TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy

Significance Alzheimer’s disease (AD) is the most common cause of dementia and is a major public health problem for which there is currently no disease-modifying treatment. There is an urgent need for greater understanding of the molecular mechanisms underlying neurodegeneration in patients to create better therapeutic options. Recently, genetic studies uncovered novel AD risk variants in the microglial receptor, triggering receptor expressed on myeloid cells 2 (TREM2). Previous studies suggested that loss of TREM2 function worsens amyloid-β (Aβ) plaque-related toxicity. In contrast, we observe TREM2 deficiency mitigates neuroinflammation and protects against brain atrophy in the context of tau pathology. These findings indicate dual roles for TREM2 and microglia in the context of amyloid versus tau pathology, which are important to consider for potential treatments targeting TREM2.</jats:p

PEDOT doped with algal, mammalian and synthetic dopants: polymer properties, protein and cell interactions, and influence of electrical stimulation on neuronal cell differentiation

Poly(3,4-ethylenedioxythiophene) (PEDOT) films were electrochemically polymerised with several synthetic (dodecylbenzosulfonic acid (DBSA)) and biological (dextran sulphate (DS), chondroitin sulphate (CS), alginic acid (ALG) and ulvan (ULV)) dopant anions, and their physical, mechanical and electrochemical properties characterised. PEDOT films incorporating the biological dopants ALG and ULV produced films of the greatest surface roughness (46 ± 5.1 and 31 ± 1.9 nm, respectively), and demonstrated significantly lower shear modulus values relative to all other PEDOT films (2.1 ± 0.1 and 1.2 ± 0.2 MPa, respectively). Quartz crystal microgravimetry was used to study the adsorption of the important extracellular matrix protein fibronectin, revealing protein adsorption to be greatest on PEDOT doped with DS, followed by DBSA, ULV, CS and ALG. Electrical stimulation experiments applying a pulsed current using a biphasic waveform (250 Hz) were undertaken using PEDOT doped with either DBSA or ULV. Electrical stimulation had a significant influence on cell morphology and cell differentiation for PEDOT films with either dopant incorporated, with the degree of branching per cell increased by 10.5x on PEDOT-DBSA and 6.5x on PEDOT-ULV relative to unstimulated cells, and mean neurite length per cell increasing 2.6x and 2.2x on stimulated vs. unstimulated PEDOT-DBSA and PEDOT-ULV, respectively. We demonstrate the cytocompatibility of synthetic and biologically doped PEDOT biomaterials, including the new algal derived polysaccharide dopant ulvan, which, along with DBSA doped PEDOT, is shown to significantly enhance the differentiation of PC12 neuronal cells under electrical stimulation

Electrical stimulation enhances the acetylcholine receptors available for neuromuscular junction formation

Neuromuscular junctions (NMJ) are specialized synapses that link motor neurons with muscle fibers. These sites are fundamental to human muscle activity, controlling swallowing and breathing amongst many other vital functions. Study of this synapse formation is an essential area in neuroscience; the understanding of how neurons interact and control their targets during development and regeneration are fundamental questions. Existing data reveals that during initial stages of development neurons target and form synapses driven by biophysical and biochemical cues, and during later stages they require electrical activity to develop their functional interactions. The aim of this study was to investigate the effect of exogenous electrical stimulation (ES) electrodes directly in contact with cells, on the number and size of acetylcholine receptor (AChR) clusters available for NMJ formation. We used a novel in vitro model that utilizes a flexible electrical stimulation system and allows the systematic testing of several stimulation parameters simultaneously as well as the use of alternative electrode materials such as conductive polymers to deliver the stimulation. Functionality of NMJs under our co-culture conditions was demonstrated by monitoring changes in the responses of primary myoblasts to chemical stimulants that specifically target neuronal signaling. Our results suggest that biphasic electrical stimulation at 250 Hz, 100 ¿s pulse width and current density of 1 mA/cm2 for 8 h, applied via either gold-coated mylar or the conductive polymer PPy, significantly increased the number and size of AChRs clusters available for NMJ formation. This study supports the beneficial use of direct electrical stimulation as a strategic therapy for neuromuscular disorders

Electrical stimulation using conductive polymer polypyrrole promotes differentiation of human neural stem cells: a biocompatible platform for translational neural tissue engineering

Conductive polymers (CPs) are organic materials that hold great promise for biomedicine. Potential applications include in vitro or implantable electrodes for excitable cell recording and stimulation, and conductive scaffolds for cell support and tissue engineering. Here we demonstrate the utility of electroactive CP Polypyrrole (PPy) containing the anionic dopant dodecylbenzenesulfonate (DBS) to differentiate novel clinically relevant human neural stem cells (hNSCs). Electrical stimulation of PPy(DBS) induced hNSCs to predominantly β-III Tubulin (Tuj1) expressing neurons, with lower induction of glial fibrillary acidic protein (GFAP) expressing glial cells. In addition, stimulated cultures comprised nodes or clusters of neurons with longer neurites and greater branching than unstimulated cultures. Cell clusters showed a similar spatial distribution to regions of higher conductivity on the film surface. Our findings support the use of electrical stimulation to promote neuronal induction and the biocompatibility of PPy(DBS) with hNSCs, and opens up the possibility of identifying novel mechanisms of fate determination of differentiating human stem cells for advanced in vitro modelling, translational drug discovery and regenerative medicine

Selection of ground motion prediction equations for the global earthquake model

Ground motion prediction equations (GMPEs) relate ground motion intensity measures to variables describing earthquake source, path, and site effects. From many available GMPEs, we select those models recommended for use in seismic hazard assessments in the Global Earthquake Model. We present a GMPE selection procedure that evaluates multidimensional ground motion trends (e.g., with respect to magnitude, distance, and structural period), examines functional forms, and evaluates published quantitative tests of GMPE performance against independent data. Our recommendations include: four models, based principally on simulations, for stable continental regions; three empirical models for interface and in-slab subduction zone events; and three empirical models for active shallow crustal regions. To approximately incorporate epistemic uncertainties, the selection process accounts for alternate representations of key GMPE attributes, such as the rate of distance attenuation, which are defensible from available data. Recommended models for each domain will change over time as additional GMPEs are developed

Bacterial Filtration Using Carbon Nanotube/Antibiotic Buckypaper Membranes

The preparation of free-standing carbon nanotube “buckypaper” (BP) membranes consisting of either single-walled carbon nanotubes (SWNTs) or multi-walled carbon nanotubes (MWNTs), and the antibiotic ciprofloxacin (cipro), is reported. The electrical, mechanical and morphological properties of these membranes have been characterised and are compared to those of the corresponding buckypaper membranes containing the surfactant Triton X-100 (Trix). Analysis of scanning electron microscopic images of the surfaces of SWNT/cipro and SWNT/Trix (Trix  =  Triton X-100) buckypapers revealed that the diameter of their surface pores was significantly smaller than that of the corresponding materials prepared using MWNTs. Similarly, the average internal pore diameter of both SWNT buckypapers was found to be smaller than that of their MWNT counterparts, after analysis of binding isotherms derived from nitrogen adsorption/desorption measurements performed on the materials. All four buckypaper membranes examined were found to be >99% effective for removing Escherichia coli (E. coli) from aqueous suspensions. However, buckypapers containing ciprofloxacin outperformed their counterparts containing the surfactant. Both MWNT buckypapers were more effective at preventing passage of E. coli than their analogues containing SWNTs, while fluorescence microscopic examination of stained membrane surfaces demonstrated that buckypapers composed of SWNTs had greater bactericidal properties

Establishment of a community managed marine reserve in the Bay of Ranobe, southwest Madagascar

The Bay of Ranobe, in southwest Madagascar, once noted for its high biodiversity and fish abundance, is under increasing pressure from overfishing, pollution, sedimentation and tourism. The declining health of the coral reef is reflected in fishery productivity and survey data on biological diversity. Sustainable conservation requires the engagement of all interested parties and the integration of their needs into resource management. The British NGO ReefDoctor has adopted this approach in establishing the first community-protected site in the Bay of Ranobe, the Massif des Roses. This is a large coral patch with a high percentage of live coral cover (38%) and important fish diversity compared to other sites surveyed in the lagoon. Since 25 May 2007 it has been legally recognised as a community managed marine reserve under temporary protection where fishing is banned. Tourists must now pay an entry fee to visit the site, with the proceeds contributing to the funding of community projects. In conjunction with the protection of this site, ReefDoctor has worked with local people, regional and local government, tour operators and hotels, and conservation organisations to set up ‘FIMIHARA’, an association representative of local people responsible for the management of this site and the development of sustainable conservation initiatives in the Bay of Ranobe. This paper explains the approach taken by ReefDoctor, by setting up and working with FIMIHARA, to protect the Massif des Roses site and develop other conservation initiatives and community projects in the Bay of Ranobe. RÉSUMÉ La baie de Ranobe, au sud-ouest de Madagascar, autrefois remarquable pour sa biodiversité et l’abondance de la pêche, est de plus en plus menacée par la surpêche, la sédimentation, la pollution et le tourisme. Le déclin de l’état de santé du récif corallien se reflète dans la diminution de la productivité des pêcheries et dans les suivis de la biodiversité marine. La situation est à présent critique car les ressources marines associées au récif assurent la subsistance des populations côtières vivant le long de la baie. Nous considérons ici qu’une protection pérenne nécessite un engagement concret de toutes les parties prenantes - en particulier des communautés locales - et que leurs besoins soient intégrés dans la gestion des ressources. L’ONG ReefDoctor a mis en oeuvre cette approche lors de la création de la première réserve marine dans la baie de Ranobe gérée par la communauté locale, le Massif des Roses. Cette réserve est constituée d’un grand massif de corail largement couvert de coraux et abritant une importante diversité de poissons par rapport au reste du lagon. Depuis le 25 mai 2007, ce site est légalement reconnu comme réserve marine communautaire avec un statut de protection temporaire ; la pêche et les pratiques destructrices associées au tourisme y sont interdites. De plus, les touristes doivent désormais payer un droit d’entrée pour visiter le site, qui contribue au financement de projets communautaires. En parallèle avec la protection du site, ReefDoctor a travaillé avec les communautés locales, les responsables nationaux et régionaux du gouvernement, les opérateurs touristiques et diverses organisations de protection de la nature pour créer l’association FIMIHARA, représentative de la population locale. Cette association, qui a un statut légal depuis le 11 avril 2007, a pour but d’améliorer la qualité de vie de ceux qui vivent le long de la baie de Ranobe et de mettre en oeuvre des projets de conservation des ressources marines et terrestres dans la région de la baie de Ranobe. La création de la réserve marine communautaire du Massif des Roses a rapidement connu le succès qui s’est traduit par la vente de plus d’un millier de tickets, mais l’association FIMIHARA doit encore faire face à de nombreux défis. L’objectif principal de l’association à long terme est de développer son indépendance par rapport à l’ONG ReefDoctor et sa capacité à gérer indépendamment les ressources marines de la baie de Ranobe dont les communautés locales dépendent pour leur survie

Interference of flavonoids with enzymatic assays for the determination of free fatty acid and triglyceride levels

Flavonoids are bioactive food compounds with potential lipid-lowering effects. Commercially available enzymatic assays are widely used to determine free fatty acid (FFA) and triglyceride (TG) levels both in vivo in plasma or serum and in vitro in cell culture medium or cell lysate. However, we have observed that various flavonoids interfere with peroxidases used in these enzymatic assays, resulting in incorrect lower FFA and TG levels than actually present. Furthermore, addition of isorhamnetin or the major metabolite of the flavonoid quercetin in human and rat plasma, quercetin-3-O-glucuronide, to murine serum also resulted in a significant reduction of the detected TG levels, while a trend was seen for FFA levels. It is concluded that when applying these assays, vigilance is needed and alternative analytical methods, directly assessing FFA or TG levels, should be used for studying the biological effects of flavonoids on FFA and TG levels

Periodontal treatment to improve glycaemic control in diabetic patients: study protocol of the randomized, controlled DIAPERIO trial

<p>Abstract</p> <p>Background</p> <p>Periodontitis is a common, chronic inflammatory disease caused by gram-negative bacteria leading to destruction of tissues supporting the teeth. Epidemiological studies have consistently shown increased frequency, extent and severity of periodontitis among diabetic adults. More recently, some controlled clinical trials have also suggested that periodontal treatment could improve glycaemic control in diabetic patients. However current evidence does not provide sufficient information on which to confidently base any clinical recommendations. The main objective of this clinical trial is to assess whether periodontal treatment could lead to a decrease in glycated haemoglobin levels in metabolically unbalanced diabetic patients suffering from chronic periodontitis.</p> <p>Methods</p> <p>The DIAPERIO trial is an open-label, 13-week follow-up, randomized, controlled trial. The total target sample size is planned at 150 participants, with a balanced (1:1) treatment allocation (immediate treatment vs delayed treatment). Periodontal treatment will include full mouth non-surgical scaling and root planing, systemic antibiotherapy, local antiseptics (chlorhexidine 0.12%) and oral health instructions. The primary outcome will be the difference in change of HbA1c between the two groups after the 13-weeks' follow-up. Secondary outcomes will be the difference in change of fructosamine levels and quality of life between the two groups.</p> <p>Discussion</p> <p>The DIAPERIO trial will provide insight into the question of whether periodontal treatment could lead to an improvement in glycaemic control in metabolically unbalanced diabetic patients suffering from periodontitis. The results of this trial will help to provide evidence-based recommendations for clinicians and a draft framework for designing national health policies.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN15334496</p