Exploiting formyl peptide receptor 2 to promote microglial resolution: a new approach to Alzheimer's disease treatment.

Alzheimer’s disease and dementia are among the most significant current healthcare challenges given the rapidly growing elderly population, and the almost total lack of effective therapeutic interventions. Alzheimer’s disease pathology has long been considered in terms of accumulation of amyloid beta and hyperphosphorylated tau, but the importance of neuroinflammation in driving disease has taken greater precedence over the last 15–20 years. Inflammatory activation of the primary brain immune cells, the microglia, has been implicated in Alzheimer’s pathogenesis through genetic, preclinical, imaging and postmortem human studies, and strategies to regulate microglial activity may hold great promise for disease modification. Neuroinflammation is necessary for defence of the brain against pathogen invasion or damage but is normally self-limiting due to the engagement of endogenous pro-resolving circuitry that terminates inflammatory activity, a process that appears to fail in Alzheimer’s disease. Here, we discuss the potential for a major regulator and promoter of resolution, the receptor FPR2, to restrain pro-inflammatory microglial activity, and propose that it may serve as a valuable target for therapeutic investigation in Alzheimer’s disease

It’s all about time : Precision and accuracy of Emotiv event-marking for ERPD research

Background The use of consumer-grade electroencephalography (EEG) systems for research purposes has become more prevalent. In event-related potential (ERP) research, it is critical that these systems have precise and accurate timing. The aim of the current study was to investigate the timing reliability of event-marking solutions used with Emotiv commercial EEG systems. Method We conducted three experiments. In Experiment 1 we established a jitter threshold (i.e. the point at which jitter made an event-marking method unreliable). To do this, we introduced statistical noise to the temporal position of event-marks of a pre-existing ERP dataset (recorded with a research-grade system, Neuroscan SynAmps2 at 1,000 Hz using parallel-port event-marking) and calculated the level at which the waveform peaks differed statistically from the original waveform. In Experiment 2 we established a method to identify ‘true’ events (i.e. when an event should appear in the EEG data). We did this by inserting 1,000 events into Neuroscan data using a custom-built event-marking system, the ‘Airmarker’, which marks events by triggering voltage spikes in two EEG channels. We used the lag between Airmarker events and events generated by Neuroscan as a reference for comparisons in Experiment 3. In Experiment 3 we measured the precision and accuracy of three types of Emotiv event-marking by generating 1,000 events, 1 s apart. We measured precision as the variability (standard deviation in ms) of Emotiv events and accuracy as the mean difference between Emotiv events and true events. The three triggering methods we tested were: (1) Parallel-port-generated TTL triggers; (2) Arduino-generated TTL triggers; and (3) Serial-port triggers. In Methods 1 and 2 we used an auxiliary device, Emotiv Extender, to incorporate triggers into the EEG data. We tested these event-marking methods across three configurations of Emotiv EEG systems: (1) Emotiv EPOC+ sampling at 128 Hz; (2) Emotiv EPOC+ sampling at 256 Hz; and (3) Emotiv EPOC Flex sampling at 128 Hz. Results In Experiment 1 we found that the smaller P1 and N1 peaks were attenuated at lower levels of jitter relative to the larger P2 peak (21 ms, 16 ms, and 45 ms for P1, N1, and P2, respectively). In Experiment 2, we found an average lag of 30.96 ms for Airmarker events relative to Neuroscan events. In Experiment 3, we found some lag in all configurations. However, all configurations exhibited precision of less than a single sample, with serial-port-marking the most precise when paired with EPOC+ sampling at 256 Hz. Conclusion All Emotiv event-marking methods and configurations that we tested were precise enough for ERP research as the precision of each method would provide ERP waveforms statistically equivalent to a research-standard system. Though all systems exhibited some level of inaccuracy, researchers could easily account for these during data processing

Ectoplasm & Superspace Integration Measure for 2D Supergravity with Four Spinorial Supercurrents

Building on a previous derivation of the local chiral projector for a two dimensional superspace with eight real supercharges, we provide the complete density projection formula required for locally supersymmetrical theories in this context. The derivation of this result is shown to be very efficient using techniques based on the Ectoplasmic construction of local measures in superspace.Comment: 18 pages, LaTeX; V2: minor changes, typos corrected, references added; V3: version to appear in J. Phys. A: Math. Theor., some comments and references added to address a referee reques

Natural organic matter in sedimentary basins and its relation to arsenic in anoxic ground water: the example of West Bengal and its worldwide implications

In order to investigate the mechanism of As release to anoxic ground water in alluvial aquifers, the authors sampled ground waters from 3 piezometer nests, 79 shallow (80 m) wells, in an area 750 m by 450 m, just north of Barasat, near Kolkata (Calcutta), in southern West Bengal. High concentrations of As (200-1180 mug L-1) are accompanied by high concentrations of Fe (3-13.7 mgL(-1)) and PO4 (1-6.5 mg L-1). Ground water that is rich in Mn (1-5.3 mg L-1) contains <50 mug L-1 of As. The composition of shallow ground water varies at the 100-m scale laterally and the metre-scale vertically, with vertical gradients in As concentration reaching 200 mug L-1 m(-1). The As is supplied by reductive dissolution of FeOOH and release of the sorbed As to solution. The process is driven by natural organic matter in peaty strata both within the aquifer sands and in the overlying confining unit. In well waters, thermotolerant coliforms, a proxy for faecal contamination, are not present in high numbers (<10 cfu/100 ml in 85% of wells) showing that faecally-derived organic matter does not enter the aquifer, does not drive reduction of FeOOH, and so does not release As to ground water.Arsenic concentrations are high (much greater than50 mug L-1) where reduction of FeOOH is complete and its entire load of sorbed As is released to solution, at which point the aquifer sediments become grey in colour as FeOOH vanishes. Where reduction is incomplete, the sediments are brown in colour and resorption of As to residual FeOOH keeps As concentrations below 10 mug L-1 in the presence of dissolved Fe. Sorbed As released by reduction of Mn oxides does not increase As in ground water because the As resorbs to FeOOH. High concentrations of As are common in alluvial aquifers of the Bengal Basin arise because Himalayan erosion supplies immature sediments, with low surface-loadings of FeOOH on mineral grains, to a depositional environment that is rich in organic mater so that complete reduction of FeOOH is common. (C) 2004 Published by Elsevier Ltd

A host-gut microbial amino acid co-metabolite, p-cresol glucuronide, promotes blood-brain barrier integrity in vivo.

The sequential activity of gut microbial and host processes can exert a powerful modulatory influence on dietary components, as exemplified by the metabolism of the amino acids tyrosine and phenylalanine to p-cresol by gut microbes, and then to p-cresol glucuronide (pCG) by host enzymes. Although such glucuronide conjugates are classically thought to be biologically inert, there is accumulating evidence that this may not always be the case. We investigated the activity of pCG, studying its interactions with the cerebral vasculature and the brain in vitro and in vivo. Male C57Bl/6 J mice were used to assess blood-brain barrier (BBB) permeability and whole-brain transcriptomic changes in response to pCG treatment. Effects were then further explored using the human cerebromicrovascular endothelial cell line hCMEC/D3, assessing paracellular permeability, transendothelial electrical resistance and barrier protein expression. Mice exposed to pCG showed reduced BBB permeability and significant changes in whole-brain transcriptome expression. Surprisingly, treatment of hCMEC/D3 cells with pCG had no notable effects until co-administered with bacterial lipopolysaccharide, at which point it was able to prevent the permeabilizing effects of endotoxin. Further analysis suggested that pCG acts as an antagonist at the principal lipopolysaccharide receptor TLR4. The amino acid phase II metabolic product pCG is biologically active at the BBB, antagonizing the effects of constitutively circulating lipopolysaccharide. These data add to the growing literature showing glucuronide conjugates to be more than merely metabolic waste products and highlight the complexity of gut microbe to host communication pathways underlying the gut-brain axis

The SU(N) Matrix Model at Two Loops

Multi-loop calculations of the effective action for the matrix model are important for carrying out tests of the conjectured relationship of the matrix model to the low energy description of M-theory. In particular, comparison with N-graviton scattering amplitudes in eleven-dimensional supergravity requires the calculation of the effective action for the matrix model with gauge group SU(N). A framework for carrying out such calculations at two loops is established in this paper. The two-loop effective action is explicitly computed for a background corresponding to the scattering of a single D0-brane from a stack of N-1 D0-branes, and the results are shown to agree with known results in the case N=2.Comment: 30 pages, 1 figure; v2 - typos corrected, references update

Human Research Ethics Committee Experiences and Views About Children's Participation in Research: Results From the MESSI Study.

As part of a larger study, Australian Human Research Ethics Committee (HREC) members and managers were surveyed about their decision-making and views about social research studies with child participants. Responses of 229 HREC members and 42 HREC managers are reported. While most HREC members had received ethical training, HREC training and guidelines specific to research involving children were rare. Most applications involving children had to go through a full ethical review, but few adverse events were reported to HRECs regarding the conduct of the studies. Revisions to study proposals requested by HRECs were mostly related to consent processes and age-appropriate language. One-third of HREC members said that they would approve research on any topic. Most were also concerned that the methodology was appropriate, and the risks and benefits were clearly articulated. Specific training and guidance are needed to increase HREC members' confidence to judge ethical research with children

A validation of Emotiv EPOC Flex saline for EEG and ERP research

Background Previous work has validated consumer-grade electroencephalography (EEG) systems for use in research. Systems in this class are cost-effective and easy to set up and can facilitate neuroscience outside of the laboratory. The aim of the current study was to determine if a new consumer-grade system, the Emotiv EPOC Saline Flex, was capable of capturing research-quality data. Method The Emotiv system was used simultaneously with a research-grade EEG system, Neuroscan Synamps2, to collect EEG data across 16 channels during five well-established paradigms: (1) a mismatch negativity (MMN) paradigm that involved a passive listening task in which rare deviant (1,500 Hz) tones were interspersed amongst frequent standard tones (1,000 Hz), with instructions to ignore the tones while watching a silent movie; (2) a P300 paradigm that involved an active listening task in which participants were asked to count rare deviant tones presented amongst frequent standard tones; (3) an N170 paradigm in which participants were shown images of faces and watches and asked to indicate whether the images were upright or inverted; (4) a steady-state visual evoked potential (SSVEP) paradigm in which participants passively viewed a flickering screen (15 Hz) for 2 min; and (5) a resting state paradigm in which participants sat quietly with their eyes open and then closed for 3 min each. Results The MMN components and P300 peaks were equivalent between the two systems (BF10 = 0.25 and BF10 = 0.26, respectively), with high intraclass correlations (ICCs) between the ERP waveforms (>0.81). Although the N170 peak values recorded by the two systems were different (BF10 = 35.88), ICCs demonstrated that the N170 ERP waveforms were strongly correlated over the right hemisphere (P8; 0.87–0.97), and moderately-to-strongly correlated over the left hemisphere (P7; 0.52–0.84). For the SSVEP, the signal-to-noise ratio (SNR) was larger for Neuroscan than Emotiv EPOC Flex (19.94 vs. 8.98, BF10 = 51,764), but SNR z-scores indicated a significant brain response at the stimulus frequency for both Neuroscan (z = 12.47) and Flex (z = 11.22). In the resting state task, both systems measured similar alpha power (BF10 = 0.28) and higher alpha power when the eyes were closed than open (BF10 = 32.27). Conclusions The saline version of the Emotiv EPOC Flex captures data similar to that of a research-grade EEG system. It can be used to measure reliable auditory and visual research-quality ERPs. In addition, it can index SSVEP signatures and is sensitive to changes in alpha oscillations

Evidence for a Long-period Planet Orbiting Epsilon Eridani

High precision radial velocity (RV) measurements spanning the years 1980.8--2000.0 are presented for the nearby (3.22 pc) K2 V star $\epsilon$ Eri. These data, which represent a combination of six independent data sets taken with four different telescopes, show convincing variations with a period of $\approx$ 7 yrs. A least squares orbital solution using robust estimation yields orbital parameters of period, $P$ = 6.9 yrs, velocity $K$-amplitude $=$ 19 {\ms}, eccentricity $e$ $=$ 0.6, projected companion mass $M$ sin $i$ = 0.86 $M_{Jupiter}$, and semi-major axis $a_2$ $=$ 3.3 AU. Ca II H&K S-index measurements spanning the same time interval show significant variations with periods of 3 and 20 yrs, yet none at the RV period. If magnetic activity were responsible for the RV variations then it produces a significantly different period than is seen in the Ca II data. Given the lack of Ca II variation with the same period as that found in the RV measurements, the long-lived and coherent nature of these variations, and the high eccentricity of the implied orbit, Keplerian motion due to a planetary companion seems to be the most likely explanation for the observed RV variations. The wide angular separation of the planet from the star (approximately 1 arc-second) and the long orbital period make this planet a prime candidate for both direct imaging and space-based astrometric measurements.Comment: To appear in Astrophysical Journal Letters. 9 pages, 2 figure

Wess-Zumino Terms in Supersymmetric Gauge Theories

The Wess-Zumino term is constructed for supersymmetric QCD with two colors and flavors, and is shown to correctly reproduce the anomalous Ward identities. Supersymmetric QCD is also shown not to have topologically stable skyrmion solutions because of baryon flat directions, which allow them to unwind. The generalization of these results to other supersymmetric theories with quantum modified constraints is discussed.Comment: 4 pages (revtex