Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease.

Dopaminergic cell loss due to the accumulation of α-syn is a core feature of the pathogenesis of Parkinson disease. Neuroinflammation specifically induced by α-synuclein has been shown to exacerbate neurodegeneration, yet the role of central nervous system (CNS) resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating α-synuclein related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the α-synuclein-mediated neuroinflammatory response.

Magnetic Field Annihilation in a Magnetotail Electron Diffusion Region With Electron-Scale Magnetic Island.

We present observations in Earth's magnetotail by the Magnetospheric Multiscale spacecraft that are consistent with magnetic field annihilation, rather than magnetic topology change, causing fast magnetic-to-electron energy conversion in an electron-scale current sheet. Multi-spacecraft analysis for the magnetic field reconstruction shows that an electron-scale magnetic island was embedded in the observed electron diffusion region (EDR), suggesting an elongated shape of the EDR. Evidence for the annihilation was revealed in the form of the island growing at a rate much lower than expected for the standard X-type geometry of the EDR, which indicates that magnetic flux injected into the EDR was not ejected from the X-point or accumulated in the island, but was dissipated in the EDR. This energy conversion process is in contrast to that in the standard EDR of a reconnecting current sheet where the energy of antiparallel magnetic fields is mostly converted to electron bulk-flow energy. Fully kinetic simulation also demonstrates that an elongated EDR is subject to the formation of electron-scale magnetic islands in which fast but transient annihilation can occur. Consistent with the observations and simulation, theoretical analysis shows that fast magnetic diffusion can occur in an elongated EDR in the presence of nongyrotropic electron effects. We suggest that the annihilation in elongated EDRs may contribute to the dissipation of magnetic energy in a turbulent collisionless plasma.

Therapeutic glucocorticoids prevent bone loss but drive muscle wasting when administered in chronic polyarthritis.

BACKGROUND: Patients with rheumatoid arthritis (RA) experience extra-articular manifestations including osteoporosis and muscle wasting, which closely associate with severity of disease. Whilst therapeutic glucocorticoids (GCs) reduce inflammation in RA, their actions on muscle and bone metabolism in the context of chronic inflammation remain unclear. We utilised the TNF-tg model of chronic polyarthritis to ascertain the impact of therapeutic GCs on bone and muscle homeostasis in the context of systemic inflammation. METHODS: TNF-tg and wild-type (WT) animals received either vehicle or the GC corticosterone (100 µg/ml) in drinking water at onset of arthritis. Arthritis severity and clinical parameters were measured, serum collected for ELISA and muscle and bone biopsies collected for µCT, histology and mRNA analysis. In vivo findings were examined in primary cultures of osteoblasts, osteoclasts and myotubes. RESULTS: TNF-tg mice receiving GCs showed protection from inflammatory bone loss, characterised by a reduction in serum markers of bone resorption, osteoclast numbers and osteoclast activity. In contrast, muscle wasting was markedly increased in WT and TNF-tg animals receiving GCs, independently of inflammation. This was characterised by a reduction in muscle weight and fibre size, and an induction in anti-anabolic and catabolic signalling. CONCLUSIONS: This study demonstrates that when given in early onset chronic polyarthritis, oral GCs partially protect against inflammatory bone loss, but induce marked muscle wasting. These results suggest that in patients with inflammatory arthritis receiving GCs, the development of interventions to manage deleterious side effects in muscle should be prioritised.

Wave Phenomena and Beam-Plasma Interactions at the Magnetopause Reconnection Region.

This paper reports on Magnetospheric Multiscale observations of whistler mode chorus and higher-frequency electrostatic waves near and within a reconnection diffusion region on 23 November 2016. The diffusion region is bounded by crescent-shaped electron distributions and associated dissipation just upstream of the X-line and by magnetic field-aligned currents and electric fields leading to dissipation near the electron stagnation point. Measurements were made southward of the X-line as determined by southward directed ion and electron jets. We show that electrostatic wave generation is due to magnetosheath electron beams formed by the electron jets as they interact with a cold background plasma and more energetic population of magnetospheric electrons. On the magnetosphere side of the X-line the electron beams are accompanied by a strong perpendicular electron temperature anisotropy, which is shown to be the source of an observed rising-tone whistler mode chorus event. We show that the apex of the chorus event and the onset of electrostatic waves coincide with the opening of magnetic field lines at the electron stagnation point.

Instability of Agyrotropic Electron Beams near the Electron Diffusion Region.

During a magnetopause crossing the Magnetospheric Multiscale spacecraft encountered an electron diffusion region (EDR) of asymmetric reconnection. The EDR is characterized by agyrotropic beam and crescent electron distributions perpendicular to the magnetic field. Intense upper-hybrid (UH) waves are found at the boundary between the EDR and magnetosheath inflow region. The UH waves are generated by the agyrotropic electron beams. The UH waves are sufficiently large to contribute to electron diffusion and scattering, and are a potential source of radio emission near the EDR. These results provide observational evidence of wave-particle interactions at an EDR, and suggest that waves play an important role in determining the electron dynamics.

Efficacy and safety of topical WBI-1001 in patients with mild to moderate psoriasis: results from a randomized double-blind placebo-controlled, phase II trial.

BACKGROUND: There is a need for the development of novel non-steroidal topical drugs for the treatment of psoriasis. OBJECTIVE: To assess the efficacy and safety of topical 1.0% WBI-1001 in patients with mild to moderate plaque psoriasis. METHODS: A total of 61 patients with 1-10% body surface area (BSA) covered with plaque psoriasis and a physician's global assessment score (PGA) of 2-4 were randomized (2:1) to receive either 1% WBI-1001 in a cream formulation or placebo, applied twice daily for 12 weeks. Efficacy was evaluated using PGA, BSA and Psoriasis Area and Severity Index (PASI). The primary endpoint was the change from baseline (Day 0) in PGA at week 12. RESULTS: The improvement in PGA at week 12 was 62.8% for patients randomized to WBI-1001 when compared with 13.0% for patients randomized to placebo (P<0.0001). At week 12, the proportion of patients who achieved a PGA of clear or almost clear and the mean improvement in BSA were 67.5% and 79.1%, respectively, for patients randomized to WBI-1001, when compared with 4.8% (P<0.0001) and an increase of 9.4% (P<0.0001), respectively, for patients randomized to placebo. More application site adverse drug reactions were observed in patients randomized to WBI-1001 than in those randomized to placebo. These adverse drug reactions were all mild or moderate in intensity. CONCLUSION: Topical WBI-1001 induces rapid and significant improvement in patients with plaque psoriasis.

Male and female rural probationers: HIV risk behaviors and knowledge.

Individuals involved in the criminal justice system are at substantial risk for HIV infection and have elevated rates of AIDS. Offenders under community supervision, such as probationers, have substantially more opportunities to engage in high-risk behaviors than prisoners. Furthermore, probationers in rural areas are at risk because rural areas may be slower to adopt HIV risk-reduction approaches. Consequently, the primary goal of this study is to describe the HIV risk behaviors and level of HIV knowledge of 800 rural felony probationers. Bivariate results indicate that males have substantially greater criminal histories and engage in more substance use risk behaviors than females. Overall, there was minimal and inconsistent use of condoms, but there were no significant differences by gender. Gender differences prevailed in perceived HIV knowledge, with females reporting high levels of perceived HIV knowledge. Multivariate models did not support the hypothesis that perceived knowledge would be a more robust correlate of scores on the HIV Risk Behavior Knowledge Test for males than females. Results suggest that rural residents are not protected from engaging in HIV risk behaviors and future studies should examine gender discrepancies between perceived and actual HIV knowledge among offenders under community supervision.

Temporary changes in populations of soil organisms after field application of entomopathogenic nematodes.

To assess the effect of an inundative release of entomopathogenic nematodes on soil organisms, population densities of soil-dwelling organisms were monitored before and after an application of an aqueous suspension of Heterorhabditis megidis to field plots in mown grassland (Exp. I) at a level of 0.38 million/m(2) and to plots (Exp. II) situated in a forested area, a grass sports field and an orchard at a level of 1.5 million/m(2). At the forested site, heat-killed H. megidis (1.5 million/m(2)) also were applied to two plots to compare the impact on soil organisms of a large introduction of living and dead nematodes. Post-treatment, temporary changes in natural population densities of several nematode genera and other organisms were detected in H. megidis-treated plots in both experiments. Temporary changes in the nematode trophic structure occurred in the percentages of nematode omnivores, herbivores and predators in both experiments. Evidence from all sites suggests that the changes were temporary and that the presence of decaying H. megidis following treatment contributed to nutrient enrichment of the soil and to direct and indirect effects on the nematode community.

Antimicrobial activity of Xenorhabdus sp. RIO (Enterobacteriaceae), symbiont of the entomopathogenic nematode, Steinernema riobrave (Rhabditida: Steinernematidae).

Galleria mellonella larvae infected with Steinernema riobrave soon showed (after 24 h) the typical growth of its Xenorhabdus sp. RIO symbiont and, in parallel, the growth of another Gram negative bacterial species in the body cavity. A population of Entercoccus sp. in the nematode infected larvae collapsed to zero by 96 h. The level of antibiotic and antimycotic activity followed a pattern similar to that of the growth curve to stationary phase of the Xenorhabdus sp. RIO symbiont, over a period of 168 h. The antimycotic activity was composed of exo- and endochitinases as well as other proteinaceous and some small molecule compounds. The changing pH, relatively high growth rate of Xenorhabdus sp. RIO compared with that of other Gram negative bacterial species and of collapse of the Enterococcus sp. population enabled Xenorhabdus sp. RIO to out-compete other species.

Data standardisation in GlycoSuiteDB.

GlycoSuiteDB, a database of glycan structures, has been constructed with an emphasis on quality, consistency and data integrity. Importance has been placed on making the database a reliable and useful resource for all researchers. This database can help researchers to identify what glycan structures are known to be attached to certain glycoproteins, as well as more generally identifying what types of glycan structures are associated with different states, for example, different species, tissues and diseases. To achieve this, a major effort has gone into data standardisation. Many rules and standards have been adopted, especially for representing glycan structure and biological source information. This paper describes some of the challenges faced during the continuous development of GlycoSuiteDB.

Antibiotic production in relation to bacterial growth and nematode development in Photorhabdus--Heterorhabditis infected Galleria mellonella larvae.

The population of Photorhabdus luminescens C9, bacterial symbiont of the entomopathogenic nematode, Heterorhabditis megidis 90, increased rapidly to 1.2-2.6x10(9) cells g(-1) wet Galleria mellonella larvae within 24 h of nematode infection of the larvae, and maintained a relatively constant level (1.2-2.0x10(10) cells g(-1)) through the entire 14-day period of nematode development. The antibiotic, 3, 5-dihydroxy-4-isopropylstilbene, was produced by P. luminescens C9 after 24 h of nematode infection, increased rapidly at 2-5 days postinfection and remained at a level of 3000-3600 microg g(-1) wet larvae until about 21 days, decreasing gradually thereafter. The early production and continued presence of a relatively large amount of 3,5-dihydroxy-4-isopropylstilbene in the infected insect supports the hypothesis that the antibiotics produced by the bacterial symbiont help minimize competition from other microorganisms and prevents the putrefaction of the nematode-infected insect cadaver.

Influence of insect larvae and seedling roots on the host-finding ability of Steinernema feltiae (Nematoda: Steinernematidae).

The ability of nematode foragers to locate appropriate insect hosts is essential to their performance as successful biological control agents. We investigated the host-finding ability and chemotaxis of Steinernema feltiae in the presence of cues from Galleria mellonella larvae and tomato and radish seedling roots, given individually and in combination, over 120 min. In agar arena tests, infective juveniles of S. feltiae responded positively to unsterilized and sterilized larvae and tomato seedling roots and negatively to unsterilized radish seedling roots. This negative response changed following surface sterilization of these seeds. The response of the infective juveniles to a combination of larva and seedling roots depended on the nature of the individual cues and their proximity to each other. For example, the response of the nematodes to a combination of cues from a sterilized larva and an unsterilized tomato seedling root placed adjacent to each other was intermediate to the separate responses to cues from a sterilized larva and an unsterilized tomato seedling root given individually. However, the response of the nematodes to a combination of adjacent cues from a sterilized larva and an unsterilized radish seedling root was not significantly different from that to cues from an unsterilized radish seedling root given individually. When the cues from the larva and seedling roots were separated by a distance, the response of the nematodes favored the larva. However, this positive effect was lessened when the larva was surface sterilized as compared with the response to the unsterilized larva. The altered responses of the infective juveniles to target cues following surface sterilization suggest that cues from the larval cuticle and seedling roots, such as those associated with their surface microflora, may significantly influence their host-finding ability. The use of entomopathogenic nematodes as biological control agents under field applications can be improved by careful consideration of the application protocols and by the recognition that chemical alterations of the soil rhizosphere may influence their host-finding ability.

Ecological factors in schistosome transmission, and an environmentally benign method for controlling snails in a recreational lake with a record of schistosome dermatitis.

The avian schistosomes, Trichobilharzia stagnicolae, T. physellae and Gigantobilharzia sp., that cause Schistosome Dermatitis (Swimmers' Itch) in humans were studied in the laboratory and at Cultus Lake, British Columbia, Canada in relation to the biology and behavior of their intermediate snail hosts, Stagnicola catascopium, Physa sp. and Gyraulus parvus, respectively, and their definite bird hosts. Wind-driven, surface currents were measured. Populations of snails, close to host-bird roosting logs had a very high prevalence of schistosome infections. An experiment that mechanically disturbed the epilithic habitat of the snails using a boat-mounted rototiller or a tractor and rake, eliminated almost all of the snails if the disturbance was done in areas of high snail concentration in shallow areas of the lake during the breeding and early development phase of the snail. It is proposed that the incorporation of snail habitat disturbance into management programs is an effective way to control Schistosome Dermatitis.

Development of Kudoa thyrsites (Myxozoa: Myxosporea) in netpen-reared Atlantic salmon determined by light microscopy and a polymerase chain reaction test.

The intramuscular phase of development of Kudoa thyrsites, the myxosporean associated with post-mortem myoliquefaction, or 'soft flesh syndrome', is described using histological preparations of the musculature of seawater netpen-reared Atlantic salmon Salmo salar. Hatchery-reared Atlantic salmon were naturally exposed to the infective stage while held in the experimental seawater netpens of the Pacific Biological Station in Nanaimo, British Columbia, Canada. In fish exposed during the summer of 1995, K. thyrsites infections were first detected in the somatic musculature at 13 wk post-exposure (p.e.) using only light microscopy. In the 1997 exposure, infections were first detected at 6 wk p.e. using a PCR test and at 9 wk p.e. using light microscopy. The earliest stage detected by histology was a small plasmodium containing 4 nuclei. No host response was observed that was directly related to the presence of intact plasmodia within muscle fibers. However, a response was associated with ruptured plasmodia, which was characterized by chronic, multifocal inflammation between the muscle fibers.

Infectivity, distribution, and persistence of the entomopathogenic nematode Steinernema carpocapsae all strain (Rhabditida: Steinernematidae) applied by sprinklers or boom sprayer to dry-pick cranberries.

We evaluated infectivity, distribution, and persistence of commercially produced Steinernema carpocapsae (Weiser) All strain applied through solid set sprinkler irrigation or boom sprayer to 2 dry-pick cranberry farms on peat soil in British Columbia in 1993. Most infectivity assays used Galleria mellonella (L.) larvae. When possible, larvae of the target pest, Otiorynchus sulcatas (F.) were used as assay organisms. Nematodes in almost all samples of nematode suspensions diluted from shipping containers, from spray tanks, or collected in cups after passage through application equipment were infective to G. mellonella larvae. When O. sulcatus larvae were used as assay organisms, 93% (n = 14) of assays from the spray tank and 67% (n = 12) of assays after application showed infectivity. In the spring, sprinklers delivered nematodes to only 15 of 20 sample points on the 0.2-ha plot; delivery by the boom sprayer was better but 2 of 20 points on the 0.2-ha plot received approximately twice as many nematodes as the other points. In the fall, nematode delivery by both systems was more even. However, the average number of nematodes per milliliter of sprayed water collected from the 20 samples on each farm after each application did not correspond to the rates of nematodes applied. Persistence of nematodes in the soil was encouraging, but percentage of infectivity was lower than expected. After application in the spring, assays using G. mellonella larvae showed the presence of infective nematodes in soil samples (0-5 and 5-10 cm deep) on each sampling day (0, 3, 7, and 25) after application by boom sprayer, and on days 0, 3, and 7 after application through sprinklers. In the fall, G. mellonella assays showed infective nematodes in soil samples on each sampling day (0, 3, 7, and 25) after application by boom sprayer, and on days 0, 3, 7, 35, 60, 135, and 250 after application through sprinklers. In the spring, when assays lasted 4 d, percentage of infectivity rose to a maximum of 45% on the 3rd d after application by boom sprayer and declined thereafter. In the fall, when assays lasted 10 d, percentage of infectivity rose to a maximum of 58% on the 7th d after application through sprinklers and remained between 20 and 58% until day 135, declining thereafter; infectivity after boom application remained between 37 and 45% on days 3 and 7, and began to decline on day 25. Nematode infectivity was not compromised in peat soil, muck, or silty clay loam, but infectivity in loam (that may have contained nematicide residues) was very low. We suggest that the inconsistent control of O. sulcatus by S. carpocapsae on British Columbia cranberry farms may be partially explained by problems associated with application and factors related to nematode entry into the soil.

Factors influencing the infectivity of a Canadian isolate of Steinernema kraussei (Nematoda: Steinernematidae) at low temperature.

The effectiveness of Canadian isolate 76 of Steinernema kraussei, at 10 degrees C, in penetrating Galleria mellonella larvae (percentage parasitism and number of IJs developed to adult nematodes) was measured at different host densities (differing number of larvae and size of experimental arena) and for different durations of exposure. The greater the size of the inoculum of infective juvenile nematodes per unit area and the longer the duration of exposure, the greater the number of larvae that were killed and the larger the number of mature nematodes in the larval host. The infection rate (alpha) and the adjusted infection rate (beta) were determined using the modified Anderson model. This model successfully described the behavior of the S. kraussei-G. mellonella interaction.

Down-regulation of types I, II and III inositol 1,4,5-trisphosphate receptors is mediated by the ubiquitin/proteasome pathway.

Activation of certain phosphoinositidase-C-linked cell-surface receptors is known to cause an acceleration of the proteolysis of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptors and, thus, lead to Ins(1,4,5)P3-receptor down-regulation. In the current study we have sought to determine whether the ubiquitin/proteasome pathway is involved in this adaptive response. The data presented show (i) that activation of phosphoinositidase-C-linked receptors causes Ins(1,4,5)P3-receptor ubiquitination in a range of cell types (AR4-2J cells, INS-1 cells and rat cerebellar granule cells), (ii) that the Ins(1,4,5)P3-receptor down-regulation induced by activation of these receptors is blocked by proteasome inhibitors, (iii) that all known Ins(1,4,5)P3 receptors (types I, II and III) are substrates for ubiquitination, (iv) that ubiquitination occurs while Ins(1,4,5)P3 receptors are membrane-bound, (v) that Ins(1,4, 5)P3-receptor ubiquitination and down-regulation are stimulated only by those agonists that elevate Ins(1,4,5)P3 concentration persistently, and (vi) that a portion of cellular Ins(1,4,5)P3 receptors (those that are not type-I-receptor-associated) can be resistant to ubiquitination and degradation. In total these data indicate that the ubiquitin/proteasome pathway mediates Ins(1,4, 5)P3-receptor down-regulation and suggest that ubiquitination is stimulated by the binding of Ins(1,4,5)P3 to its receptor.

Temperature Effects on Heterorhabditis megidis and Steinernema carpocapsae Infectivity to Galleria mellonella.

The effect of temperature on the infection of larvae of the greater wax moth, Galleria mellonella, by Heterorhabditis megidis H90 and Steinernema carpocapsae strain All, was determined. For both species, infection, reproduction, and development were fastest at 20 to 24 degrees C. Infection by both H. megidis and S. carpocapsae occurred between 8 and 16 degrees C; however, neither species reproduced at 8 degrees C. Among the nematodes used in experiments at 8 degrees C, no H. megidis and very few S. carpocapsae developed beyond the infective juvenile stage. Compared with H. megidis, S. carpocapsae invaded and killed G. mellonella larvae faster at 8 to 16 degrees C. By comparing invasion rates, differences in infectivity between the two nematode species were detected that could not be detected in conventional petri dish bioassays where mortality was measured after a specified period. Invasion of G. mellonella larvae by H. megidis was faster at 24 than at 16 degrees C.

Parasitic worms: an ally in the war against the superbugs.

The entomopathogenic nematodes are now of considerable scientific interest not only because of their function as biological control agents, but because of the potential medical and agricultural importance of the metabolic products of their symbiotic bacteria. Initial exploration in Australia, a decade ago, has blossomed into a significant area of research activity as we discover the nematicidal, anticancer, antimycotic and antibiotic properties of these bacterially derived compounds. Some of the antibiotics are novel compounds, and they might form the basis of the next round of drugs against the superbugs, as discussed here by John Webster, Genhui Chen and Jianxong Li.