Correction: Identifying connectivity for two sympatric carnivores in human-dominated landscapes in central Iran.

[This corrects the article DOI: 10.1371/journal.pone.0269179.].

Identifying connectivity for two sympatric carnivores in human-dominated landscapes in central Iran.

Central Iran supports a diversity of carnivores, most of which are threatened by habitat loss and fragmentation. Carnivore conservation requires the identification and preservation of core habitats and ensuring connectivity between them. In the present study, we used species distribution modeling to predict habitat suitability and connectivity modeling to predict linkage (resistant kernel and factorial least-cost path analyses) for grey wolf and golden jackal in central Iran. For grey wolf, elevation, topographic ruggedness, and distance to Conservation Areas (CAs) were the strongest predictors; for golden jackal, distance to human settlements, dump sites and topographic ruggedness were the most influential variables in predicting the occurrence of this species. Our results also indicated a high potential for large parts of the landscape to support the occurrence of these two canid species. The largest and the most crucial core habitats and corridor paths for the conservation of both species are located in the southern part of the study landscape. We found a small overlap between golden jackal corridor paths and core habitats with CAs, which has important implications for conservation and future viability of the golden jackal populations. Some sections of core areas are bisected by roads, where most vehicle collisions with grey wolf and golden jackal occurred. To minimize mortality risk, we propose that successful conservation of both species will necessitate integrated landscape-level management, as well as conservation of core areas and corridors and development of mitigation strategies to reduce vehicle collisions.

Prevalence and Coinfection of Three Tick-Borne Pathogens in Questing Adult Blacklegged Ticks Ixodes scapularis (Vilas County, Wisconsin).

Introduction: In North America, the blacklegged tick (Ixodes scapularis) is a vector of several human pathogens, and tick-borne disease incidence is increasing. Objectives: We estimated the prevalence of questing blacklegged ticks vectoring three zoonotic pathogens in Vilas County, Wisconsin. Materials and Methods: We collected 461 adult blacklegged ticks and used PCR to screen for the presence of pathogens that cause Lyme disease (Borrelia burgdorferi), human granulocytic anaplasmosis (HGA, Anaplasma phagocytophilum), and babesiosis (Babesia microti). Results: We found that 52.5% of ticks carried at least one pathogen. The estimated infection prevalence in the tick population was 17.4% (Lyme disease), 14.3% (HGA), and 6.5% (babesiosis). Multiple pathogens were present in 14.3% of ticks surveyed. Conclusion: About half of questing ticks tested in this study carried at least one zoonotic pathogen. Coinfection was common in our study area and, if not properly recognized, leads to greater risk of underdiagnosis.

Development of a novel NURR1/NOT agonist from hit to lead and candidate for the potential treatment of Parkinson's disease.

In the course of a programme aimed at identifying Nurr1/NOT agonists for potential treatment of Parkinson's disease, a few hits from high throughput screening were identified and characterized. A combined optimization pointed to a very narrow and stringent structure activity relationship. A comprehensive program of optimization led to a potent and safe candidate drug displaying neuroprotective and anti-inflammatory activity in several in vitro and in vivo models.

Dewatering Oil Sands Tailings with Degradable Polymer Flocculants.

We synthesized hydrolytically degradable cationic polymers by micellar radical polymerization of a short-chain polyester macromonomer, polycaprolactone choline iodide ester methacrylate (PCL2ChMA) with two polyester units, and used them to flocculate oil sands mature fine tailings (MFT). We evaluated the flocculation performance of the homopolymer and copolymers with 30 mol % acrylamide (AM) by measuring initial settling rate (ISR), supernatant turbidity, and capillary suction time (CST) of the sediments. Flocculants made with trimethylaminoethyl methacrylate chloride (TMAEMC), the monomer corresponding to PCLnChMA with n = 0, have improved performance over poly(PCL2ChMA) at equivalent loadings due to their higher charge density per gram of polymer. However, MFT sediments flocculated using the PCL2ChMA-based polymers are easier to dewater (up to an 85% reduction in CST) after accelerated hydrolytic degradation of the polyester side chains. This study demonstrates the potential of designing cationic polymers that effectively flocculate oil sands tailings ponds, and also further dewater the resulting solids through polymer degradation.

NF-L in cerebrospinal fluid and serum is a biomarker of neuronal damage in an inducible mouse model of neurodegeneration.

Accumulation of neurofilaments (NFs), the major constituents of the neuronal cytoskeleton, is a distinctive feature of neurological diseases and several studies have shown that soluble NFs can be detected in the cerebrospinal fluid (CSF) of patients with neurological diseases, such as multiple sclerosis and frontotemporal dementia. Here we have used an inducible transgenic mouse model of neurodegeneration, CamKII-TetOp25 mice, to evaluate whether NF-L levels in CSF or blood can be used as a biochemical biomarker of neurodegeneration. Induction of p25 transgene brain expression led to increase in CSF and serum NF-L levels that correlated with ongoing neurodegeneration. Switching off p25 prevented further increases in both CSF and serum NF-L levels and concomitantly stopped the progression of neurodegeneration. The levels of CSF NF-L detected in p25 mice are about 4-fold higher than the CSF levels detected in patients with chronic neurodegenerative diseases, such as symptomatic FTD (bvFTD). In addition, our data indicate that the NF-L detected in CSF is most likely a cleaved form of NF-L. These results suggest that CSF and serum NF-L are of interest to be further explored as potential translational dynamic biomarkers of neurodegeneration or as pharmacodynamics biomarkers at least in preclinical animal studies.

Deer herbivory reduces web-building spider abundance by simplifying forest vegetation structure.

Indirect ecological effects are a common feature of ecological systems, arising when one species affects interactions among two or more other species. We examined how browsing by white-tailed deer (Odocoileus virginianus) indirectly affected the abundance and composition of a web-building spider guild through their effects on the structure of the ground and shrub layers of northern hardwood forests. We examined paired plots consisting of deer-free and control plots in the Allegheny Plateau region Pennsylvania and Northern Highlands region of Wisconsin. We recorded the abundance of seven types of webs, each corresponding to a family of web-building spiders. We quantified vegetation structure and habitat suitability for the spiders by computing a web scaffold availability index (WSAI) at 0.5 m and 1.0 m above the ground. At Northern Highlands sites, we recorded prey availability. Spider webs were twice as abundant in deer-free plots compared to control plots, while WSAI was 7-12 times greater in deerfree plots. Prey availability was lower in deer-free plots. With the exception of funnel web-builders, all spider web types were significantly more abundant in deer-free plots. Both deer exclusion and the geographic region of plots were significant predictors of spider community structure. In closed canopy forests with high browsing pressure, the low density of tree saplings and shrubs provides few locations for web-building spiders to anchor webs. Recruitment of these spiders may become coupled with forest disturbance events that increase tree and shrub recruitment. By modifying habitat structure, deer appear to indirectly modify arthropod food web interactions. As deer populations have increased in eastern North America over the past several decades, the effects of deer on web-building spiders may be widespread.

In Vivo Detection of Amyloid Plaques by Gadolinium-Stained MRI Can Be Used to Demonstrate the Efficacy of an Anti-amyloid Immunotherapy.

Extracellular deposition of ß amyloid plaques is an early event associated to Alzheimer's disease. Here, we have used in vivo gadolinium-stained high resolution (29(∗)29(∗)117 µm(3)) magnetic resonance imaging (MRI) to follow-up in a longitudinal way individual amyloid plaques in APP/PS1 mice and evaluate the efficacy of a new immunotherapy (SAR255952) directed against protofibrillar and fibrillary forms of Aß. APP/PS1 mice were treated for 5 months between the age of 3.5 and 8.5 months. SAR255952 reduced amyloid load in 8.5-months-old animals, but not in 5.5-months animals compared to mice treated with a control antibody (DM4). Histological evaluation confirmed the reduction of amyloid load and revealed a lower density of amyloid plaques in 8.5-months SAR255952-treated animals. The longitudinal follow-up of individual amyloid plaques by MRI revealed that plaques that were visible at 5.5 months were still visible at 8.5 months in both SAR255952 and DM4-treated mice. This suggests that the amyloid load reduction induced by SAR255952 is related to a slowing down in the formation of new plaques rather than to the clearance of already formed plaques.

High-throughput 3D whole-brain quantitative histopathology in rodents.

Histology is the gold standard to unveil microscopic brain structures and pathological alterations in humans and animal models of disease. However, due to tedious manual interventions, quantification of histopathological markers is classically performed on a few tissue sections, thus restricting measurements to limited portions of the brain. Recently developed 3D microscopic imaging techniques have allowed in-depth study of neuroanatomy. However, quantitative methods are still lacking for whole-brain analysis of cellular and pathological markers. Here, we propose a ready-to-use, automated, and scalable method to thoroughly quantify histopathological markers in 3D in rodent whole brains. It relies on block-face photography, serial histology and 3D-HAPi (Three Dimensional Histology Analysis Pipeline), an open source image analysis software. We illustrate our method in studies involving mouse models of Alzheimer's disease and show that it can be broadly applied to characterize animal models of brain diseases, to evaluate therapeutic interventions, to anatomically correlate cellular and pathological markers throughout the entire brain and to validate in vivo imaging techniques.

SAR110894, a potent histamine H3-receptor antagonist, displays disease-modifying activity in a transgenic mouse model of tauopathy.

INTRODUCTION: Tau hyperphosphorylation and neurofibrillary tangles are histopathologic hallmarks of tauopathies. Histamine H3-receptor antagonists have been proposed to reduce tau hyperphosphorylation in preclinical models. METHODS: We evaluated the ability of SAR110894, a selective histamine H3-receptor antagonist, to inhibit tau pathology and prevent cognitive deficits in a tau transgenic mouse model (THY-Tau22). RESULTS: SAR110894 treatment for 6 months (but not 2 weeks) in THY-Tau22 mice decreased both tau hyperphosphorylation at pSer396-pSer404 (AD2 signal) in the hippocampus and the number of AT8 (pSer199/202-Thr205) positive cells in the cortex and decreased the formation of neurofibrillary tangles in the cortex, hippocampus, and amygdala. Macrophage inflammatory protein 1-alpha messenger RNA expression was decreased in the hippocampus. SAR110894 also prevented episodic memory deficits, and this effect was still detected after treatment washout. DISCUSSION: Long-term SAR110894 treatment could have potential disease modifying activity in neurodegenerative tauopathies.

A Nurr1 agonist causes neuroprotection in a Parkinson's disease lesion model primed with the toll-like receptor 3 dsRNA inflammatory stimulant poly(I:C).

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) are characterized by the expression of genes required for dopamine synthesis, handling and reuptake and the expression of these genes is largely controlled by nuclear receptor related 1 (Nurr1). Nurr1 is also expressed in astrocytes and microglia where it functions to mitigate the release of proinflammatory cytokines and neurotoxic factors. Given that Parkinson's disease (PD) pathogenesis has been linked to both loss of Nurr1 expression in the SNpc and inflammation, increasing levels of Nurr1 maybe a promising therapeutic strategy. In this study a novel Nurr1 agonist, SA00025, was tested for both its efficiency to induce the transcription of dopaminergic target genes in vivo and prevent dopaminergic neuron degeneration in an inflammation exacerbated 6-OHDA-lesion model of PD. SA00025 (30mg/kg p.o.) entered the brain and modulated the expression of the dopaminergic phenotype genes TH, VMAT, DAT, AADC and the GDNF receptor gene c-Ret in the SN of naive rats. Daily gavage treatment with SA00025 (30mg/kg) for 32 days also induced partial neuroprotection of dopaminergic neurons and fibers in rats administered a priming injection of polyinosinic-polycytidylic acid (poly(I:C) and subsequent injection of 6-OHDA. The neuroprotective effects of SA00025 in this dopamine neuron degeneration model were associated with changes in microglial morphology indicative of a resting state and a decrease in microglial specific IBA-1 staining intensity in the SNpc. Astrocyte specific GFAP staining intensity and IL-6 levels were also reduced. We conclude that Nurr1 agonist treatment causes neuroprotective and anti-inflammatory effects in an inflammation exacerbated 6-OHDA lesion model of PD.

White-tailed deer are a biotic filter during community assembly, reducing species and phylogenetic diversity.

Community assembly entails a filtering process, where species found in a local community are those that can pass through environmental (abiotic) and biotic filters and successfully compete. Previous research has demonstrated the ability of white-tailed deer (Odocoileus virginianus) to reduce species diversity and favour browse-tolerant plant communities. In this study, we expand on our previous work by investigating deer as a possible biotic filter altering local plant community assembly. We used replicated 23-year-old deer exclosures to experimentally assess the effects of deer on species diversity (H'), richness (SR), phylogenetic community structure and phylogenetic diversity in paired browsed (control) and unbrowsed (exclosed) plots. Additionally, we developed a deer-browsing susceptibility index (DBSI) to assess the vulnerability of local species to deer. Deer browsing caused a 12 % reduction in H' and 17 % reduction in SR, consistent with previous studies. Furthermore, browsing reduced phylogenetic diversity by 63 %, causing significant phylogenetic clustering. Overall, graminoids were the least vulnerable to deer browsing based on DBSI calculations. These findings demonstrate that deer are a significant driver of plant community assembly due to their role as a selective browser, or more generally, as a biotic filter. This study highlights the importance of knowledge about the plant tree of life in assessing the effects of biotic filters on plant communities. Application of such knowledge has considerable potential to advance our understanding of plant community assembly.

Synthesis and preliminary evaluation of a new fluorine-18 labelled triazine derivative for PET imaging of cannabinoid CB2 receptor.

Cannabinoid CB2 PET tracers are considered as a promising alternative to PBR/TSPO tracers for the in-vivo imaging of neuroinflammation. We describe here the synthesis and characterization of compound 3, a new potent and brain penetrating CB2 ligand based on an original triazine template. The PET tracer [(18)F]-dideutero-3 was prepared in a three steps radiosynthesis, and demonstrated significant uptake in rhesus macaque and baboon brain with a maximum SUV of about 0.7-0.9g/mL, followed by a moderate washout over time.

A methyl methacrylate-HEMA-CL(n) copolymerization investigation: from kinetics to bioapplications.

The radical copolymerization kinetics of methyl methacrylate (MMA) and poly-ϵ-caprolactone macromonomer functionalized with a vinyl end group (HEMA-CL(n)) is studied using a pulsed-laser technique. The reactivity ratios for this system are near unity, while a linear relationship between k(p,cop), the copolymer-averaged propagation rate coefficient, and the composition of macromonomer in the feed (0-80 wt% range) is determined. At 50 wt% macromonomer in the feed, a 1.67 ± 0.02 and 1.64 ± 0.06 increase in k(p,cop)/k(p,MMA) is determined for HEMA-CL3 and HEMA-CL2, respectively. These macromonomers are adopted to synthesize nanoparticles (NPs) in the range of 100-150 nm through batch emulsion free radical polymerization (BEP) to produce partially degradable drug delivery carriers. The produced NPs are tested in 4T1 cell line and show excellent characteristics as carriers: they do not affect cell proliferation, and a relevant number of NPs, thousands per cell, are internalized.

Fast in vivo imaging of amyloid plaques using µ-MRI Gd-staining combined with ultrasound-induced blood-brain barrier opening.

Amyloid plaques are one of the major microscopic lesions that characterize Alzheimer's disease. Current approaches to detect amyloid plaques by using magnetic resonance imaging (MRI) contrast agents require invasive procedures to penetrate the blood-brain barrier (BBB) and to deliver the contrast agent into the vicinity of amyloid plaques. Here we have developed a new protocol (US-Gd-staining) that enables the detection of amyloid plaques in the brain of an APP/PS1 transgenic mouse model of amyloidosis after intra-venous injection of a non-targeted, clinically approved MRI contrast agent (Gd-DOTA, Dotarem®) by transiently opening the BBB with unfocused ultrasound (1 MHz) and clinically approved microbubbles (Sonovue®, Bracco). This US-Gd-staining protocol can detect amyloid plaques with a short imaging time (32 min) and high in-plane resolution (29 µm). The sensitivity and resolution obtained is at least equal to that provided by MRI protocols using intra-cerebro-ventricular injection of contrast agents, a reference method used to penetrate the BBB. To our knowledge this is the first study to demonstrate the ability of MR imaging to detect amyloid plaques by using a peripheral intra-venous injection of a clinically approved NMR contrast agent.

Increased regional cerebral glucose uptake in an APP/PS1 model of Alzheimer's disease.

Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is characterized by the invariant cerebral accumulation of ß-amyloid peptide. This event occurs early in the disease process. In humans, [18F]-fluoro-2-deoxy-D-glucose ([18F]-FDG) positron emission tomography (PET) is largely used to follow-up in vivo cerebral glucose utilization (CGU) and brain metabolism modifications associated with the Alzheimer's disease pathology. Here, [18F]-FDG positron emission tomography was used to study age-related changes of cerebral glucose utilization under resting conditions in 3-, 6-, and 12-month-old APP(SweLon)/PS1(M146L), a mouse model of amyloidosis. We showed an age-dependent increase of glucose uptake in several brain regions of APP/PS1 mice but not in control animals and a higher [18F]-FDG uptake in the cortex and the hippocampus of 12-month-old APP/PS1 mice as compared with age-matched control mice. We then developed a method of 3-D microscopic autoradiography to evaluate glucose uptake at the level of amyloid plaques and showed an increased glucose uptake close to the plaques rather than in amyloid-free cerebral tissues. These data suggest a macroscopic and microscopic reorganization of glucose uptake in relation to cerebral amyloidosis.

Recognition and management of perioperative serotonin syndrome.

Mild forms of serotonin syndrome can potentially be fatal, if not recognized. The increased use of serotonergic agents makes the awareness of its prevalence, various presentations, diagnostic evaluation, and treatment a clinical imperative. It is important to note that serotonin syndrome can only be diagnosed clinically in the presence of 3 clinical criteria: mental status changes, autonomic manifestations, and neuromuscular abnormalities. This case report describes a patient who underwent an uncomplicated closed nasal fracture reduction and subsequently developed serotonin syndrome.

Gadolinium-staining reveals amyloid plaques in the brain of Alzheimer's transgenic mice.

Detection of amyloid plaques in the brain by in vivo neuroimaging is a very promising biomarker approach for early diagnosis of Alzheimer's disease (AD) and evaluation of therapeutic efficacy. Here we describe a new method to detect amyloid plaques by in vivo magnetic resonance imaging (MRI) based on the intracerebroventricular injection of a nontargeted gadolinium (Gd)-based contrast agent, which rapidly diffuses throughout the brain and increases the signal and contrast of magnetic resonance (MR) images by shortening the T1 relaxation time. This gain in image sensitivity after in vitro and in vivo Gd staining significantly improves the detection and resolution of individual amyloid plaques in the cortex and hippocampus of AD transgenic mice. The improved image resolution is sensitive enough to demonstrate an age-dependent increase of amyloid plaque load and a good correlation between the amyloid load measured by µMRI and histology. These results provide the first demonstration that nontargeted Gd staining can enhance the detection of amyloid plaques to follow the progression of AD and to evaluate the activity of amyloid-lowering therapeutic strategies in longitudinal studies.

In vivo imaging of neuroinflammation in the rodent brain with [11C]SSR180575, a novel indoleacetamide radioligand of the translocator protein (18 kDa).

PURPOSE: Neuroinflammation is involved in neurological disorders through the activation of microglial cells. Imaging of neuroinflammation with radioligands for the translocator protein (18 kDa) (TSPO) could prove to be an attractive biomarker for disease diagnosis and therapeutic evaluation. The indoleacetamide-derived 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, SSR180575, is a selective high-affinity TSPO ligand in human and rodents with neuroprotective effects. METHODS: Here we report the radiolabelling of SSR180575 with (11)C and in vitro and in vivo imaging in an acute model of neuroinflammation in rats. RESULTS: The image contrast and the binding of [(11)C]SSR180575 are higher than that obtained with the isoquinoline-based TSPO radioligand, [(11)C]PK11195. Competition studies demonstrate that [(11)C]SSR180575 has high specific binding for the TSPO. CONCLUSION: [(11)C]SSR180575 is the first PET radioligand for the TSPO based on an indoleacetamide scaffold designed for imaging neuroinflammation in animal models and in the clinic.

Community-associated methicillin-resistant Staphylococcus aureus survival on artificial turf substrates.

OBJECTIVE: Artificial turf has been suggested as a risk factor for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). This is an experimental study looking at survival of CA-MRSA on artificial turf. METHODS: MRSA strain USA-300-0114 was grown as either planktonic cells or biofilms in liquid cultures of beef heart infusion broth overnight at 37 °C. Beakers containing ProGrass (Pittsburgh, PA) turf were inoculated at the dirt interface with either ∼5 × 10 planktonic bacteria or with biofilms. The inoculum included varying nutrient conditions consisting of spent medium, saline, or 5% mucin. The beakers were incubated at 37 °C in ambient air. The main outcome measure was the number of surviving colony-forming units determined by plating on mannitol salt agar. RESULTS: Survival was biphasic with a colony-forming unit drop from ∼5 × 10 to ∼5 × 10 after the first week followed by survival of between 10 and 10 bacteria until termination of the experiment (20-50 d). Survival was dependent on nutrients, and washed cells survived less than 1 d. Mucin could serve as a nutrient source and slightly increased surviving numbers to 10-10 bacteria. Biofilm formation did not influence survival. CONCLUSIONS: CA-MRSA survivability on artificial turf surfaces is dependent on the availability of nutrients. These results suggest that CA-MRSA could survive on artificial turf in significant numbers for 1 wk, and lower numbers for at least 1 month, if supplied with appropriate nutrients. Outdoor environmental conditions may affect these findings.