Macrophages in Alzheimer’s disease: the blood-borne identity

Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder clinically characterized by cognitive decline involving loss of memory, reasoning and linguistic ability. The amyloid cascade hypothesis holds that mismetabolism and aggregation of neurotoxic amyloid-β (Aβ) peptides, which are deposited as amyloid plaques, are the central etiological events in AD. Recent evidence from AD mouse models suggests that blood-borne mononuclear phagocytes are capable of infiltrating the brain and restricting β-amyloid plaques, thereby limiting disease progression. These observations raise at least three key questions: (1) what is the cell of origin for macrophages in the AD brain, (2) do blood-borne macrophages impact the pathophysiology of AD and (3) could these enigmatic cells be therapeutically targeted to curb cerebral amyloidosis and thereby slow disease progression? This review begins with a historical perspective of peripheral mononuclear phagocytes in AD, and moves on to critically consider the controversy surrounding their identity as distinct from brain-resident microglia and their potential impact on AD pathology

Non-invasive measurements of atherosclerosis in adult cystinosis patients

Item does not contain fulltextBACKGROUND: Cystinosis is characterized by intralysosomal cystine accumulation, causing end stage renal disease around 10 years of age if not treated with cysteamine. Cystine accumulation in blood vessels might increase atheroma formation or arterial stiffness and therefore increase the risk for cardiovascular disease (CVD). This study aimed to investigate the risk for CVD by non-invasive measures of atherosclerosis (NIMA) and to evaluate the effect of cysteamine treatment. PATIENTS AND METHODS: Thirteen Dutch adult cystinosis patients were included. White blood cell (WBC) cystine levels, glomerular filtration rate (GFR) and concommitant medications were obtained from medical records. NIMA included carotid intima-media thickness (cIMT, n = 13), pulse wave velocity (PWV, n = 8) and pulse wave analysis (PWA, n = 6). Results : GFR ranged between 4-95 mL/min/1.73 m(2). All but one patient were treated with cysteamine, mean WBC cystine values ranged between 0.34-1.64 nmol cystine/mg protein, 8 patients had mean WBC cystine levels <1 nmol cystine/mg protein. When compared to healthy subjects, cIMT and PWV levels were above normal values in 1 patient for each measure. PWA measurements showed high augmentation index in three patients who did not receive lipid-lowering medication. When corrected for renal function, cIMT and PWV levels were within the normal range. CONCLUSION: Young adult cystinosis patients treated with cysteamine have no additional risk for CVD when compared to patients with chronic kidney disease of other causes

CNS Infiltration of Peripheral Immune Cells: D-Day for Neurodegenerative Disease?

While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as “immune privilege,” it is now clear that immune responses do occur in the CNS—giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue

SSWAP: A Simple Semantic Web Architecture and Protocol for semantic web services

<p>Abstract</p> <p>Background</p> <p>SSWAP (<b>S</b>imple <b>S</b>emantic <b>W</b>eb <b>A</b>rchitecture and <b>P</b>rotocol; pronounced "swap") is an architecture, protocol, and platform for using reasoning to semantically integrate heterogeneous disparate data and services on the web. SSWAP was developed as a hybrid semantic web services technology to overcome limitations found in both pure web service technologies and pure semantic web technologies.</p> <p>Results</p> <p>There are currently over 2400 resources published in SSWAP. Approximately two dozen are custom-written services for QTL (Quantitative Trait Loci) and mapping data for legumes and grasses (grains). The remaining are wrappers to Nucleic Acids Research Database and Web Server entries. As an architecture, SSWAP establishes how clients (users of data, services, and ontologies), providers (suppliers of data, services, and ontologies), and discovery servers (semantic search engines) interact to allow for the description, querying, discovery, invocation, and response of semantic web services. As a protocol, SSWAP provides the vocabulary and semantics to allow clients, providers, and discovery servers to engage in semantic web services. The protocol is based on the W3C-sanctioned first-order description logic language OWL DL. As an open source platform, a discovery server running at <url>http://sswap.info</url> (as in to "swap info") uses the description logic reasoner Pellet to integrate semantic resources. The platform hosts an interactive guide to the protocol at <url>http://sswap.info/protocol.jsp</url>, developer tools at <url>http://sswap.info/developer.jsp</url>, and a portal to third-party ontologies at <url>http://sswapmeet.sswap.info</url> (a "swap meet").</p> <p>Conclusion</p> <p>SSWAP addresses the three basic requirements of a semantic web services architecture (<it>i.e</it>., a common syntax, shared semantic, and semantic discovery) while addressing three technology limitations common in distributed service systems: <it>i.e</it>., <it>i</it>) the fatal mutability of traditional interfaces, <it>ii</it>) the rigidity and fragility of static subsumption hierarchies, and <it>iii</it>) the confounding of content, structure, and presentation. SSWAP is novel by establishing the concept of a canonical yet mutable OWL DL graph that allows data and service providers to describe their resources, to allow discovery servers to offer semantically rich search engines, to allow clients to discover and invoke those resources, and to allow providers to respond with semantically tagged data. SSWAP allows for a mix-and-match of terms from both new and legacy third-party ontologies in these graphs.</p

The next generation of training for arabidopsis researchers: Bioinformatics and Quantitative Biology

It has been more than 50 years since Arabidopsis (Arabidopsis thaliana) was first introduced as a model organism to understand basic processes in plant biology. A well-organized scientific community has used this small reference plant species to make numerous fundamental plant biology discoveries (Provart et al., 2016). Due to an extremely well-annotated genome and advances in high-throughput sequencing, our understanding of this organism and other plant species has become even more intricate and complex. Computational resources, including CyVerse,3 Araport,4 The Arabidopsis Information Resource (TAIR),5 and BAR,6 have further facilitated novel findings with just the click of a mouse. As we move toward understanding biological systems, Arabidopsis researchers will need to use more quantitative and computational approaches to extract novel biological findings from these data. Here, we discuss guidelines, skill sets, and core competencies that should be considered when developing curricula or training undergraduate or graduate students, postdoctoral researchers, and faculty. A selected case study provides more specificity as to the concrete issues plant biologists face and how best to address such challenges

Effectiveness of a mobile smoking cessation service in reaching elderly smokers and predictors of quitting

<p>Abstract</p> <p>Background</p> <p>Different smoking cessation programmes have been developed in the last decade but utilization by the elderly is low. We evaluated a pilot mobile smoking cessation service for the Chinese elderly in Hong Kong and identified predictors of quitting.</p> <p>Methods</p> <p>The Mobile Smoking Cessation Programme (MSCP) targeted elderly smokers (aged 60 or above) and provided service in a place that was convenient to the elderly. Trained counsellors provided individual counselling and 4 week's free supply of nicotine replacement therapy (NRT). Follow up was arranged at 1 month by face-to-face and at 3 and 6 months by telephone plus urinary cotinine validation. A structured record sheet was used for data collection. The service was evaluated in terms of process, outcome and cost.</p> <p>Results</p> <p>102 governmental and non-governmental social service units and private residential homes for the elderly participated in the MSCP. We held 90 health talks with 3266 elderly (1140 smokers and 2126 non-smokers) attended. Of the 1140 smokers, 365 (32%) received intensive smoking cessation service. By intention-to-treat, the validated 7 day point prevalence quit rate was 20.3% (95% confidence interval: 16.2%–24.8%). Smoking less than 11 cigarettes per day and being adherent to NRT for 4 weeks or more were significant predictors of quitting. The average cost per contact was US$54 (smokers only); per smoker with counselling: US$168; per self-reported quitter: US$594; and per cotinine validated quitter: US$827.</p> <p>Conclusion</p> <p>This mobile smoking cessation programme was acceptable to elderly Chinese smokers, with quit rate comparable to other comprehensive programmes in the West. A mobile clinic is a promising model to reach the elderly and probably other hard to reach smokers.</p

NLRP3 Inflammasome: Key Mediator of Neuroinflammation in Murine Japanese Encephalitis

Background: Japanese Encephalitis virus (JEV) is a common cause of acute and epidemic viral encephalitis. JEV infection is associated with microglial activation resulting in the production of pro-inflammatory cytokines including Interleukin-1 b (IL-1b) and Interleukin-18 (IL-18). The Pattern Recognition Receptors (PRRs) and the underlying mechanism by which microglia identify the viral particle leading to the production of these cytokines is unknown. Methodology/Principal Findings: For our studies, we have used murine model of JEV infection as well as BV-2 mouse microglia cell line. In this study, we have identified a signalling pathway which leads to the activation of caspase-1 as the key enzyme responsible for the maturation of both IL-1b and IL-18 in NACHT, LRR and PYD domains-containing protein-3 (NLRP3) dependent manner. Depletion of NLRP3 results in the reduction of caspase-1 activity and subsequent production of these cytokines. Conclusion/Significance: Our results identify a mechanism mediated by Reactive Oxygen Species (ROS) production and potassium efflux as the two danger signals that link JEV infection to caspase-1 activation resulting in subsequent IL-1b an

Beta-Amyloid Peptides Enhance the Proliferative Response of Activated CD4+CD28+ Lymphocytes from Alzheimer Disease Patients and from Healthy Elderly

Alzheimer's disease (AD) is the most frequent form of dementia among elderly. Despite the vast amount of literature on non-specific immune mechanisms in AD there is still little information about the potential antigen-specific immune response in this pathology. It is known that early stages of AD include β-amyloid (Aβ)- reactive antibodies production and inflammatory response. Despite some evidence gathered proving cellular immune response background in AD pathology, the specific reactions of CD4+ and CD8+ cells remain unknown as the previous investigations yielded conflicting results. Here we investigated the CD4+CD28+ population of human peripheral blood T cells and showed that soluble β-amyloids alone were unable to stimulate these cells to proliferate significantly, resulting only in minor, probably antigen-specific, proliferative response. On the other hand, the exposure of in vitro pre-stimulated lymphocytes to soluble Aβ peptides significantly enhanced the proliferative response of these cells which had also lead to increased levels of TNF, IL-10 and IL-6. We also proved that Aβ peptide-enhanced proliferative response of CD4+CD28+ cells is autonomous and independent from disease status while being associated with the initial, ex vivo activation status of the CD4+ cells. In conclusion, we suggest that the effect of Aβ peptides on the immune system of AD patients does not depend on the specific reactivity to Aβ epitope(s), but is rather a consequence of an unspecific modulation of the cell cycle dynamics and cytokine production by T cells, occurring simultaneously in a huge proportion of Aβ peptide-exposed T lymphocytes and affecting the immune system performance

Randomized pilot study to disseminate caries-control services in dentist offices

BACKGROUND: To determine whether education and financial incentives increased dentists' delivery of fluoride varnish and sealants to at risk children covered by capitation dental insurance in Washington state (U.S.). METHODS: In 1999, 53 dental offices in Washington Dental Service's capitation dental plan were invited to participate in the study, and consenting offices were randomized to intervention (n = 9) and control (n = 10) groups. Offices recruited 689 capitation children aged 6–14 and at risk for caries, who were followed for 2 years. Intervention offices received provider education and fee-for-service reimbursement for delivering fluoride varnish and sealants. Insurance records were used to calculate office service rates for fluoride, sealants, and restorations. Parents completed mail surveys after follow-up to measure their children's dental utilization, dental satisfaction, dental fear and oral health status. Regression models estimated differences in service rates between intervention and control offices, and compared survey measures between groups. RESULTS: Nineteen offices (34%) consented to participate in the study. Fluoride and sealant rates were greater in the intervention offices than the control offices, but the differences were not statistically significant. Restoration rates were lower in the intervention offices than the control offices. Parents in the intervention group reported their children had less dental fear than control group parents. CONCLUSION: Due to low dentist participation the study lacked power to detect an intervention effect on dentists' delivery of caries-control services. The intervention may have reduced children's dental fear

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion