A GSS Tool for Collaborative Cause and Effect Diagramming: Motivation and Design

Although GSSs provide a variety of problem solving methods, current GSSs do not provide groups the capability to employ traditionally used diagramming techniques. This paper presents a tool specifically designed to support collaborative cause and effect (C&E) diagramming. The C&E tool takes advantage of both GSS and representational approaches and provides a unique problem formulation and identification aid. The place of the GSS tool in a cumulative program of information systems research is described

Teaching literature with a specific emphasis on critical thinking : an interpretive investigation of student perceptions

The purpose of this study was to examine and interpret students' impressions and attitudes toward a study of literature which emphasized critical thinking. The following questions guided the inquiry: (a) How do students perceive the study of literature based on previous experience? (b) How does an emphasis on critical thinking affect students' feelings about the study of literature? (c) To what extent do students feel that an emphasis on critical thinking affects their approach to literature? Data were obtained through observations, interviews, and reading attitude assessments. All data were reviewed and interpreted in response to the questions posed. Themes were identified using triangulation procedures with particular attention to changes in impressions and attitudes over time

Gold nanoparticle enhanced capillary electrophoresis separations for Alzheimer's disease biomarker detection.

Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by memory and cognitive loss, the formation of senile plaques containing amyloid-beta (Aß) peptides, degeneration of the cholinergic neurons and the development of neurofibrillary tangles in the brains of the affected people.1 It is estimate that 5.1 million people in the United States are suffering from AD. The total annual care cost associated with AD is more than $ 148 billion and is constantly increasing3. Presently, there is no specific clinical test to diagnose AD, however, amyloid beta peptides and tau proteins have been shown to be reliable biomarkers that can be used for AD diagnosis and tracking disease progression.5 It is important therefore that proper methods and techniques be devised for the identification, quantification and analysis of AD biomarkers to enable the reliable clinical diagnosis of the disease. In this study, modified gold nanoparticles were used as a pseudo stationary phase in a capillary electrochromatography technique. An asymmetric disulfide synthesized from mercaptoundecanoic acid and dodecanethiol was chemisorbed onto 10 nm gold nanoparticles to form the pseudo stationary phase. With the help of the gold nanoparticle pseudo stationary phase, the separation of two Alzheimer’s disease biomarkers namely; amyloid beta 40 and amyloid beta 42 was accomplished. This study demonstrates that the presence of modified gold nanoparticles in capillary electrochromatography can greatly influence the separation of amyloid beta peptides

Mass spectrometric methods and bioinformatics tools for accurate identification of MicroRNA biomarkers

MicroRNA (miRNA) are a class of endogenous non-protein-coding RNA of ~19-25 nucleotides long that post-transcriptionally regulate protein expression by targeting messenger RNAs for cleavage or translational repression. MiRNAs have been implicated in the initiation and progression of 160+ human diseases. Unique miRNA differential expression signatures can be used as a basis of discriminating against the presence or absence of human diseases. MiRNAs are therefore a promising and emerging class of disease biomarkers and therapeutic targets; however, the accurate detection of a specific miRNA has continued to be a challenging issue. Recently, mass spectrometry (MS) has seen remarkable technological advancements making it an attractive alternative to the conventional molecular biology miRNA characterization techniques. This study consistently documents the development of various analytical techniques aimed at characterization of miRNAs. The current literature in the field of miRNA is covered in chapter one. In chapter two, two new MS based concepts for detection of miRNA are introduced; a) the miRNA is captured using a specific complementary DNA probe, eluted and digested with specific endonuclease. The digested miRNA fragments are measured by MS resulting in a peak pattern that is dependent on the miRNA sequence i.e. an intrinsic mass signature and b) a unique mass signature is created by incorporating extra nucleotide(s) to the 3' end of miRNA and the extended miRNA is measured by using MS. The molecular mass of the extended miRNA, which is defined as extended mass signature, is expected to be different from the other miRNA within the same sample. These two approaches can improve the accuracy on qualitative MS identification of specific miRNA. To better understand miRNA function however, it is important to elucidate the nucleotide sequence of the miRNA. Chapter three of this study introduces a novel MS based assay for the sequencing of miRNA through chemical hydrolysis. In this study, by taking advantage of the mixing between a miRNA sample and an acidic MALDI matrix prior to the MALDI-TOF MS measurements, a unique yet simple and relatively cost-effective approach to generate miRNA sequencing ladders was developed. By using this method, 100% sequence coverage and accuracy in the sequencing of selected miRNAs were achieved. When many samples are involved, the data generated from miRNA measurements can be complex and manual data processing is tedious and challenging, as such, the spectral interpretation of mass spectrometric data can quickly turn out to be the bottleneck in miRNA analysis. The success of MS as a tool for analysis of miRNA will therefore strongly depend on the development of relevant computational software with the ability to properly interpret and analyze the large data. To meet this need, chapter four of this work explains the development of MicroRNA MultiTool, a computational software for the rapid interpretation of MS data containing human miRNA. Users can directly enter data obtained from mass spectrometric measurement in order to obtain the identify of miRNA, highly reducing the time needed to process data. The development of such analytical and bioinformatics tools will provide scientists with the opportunity to better understand miRNA functions and will be influential in propelling the breakthroughs of miRNA in clinical diagnostics and therapeutic fields

Diagnosing Dementia in the Clinical Setting: Can Amyloid PET Provide Additional Value Over Cerebrospinal Fluid?

Cerebrospinal fluid (CSF) measures of amyloid and tau are the first-line Alzheimer's disease biomarkers in many clinical centers. We assessed if and when the addition of amyloid PET following CSF measurements provides added diagnostic value. Twenty patients from a cognitive clinic, who had undergone detailed assessment including CSF measures, went on to have amyloid PET. The treating neurologist's working diagnosis, and degree of diagnostic certainty, was assessed both before and after the PET. Amyloid PET changed the diagnosis in 7/20 cases. Amyloid PET can provide added diagnostic value, particularly in young-onset, atypical dementias, where CSF results are borderline and diagnostic uncertainty remains

Cerebrospinal fluid biomarkers in cerebral amyloid angiopathy

BACKGROUND: There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA). OBJECTIVE: To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA. METHODS: We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer’s disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service. RESULTS: We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, CAA patients had a distinctive CSF biomarker profile, with significantly lower (p < 0.01) median concentrations of Aβ_{38}, Aβ_{40}, Aβ_{42}, sAβPPα, and sAβPPβ. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p < 0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aβ_{38}, Aβ_{40}, Aβ_{42}, and sAβPPβ. Comparing CAA patients with amyloid-PET positive (n = 5) and negative (n = 5) scans, PET positive individuals had lower (p < 0.05) concentrations of CSF Aβ_{42}, and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an “AD-like” profile. CONCLUSION: CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed

Using florbetapir positron emission tomography to explore cerebrospinal fluid cut points and gray zones in small sample sizes

INTRODUCTION: We aimed to assess the feasibility of determining Alzheimer's disease cerebrospinal fluid (CSF) cut points in small samples through comparison with amyloid positron emission tomography (PET). METHODS: Twenty-three individuals (19 patients, four controls) had CSF measures of amyloid beta (Aβ)1-42 and total tau/Aβ1-42 ratio, and florbetapir PET. We compared CSF measures with visual and quantitative (standardized uptake value ratio [SUVR]) PET measures of amyloid. RESULTS: Seventeen of 23 were amyloid-positive on visual reads, and 14 of 23 at an SUVR of ≥1.1. There was concordance (positive/negative on both measures) in 20 of 23, of whom 19 of 20 were correctly classified at an Aβ1-42 of 630 ng/L, and 20 of 20 on tau/Aβ1-42 ratio (positive ≥0.88; negative ≤0.34). Three discordant cases had Aβ1-42 levels between 403 and 729 ng/L and tau/Aβ1-42 ratios of 0.54-0.58. DISCUSSION: Comparing amyloid PET and CSF biomarkers provides a means of assessing CSF cut points in vivo, and can be applied to small sample sizes. CSF tau/Aβ1-42 ratio appears robust at predicting amyloid status, although there are gray zones where there remains diagnostic uncertainty

Agronomic Management of Indigenous Mycorrhizas

Many of the advantages conferred to plants by arbuscular mycorrhiza (AM) are associated to the ability of AM plants to explore a greater volume of soil through the extraradical mycelium. Sieverding (1991) estimates that for each centimetre of colonized root there is an increase of 15 cm3 on the volume of soil explored, this value can increase to 200 cm3 depending on the circumstances. Due to the enhancement of the volume of soil explored and the ability of the extraradical mycelium to absorb and translocate nutrients to the plant, one of the most obvious and important advantages resulting from mycorrhization is the uptake of nutrients. Among of which the ones that have immobilized forms in soil, such as P, assume particular significance. Besides this, many other benefits are recognized for AM plants (Gupta et al, 2000): water stress alleviation (Augé, 2004; Cho et al, 2006), protection from root pathogens (Graham, 2001), tolerance to toxic heavy metals and phytoremediation (Audet and Charest, 2006; Göhre and Paszkowski, 2006), tolerance to adverse conditions such as very high or low temperature, high salinity (Sannazzaro et al, 2006), high or low pH (Yano and Takaki, 2005) or better performance during transplantation shock (Subhan et al, 1998). The extraradical hyphae also stabilize soil aggregates by both enmeshing soil particles (Miller e Jastrow, 1992) and producing a glycoprotein, golmalin, which may act as a glue-like substance to adhere soil particles together (Wright and Upadhyaya, 1998). Despite the ubiquous distribution of mycorrhizal fungi (Smith and Read, 2000) and only a relative specificity between host plants and fungal isolates (McGonigle and Fitter, 1990), the obligate nature of the symbiosis implies the establishment of a plant propagation system, either under greenhouse conditions or in vitro laboratory propagation. These techniques result in high inoculum production costs, which still remains a serious problem since they are not competitive with production costs of phosphorus fertilizer. Even if farmers understand the significance of sustainable agricultural systems, the reduction of phosphorus inputs by using AM fungal inocula alone cannot be justified except, perhaps, in the case of high value crops (Saioto and Marumoto, 2002). Nurseries, high income horticulture farmers and no-agricultural application such as rehabilitation of degraded or devegetated landscapes are examples of areas where the use of commercial inoculum is current. Another serious problem is quality of commercial available products concerning guarantee of phatogene free content, storage conditions, most effective application methods and what types to use. Besides the information provided by suppliers about its inoculum can be deceiving, as from the usually referred total counts, only a fraction may be effective for a particular plant or in specific soil conditions. Gianinazzi and Vosátka (2004) assume that progress should be made towards registration procedures that stimulate the development of the mycorrhizal industry. Some on-farm inoculum production and application methods have been studied, allowing farmers to produce locally adapted isolates and generate a taxonomically diverse inoculum (Mohandas et al, 2004; Douds et al, 2005). However the inocula produced this way are not readily processed for mechanical application to the fields, being an obstacle to the utilization in large scale agriculture, especially row crops, moreover it would represent an additional mechanical operation with the corresponding economic and soil compaction costs. It is well recognized that inoculation of AM fungi has a potential significance in not only sustainable crop production, but also environmental conservation. However, the status quo of inoculation is far from practical technology that can be widely used in the field. Together a further basic understanding of the biology and diversity of AM fungi is needed (Abbott at al, 1995; Saito and Marumoto, 2002). Advances in ecology during the past decade have led to a much more detailed understanding of the potential negative consequences of species introductions and the potential for negative ecological consequences of invasions by mycorrhizal fungi is poorly understood. Schwartz et al, (2006) recommend that a careful assessment documenting the need for inoculation, and the likelihood of success, should be conducted prior to inoculation because inoculations are not universally beneficial. Agricultural practices such as crop rotation, tillage, weed control and fertilizer apllication all produce changes in the chemical, physical and biological soil variables and affect the ecological niches available for occupancy by the soil biota, influencing in different ways the symbiosis performance and consequently the inoculum development, shaping changes and upset balance of native populations. The molecular biology tools developed in the latest years have been very important for our perception of these changes, ensuing awareness of management choice implications in AM development. In this context, for extensive farming systems and regarding environmental and economic costs, the identification of agronomic management practices that allow controlled manipulation of the fungal community and capitalization of AM mutualistic effect making use of local inoculum, seem to be a wise option for mycorrhiza promotion and development of sustainable crop production

Updating the study protocol: Insight 46 – a longitudinal neuroscience sub-study of the MRC National Survey of Health and Development – phases 2 and 3

Background: Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person’s risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46—a multi-phase longitudinal observational study—are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. Methods/Design: Phase 1 of Insight 46 (2015–2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018–2021) and phase 3 (2021–ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. Discussion: The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community

Neuronal intranuclear inclusion disease is genetically heterogeneous

Neuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico-based screening using whole-genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases