fibrous histiocytomas (MFHs) that spontaneously developed in young pet dogs. To classify these tumors, we applied a panel of antibodies (vimentin, desmin, α-SMA, and ED1) and Azan staining for collagen. The MFHs were most consistent with osteoclast-like giant and inflammatory cell types. The first case had positive staining for ED1 and vimentin, and given the osteoclast-like giant cells, calcification sites accompanying peripheral giant cell infiltrates. The latter case, the inflammatory cell type, exhibited a storiform-pleomorphic variant of neoplastic cells, including an ossifying matrix. MFHs are among the most highly aggressive tumors occurring in soft tissue sarcomas in elderly dogs; however, MFHs have been poorly studied from a diagnostic point of view. Herein, we describe the histologic and immunohistologic features of MFHs in detail, thus classifying the subtypes of these tumors

New horizons for plant translational research

In this issue, we launch a new article collection "The Promise of Plant Translational Research," featuring articles from leading plant researchers and call for additional plant translational research to be submitted to PLOS Biology for inclusion in this collection. We also discuss in this Editorial why this field has a vital role to play in meeting the challenges of sustainably feeding a growing world population

The Random Nature of Genome Architecture: Predicting Open Reading Frame Distributions

Background: A better understanding of the size and abundance of open reading frames (ORFS) in whole genomes may shed light on the factors that control genome complexity. Here we examine the statistical distributions of open reading frames (i.e. distribution of start and stop codons) in the fully sequenced genomes of 297 prokaryotes, and 14 eukaryotes. Methodology/Principal Findings: By fitting mixture models to data from whole genome sequences we show that the size-frequency distributions for ORFS are strikingly similar across prokaryotic and eukaryotic genomes. Moreover, we show that i) a large fraction (60–80%) of ORF size-frequency distributions can be predicted a priori with a stochastic assembly model based on GC content, and that (ii) size-frequency distributions of the remaining “non-random” ORFs are well-fitted by log-normal or gamma distributions, and similar to the size distributions of annotated proteins. Conclusions/Significance: Our findings suggest stochastic processes have played a primary role in the evolution of genome complexity, and that common processes govern the conservation and loss of functional genomics units in both prokaryotes and eukaryotes.8 page(s

Species-level functional profiling of metagenomes and metatranscriptomes.

Functional profiles of microbial communities are typically generated using comprehensive metagenomic or metatranscriptomic sequence read searches, which are time-consuming, prone to spurious mapping, and often limited to community-level quantification. We developed HUMAnN2, a tiered search strategy that enables fast, accurate, and species-resolved functional profiling of host-associated and environmental communities. HUMAnN2 identifies a community's known species, aligns reads to their pangenomes, performs translated search on unclassified reads, and finally quantifies gene families and pathways. Relative to pure translated search, HUMAnN2 is faster and produces more accurate gene family profiles. We applied HUMAnN2 to study clinal variation in marine metabolism, ecological contribution patterns among human microbiome pathways, variation in species' genomic versus transcriptional contributions, and strain profiling. Further, we introduce 'contributional diversity' to explain patterns of ecological assembly across different microbial community types