Increasing Precision of Clinical Diagnosis of Alzheimer\u27s Disease Using a Combined Algorithm Incorporating Clinical and Novel Biomarker Data

Establishing the in vivo diagnosis of Alzheimer€™s disease (AD) or other dementias relies on clinical criteria; however, the accuracy of these criteria can be limited. The diagnostic accuracy is 77% for a clinical diagnosis of AD, even among experts. We performed a review through PubMed of articles related to specific diagnostic modalities, including APOE genotyping, cerebrospinal fluid (CSF) testing, fludeoxyglucose F 18 positron emission tomography (PET), amyloid PET, tau PET, computed tomography (CT), single-photon emission CT, magnetic resonance imaging (MRI), and B12 and thyroid-stimulating hormone screening, to determine the specificity and sensitivity of each test used in the clinical diagnosis of AD. We added a novel immunomagnetic reduction assay that provides ultrasensitivity for analyzing the levels of plasma tau and beta amyloid 42 (Aβ42). The sensitivity and specificity of the current diagnostic approach (structural CT or MRI with screening labs) remain low for clinical detection of AD and are primarily used to exclude other conditions. Because of limited diagnostic capabilities, physicians do not feel comfortable or skilled in rendering a clinical diagnosis of AD. Compounding this problem is the fact that inexpensive, minimally invasive diagnostic tests do not yet exist. Biomarkers (obtained through CSF testing or PET imaging), which are not routinely incorporated in clinical practice, correlate well with pathologic changes. While PET is particularly costly and difficult to assess, CSF measures of tau and beta amyloid are not costly, and these tests may be worthwhile when the tiered approach proposed here warrants further testing. There is a need for developing bloodborne biomarkers that can aid in the clinical diagnosis of AD. Here we present a streamlined questionnaire-enriched, biomarker-enriched approach that is more cost-effective than the current diagnosis of exclusion and is designed to increase clinical confidence for a diagnosis of dementia due to AD

Onboarding AI

In a 2018 Workforce Institute survey of 3,000 managers across eight industrialized nations, the majority of respondents described artificial intelligence as a valuable productivity tool. But respondents to that survey also expressed fears that AI would take their jobs. They are not alone. The Guardian recently reported that in the UK “more than 6 million workers fear being replaced by machines AI’s advantages can be cast in a dark light: Why would humans be needed when machines can do a better job? To allay such fears, employers must set AI up to succeed rather than to fail. The authors draw on their own and others’ research and consulting on AI and information systems implementation, along with organizational studies of innovation and work practices, to present a four-phase approach to implementing AI. It allows organizations to cultivate people’s trust—a key condition for adoption—and to work toward a distributed cognitive system in which humans and artificial intelligence both continually improv

The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission

1Infection of red blood cells (RBC) subjects the malaria parasite to oxidative stress. Therefore, efficient antioxidant and redox systems are required to prevent damage by reactive oxygen species. Plasmodium spp. have thioredoxin and glutathione (GSH) systems that are thought to play a major role as antioxidants during blood stage infection. In this report, we analyzed a critical component of the GSH biosynthesis pathway using reverse genetics. Plasmodium berghei parasites lacking expression of gamma-glutamylcysteine synthetase (γ-GCS), the rate limiting enzyme in de novo synthesis of GSH, were generated through targeted gene disruption thus demonstrating, quite unexpectedly, that γ-GCS is not essential for blood stage development. Despite a significant reduction in GSH levels, blood stage forms of pbggcs− parasites showed only a defect in growth as compared to wild type. In contrast, a dramatic effect on development of the parasites in the mosquito was observed. Infection of mosquitoes with pbggcs− parasites resulted in reduced numbers of stunted oocysts that did not produce sporozoites. These results have important implications for the design of drugs aiming at interfering with the GSH redox-system in blood stages and demonstrate that de novo synthesis of GSH is pivotal for development of Plasmodium in the mosquito

Fz2 and Cdc42 Mediate Melanization and Actin Polymerization but Are Dispensable for Plasmodium Killing in the Mosquito Midgut

The midgut epithelium of the mosquito malaria vector Anopheles is a hostile environment for Plasmodium, with most parasites succumbing to host defenses. This study addresses morphological and ultrastructural features associated with Plasmodium berghei ookinete invasion in Anopheles gambiae midguts to define the sites and possible mechanisms of parasite killing. We show by transmission electron microscopy and immunofluorescence that the majority of ookinetes are killed in the extracellular space. Dead or dying ookinetes are surrounded by a polymerized actin zone formed within the basal cytoplasm of adjacent host epithelial cells. In refractory strain mosquitoes, we found that formation of this zone is strongly linked to prophenoloxidase activation leading to melanization. Furthermore, we identify two factors controlling both phenomena: the transmembrane receptor frizzled-2 and the guanosine triphosphate–binding protein cell division cycle 42. However, the disruption of actin polymerization and melanization by double-stranded RNA inhibition did not affect ookinete survival. Our results separate the mechanisms of parasite killing from subsequent reactions manifested by actin polymerization and prophenoloxidase activation in the A. gambiae–P. berghei model. These latter processes are reminiscent of wound healing in other organisms, and we propose that they represent a form of wound-healing response directed towards a moribund ookinete, which is perceived as damaged tissue

Construction, assembly and tests of the ATLAS electromagnetic barrel calorimeter

The construction and assembly of the two half barrels of the ATLAS central electromagnetic calorimeter and their insertion into the barrel cryostat are described. The results of the qualification tests of the calorimeter before installation in the LHC ATLAS pit are given

Construction and test of a fine-grained liquid argon preshower prototype

A separate liquid argon preshower detector consisting of two layers featuring a fine granularity of 2.5~10$^{\mathrm{-3}}$ was studied by the RD3 collaboration. A prototype covering approximately 0.8 in pseudo-rapidity and 9 degrees in azimuth was built and tested at CERN in July 94. CMOS and GaAs VLSI preamplifiers were designed and tested for this occasion. The combined response of this detector and an accordion electromagnetic calorimeter prototype to muons, electrons and photons is presented. For minimum ionizing tracks a signal-to-noise ratio of 4.5 per preshower layer was measured. Above 150~GeV the space resolution for electrons is better than 250~$\mu$m in both directions. The precision on the electromagnetic shower direction, determined together with the calorimeter, is better than 4 mrad above 50~GeV. It is concluded that the preshower detector would adequately fulfil its role for future operation at CERN Large Hadron Collider

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF)

This work has been supported by Bristol Research into Alzheimer’s and Care of the Elderly (BRACE), the Sigmund Gestetner Trust Fund (University of Bristol), the Alzheimer’s Society and the Alumni of the University of Bristol. K.C. and D.J.W. were supported by UK Wellcome Trust-MRC Neurodegenerative Disease Initiative Programme. J.H.Y. was supported by the Korea-UK Alzheimer’s Research Consortium Programme under the Korean Ministry of Health and Welfare. T.M.P. and S.C. were supported by Bristol-Chonnam Frontier Programme under the Chonnam National University Hospital. K.C. was supported by the Wolfson Research Merit Award and Royal Society, London.This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging.Publisher PDFPeer reviewe