Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains

Misfolding and aggregation of host proteins are important features of the pathogenesis of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and prion diseases. In all these diseases, the misfolded protein increases in amount by a mechanism involving seeded polymerization. In prion diseases, host prion protein is misfolded to form a pathogenic protease-resistant form, PrPSc, which accumulates in neurons, astroglia and microglia in the CNS. Here using dual-staining immunohistochemistry, we compared the cell specificity of PrPSc accumulation at early preclinical times post-infection using three mouse scrapie strains that differ in brain regional pathology. PrPSc from each strain had a different pattern of cell specificity. Strain 22L was mainly associated with astroglia, whereas strain ME7 was mainly associated with neurons and neuropil. In thalamus and cortex, strain RML was similar to 22L, but in substantia nigra, RML was similar to ME7. Expression of 90 genes involved in neuroinflammation was studied quantitatively using mRNA from thalamus at preclinical times. Surprisingly, despite the cellular differences in PrPSc accumulation, the pattern of upregulated genes was similar for all three strains, and the small differences observed correlated with variations in the early disease tempo. Gene upregulation correlated with activation of both astroglia and microglia detected in early disease prior to vacuolar pathology or clinical signs. Interestingly, the profile of upregulated genes in scrapie differed markedly from that seen in two acute viral CNS diseases (LaCrosse virus and BE polytropic Friend retrovirus) that had reactive gliosis at levels similar to our prion-infected mice.     

Spatiotemporally explicit demographic modelling supports a joint effect of historical barriers to dispersal and contemporary landscape composition on structuring genomic variation in a red‐listed grasshopper

Inferring the processes underlying spatial patterns of genomic variation is fundamental to understand how organisms interact with landscape heterogeneity and to identify the factors determining species distributional shifts. Here, we use genomic data (restriction site‐associated DNA sequencing) to test biologically informed models representing historical and contemporary demographic scenarios of population connectivity for the Iberian cross‐backed grasshopper Dociostaurus hispanicus, a species with a narrow distribution that currently forms highly fragmented populations. All models incorporated biological aspects of the focal taxon that could hypothetically impact its geographical patterns of genomic variation, including (a) spatial configuration of impassable barriers to dispersal defined by topographic landscapes not occupied by the species; (b) distributional shifts resulting from the interaction between the species bioclimatic envelope and Pleistocene glacial cycles; and (c) contemporary distribution of suitable habitats after extensive land clearing for agriculture. Spatiotemporally explicit simulations under different scenarios considering these aspects and statistical evaluation of competing models within an Approximate Bayesian Computation framework supported spatial configuration of topographic barriers to dispersal and human‐driven habitat fragmentation as the main factors explaining the geographical distribution of genomic variation in the species, with no apparent impact of hypothetical distributional shifts linked to Pleistocene climatic oscillations. Collectively, this study supports that both historical (i.e., topographic barriers) and contemporary (i.e., anthropogenic habitat fragmentation) aspects of landscape composition have shaped major axes of genomic variation in the studied species and emphasizes the potential of model‐based approaches to gain insights into the temporal scale at which different processes impact the demography of natural populations.     

6-Bromoindolglyoxylamido derivatives as antimicrobial agents and antibiotic enhancers

The combination of increased incidence of drug-resistant strains of bacteria and a lack of novel drugs in development creates an urgency for the search for new antimicrobials. Initial screening of compounds from an in-house library identified two 6-bromoindolglyoxylamide polyamine derivatives (3 and 4) that exhibited intrinsic antimicrobial activity towards Gram-positive bacteria, Staphylococcus aureus and S. intermedius with polyamine 3 also displaying in vitro antibiotic enhancing properties against the resistant Gram-negative bacterium Pseudomonas aeruginosa. A series of 6-bromo derivatives (5–15) were prepared and biologically evaluated, identifying analogues with enhanced antibacterial activity towards Escherichia coli and with moderate to excellent antifungal properties. Polyamine 3, which includes a spermine chain, was the most potent of the series – its mechanism of action was attributed to rapid membrane permeabilization and depolarization in both Gram-positive and Gram-negative bacteria.     

Invasion of the gall mite Aceria genistae (Acari: Eriophyidae), a natural enemy of the invasive weed Cytisus scoparius,into California,U.S.A. and predictions for climate suitability in other regions using ecological niche modelling

Scotch broom (Cytisus scoparius (L.) Link) is a European shrub that has naturalised in several countries worldwide and is recognised as an invasive weed in much of western North America. The mite Aceria genistae (Nalepa) is a coevolved, gall-inducing herbivore associated with Scotch broom in its native range and has been intentionally introduced as a classical weed biological control agent of C. scoparius in Australia and New Zealand. An adventive, never intentionally introduced, population of A. genistae was discovered in Washington and Oregon, U.S.A. in 2005. Surveys for A. genistae in California resulted in the discovery of the gall mite in 11 counties, with a widely scattered distribution. Molecular and morphological assessments confirm the mites collected from galls in California are A. genistae. Whether natural or anthropogenic, the estimated rate of long range dispersal for A. genistae from Washington or Oregon to California ranges from 39 to 62?km/yr. Niche model predictions indicate that A. genistae will continue to expand its distribution throughout much of the Scotch broom-invaded lands of California but areas supporting the weed in the Eastern U.S.A. appear less suitable. Modelling evidence also indicates that portions of Chile and Argentina are suitable for colonisation by A. genistae, also suggesting that expansion of the mite is possible in areas of Tasmania, southeastern Australia, and New Zealand where the mite was released. The environmental safety of A. genistae in relation to non-target plants and the influence of herbivory on Scotch broom fitness are discussed.     

Do intraspecific life history patterns follow interspecific predictions? A test using latitudinal variation in ringed seals

Mammals adapted to unpredictable and low-energy environments often evolve a “bet-hedging” life history strategy characterized by less costly reproductive outputs over a longer and slower-growing life. In contrast, species adapted to more predictable (i.e., low variation) and higher energy environments may evolve greater fecundity over a shorter and faster-growing life. We tested whether this known interspecific pattern also occurs within a species. We compared life history traits of the ringed seal (Pusa hispida) in the Canadian High Arctic to those closer to the southern limit of the species' circumpolar distribution. We found that northern seals grew slower than southern seals (Brody growth coefficient), achieved a greater asymptotic body weight (82 and 69 kg vs. 74 and 54 kg female and male, respectively), reached sexual maturity later (6.1 years vs. 4.5 years), had lower fecundity (1.8 years vs. 1.3 years interbirth interval), longer average lifespan (5 years vs. 3 years median age), and greater movements (1,269 vs. 681 km). Mating systems also likely differed with northern seals showing morphological evidence of a promiscuous mating system with potential sperm competition as indicated by greater relative testes size. The northern region was also characterized by more unpredictable environmental timing of seasonal events, such as spring sea ice breakup. Life history variation between the intraspecific groups of seals appears to agree with interspecific patterns and provides a better understanding of how species' life history parameters shift in concert with environmental conditions.     

Microdiversity and temporal dynamics of marine bacterial dimethylsulfoniopropionate genes

Dimethylsulfoniopropionate (DMSP) is an abundant organic sulfur metabolite produced by many phytoplankton species and degraded by bacteria via two distinct pathways with climate-relevant implications. We assessed the diversity and abundance of bacteria possessing these pathways in the context of phytoplankton community composition over a 3-week time period spanning September–October, 2014 in Monterey Bay, CA. The dmdA gene from the DMSP demethylation pathway dominated the DMSP gene pool and was harboured mostly by members of the alphaproteobacterial SAR11 clade and secondarily by the Roseobacter group, particularly during the second half of the study. Novel members of the DMSP-degrading community emerged from dmdA sequences recovered from metagenome assemblies and single-cell sequencing, including largely uncharacterized gammaproteobacteria and alphaproteobacteria taxa. In the DMSP cleavage pathway, the SAR11 gene dddK was the most abundant early in the study, but was supplanted by dddP over time. SAR11 members, especially those harbouring genes for both DMSP degradation pathways, had a strong positive relationship with the abundance of dinoflagellates, and DMSP-degrading gammaproteobacteria co-occurred with haptophytes. This in situ study of the drivers of DMSP fate in a coastal ecosystem demonstrates for the first time correlations between specific groups of bacterial DMSP degraders and phytoplankton taxa.     

Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes

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Application of cationic conjugated polymers in microarrays using label-free DNA targets

A fluorescence-based microarray technique that does not require target DNA labeling is detailed. This 'label-free' approach utilizes a cationic, water-soluble conjugated polymer PFBT (poly[9,9'-bis(6'-(N,N,N-trimethylammonium)hexyl)fluorene-co-alt-4,7-(2,1,3-benzothiadiazole) dibromide]), and neutral PNA (peptide nucleic acid) hybridization probes. DNA hybridization to immobilized PNA spots results in a change in the net charge at that particular surface. Electrostatic interactions between the cationic polymer and negatively charged DNA bind the polymer to the hybrid DNA/PNA complex. By exciting the conjugated polymer at 488 nm on a commercial microarray scanner, the presence of the target is directly indicated by the fluorescence emission of the polymer. This feature eliminates the necessity of target labeling required in traditional microarray protocols. There are five steps involved in the procedure before scanning or imaging the array: (i) slide hydration, (ii) target hybridization, (iii) post-hybridization washing, (iv) polymer application and (v) polymer washing. Each step takes 20 min to 1 h. The overall protocol requires approximately 2-3 h.