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"Hardy, John"
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The rule of law : a novel
\"Dismas Hardy knows something is amiss with his secretary, Phyllis. Her out-of-character behavior and sudden disappearances concern Hardy, especially when he learns that her convict brother--a man who had served twenty-five years in prison for armed robbery and attempted murder--has just been released. Things take a shocking turn when Phyllis is suddenly arrested at work for allegedly being an accessory to the murder of Hector Valdez, a coyote who'd been smuggling women from El Salvador and Mexico until he was shot to death on the very same day that Phyllis first disappeared from work. The connection between Phyllis, her brother, and Hector's murder is not something Dismas can easily understand, but if his cherished colleague has any chance of going free, he needs to put all the pieces together--and fast\"-- Provided by publisher.
Book
The amyloid hypothesis of Alzheimer's disease at 25 years
Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in
post hoc
analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
Graphical Abstract
This review by Selkoe and Hardy provides a comprehensive and commanding analysis on the causative role of Abeta and the amyloid cascade hypothesis in the pathology of Alzheimer's disease.
Journal Article
The global condition : conquerors, catastrophes, and community
William H. McNeill is known for his ability to portray the grand sweep of history. The Global Condition is a classic work for understanding the grand sweep of world history in brief compass. Now with a new foreword by J. R. McNeill, this book brings together two of William Hardy McNeill's popular short books and an essay. The Human Condition provides a provocative interpretation of history as a competition of parasites, both biological and human; The Great Frontier questions the notion of \"frontier freedom\" through an examination of European expansion; the concluding essay speculates on the role of catastrophe in our lives. -- Provided by publisher.
Book
Thematic analysis of in-group and out-group debates in an online right-wing extremist community
The resurgence of Right-Wing Extremism (RWE) has become a cause for concern in Western countries during the 21st century. An increase in white nationalist sentiment in recent years has provided impetus to understand the contemporary drivers of far-right ideology. This study examines in-group and out-group debates on Stormfront.org, which is the largest and oldest online community dedicated to white nationalism and extreme right-wing political views. It used a dataset of approximately 1m posts collected from the open Opposing Views forum on Stormfront from the period 2001 to 2020 to create a corpus of over 195m words for thematic analysis. A Natural Language Processing (NLP) model was used to analyze the corpus, and a supervised phrase mining algorithm was used to identify key topics in the debate. The study finds that key issues being debated between in-group and out-group members of the Stormfront online community relate to perceptions of white identity, African American identity, racial issues, conservative political issues, and the history and politics of the United States. These findings highlight the issues of mutual importance to in-group and out-group members and identify opportunities for further research into the ideology of online RWE communities.
Journal Article
Genomewide Association Studies and Human Disease
Genomewide association studies have uncovered many genetic variants that confer susceptibility to disease. This article describes the genomewide association study and new approaches that may address some of its limitations.
Genomewide association studies have uncovered many genetic variants that confer susceptibility to disease. This article describes the genomewide association study and new approaches that may address some of its limitations.
For 20 years, genetic linkage combined with positional cloning has offered a rational and increasingly straightforward route to finding gene mutations that lead to monogenic disease, such as cystic fibrosis and Huntington's disease (see the Glossary). With a few important exceptions, these searches have led to mutations that alter the amino acid sequence of a protein and that enormously increase the risk of disease.
During the past few years, genomewide association studies have identified a large number of robust associations between specific chromosomal loci and complex human disease, such as type 2 diabetes and rheumatoid arthritis
1
(Figure 1). This approach . . .
Journal Article
Failures in Protein Clearance Partly Underlie Late Onset Neurodegenerative Diseases and Link Pathology to Genetic Risk
As we identify the loci involved in late onset neurodegenerative disease, we are finding that the majority of them are involved in damage response processes. In this short review, I propose that it is partly a failure in these damage response processes which underlie late onset disease and that the resultant pathology is a marker of the type of damage response which has failed: microglial clearance of damaged neuronal membranes in Alzheimer's disease (AD), ubiquitin proteasome clearance in the tauopathies, and lysosomal clearance in Parkinson's disease (PD). In this review, I outline this relationship. This article is not intended as a comprehensive review of the cell biology of any of these disorders but rather a summary of the evidence that the genetics and pathology of these disorders appear to point, in each case, to the removal of misfolded proteins as a critical process in disease pathogenesis.
Journal Article
Single-cell RNA sequencing analysis of human Alzheimer’s disease brain samples reveals neuronal and glial specific cells differential expression
Alzheimer’s disease is the most common neurological disease worldwide. Unfortunately, there are currently no effective treatment methods nor early detection methods. Furthermore, the disease underlying molecular mechanisms are poorly understood. Global bulk gene expression profiling suggested that the disease is governed by diverse transcriptional regulatory networks. Thus, to identify distinct transcriptional networks impacted into distinct neuronal populations in Alzheimer, we surveyed gene expression differences in over 25,000 single-nuclei collected from the brains of two Alzheimer’s in disease patients in Braak stage I and II and age- and gender-matched controls hippocampal brain samples. APOE status was not measured for this study samples (as well as CERAD and THAL scores). Our bioinformatic analysis identified discrete glial, immune, neuronal and vascular cell populations spanning Alzheimer’s disease and controls. Astrocytes and microglia displayed the greatest transcriptomic impacts, with the induction of both shared and distinct gene programs.
Journal Article
Extraction of High-Value Chemicals from Plants for Technical and Medical Applications
Plants produce a variety of high-value chemicals (e.g., secondary metabolites) which have a plethora of biological activities, which may be utilised in many facets of industry (e.g., agrisciences, cosmetics, drugs, neutraceuticals, household products, etc.). Exposure to various different environments, as well as their treatment (e.g., exposure to chemicals), can influence the chemical makeup of these plants and, in turn, which chemicals will be prevalent within them. Essential oils (EOs) usually have complex compositions (>300 organic compounds, e.g., alkaloids, flavonoids, phenolic acids, saponins and terpenes) and are obtained from botanically defined plant raw materials by dry/steam distillation or a suitable mechanical process (without heating). In certain cases, an antioxidant may be added to the EO (EOs are produced by more than 17,500 species of plants, but only ca. 250 EOs are commercially available). The interesting bioactivity of the chemicals produced by plants renders them high in value, motivating investment in their production, extraction and analysis. Traditional methods for effectively extracting plant-derived biomolecules include cold pressing and hydro/steam distillation; newer methods include solvent/Soxhlet extractions and sustainable processes that reduce waste, decrease processing times and deliver competitive yields, examples of which include microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), subcritical water extraction (SWE) and supercritical CO2 extraction (scCO2). Once extracted, analytical techniques such as chromatography and mass spectrometry may be used to analyse the contents of the high-value extracts within a given feedstock. The bioactive components, which can be used in a variety of formulations and products (e.g., displaying anti-aging, antibacterial, anticancer, anti-depressive, antifungal, anti-inflammatory, antioxidant, antiparasitic, antiviral and anti-stress properties), are biorenewable high-value chemicals.
Journal Article
Dementia in Down's syndrome
Down's syndrome is the most common genetic cause of learning difficulties, and individuals with this condition represent the largest group of people with dementia under the age of 50 years. Genetic drivers result in a high frequency of Alzheimer's pathology in these individuals, evident from neuroimaging, biomarker, and neuropathological findings, and a high incidence of cognitive decline and dementia. However, cognitive assessment is challenging, and diagnostic methods have not been fully validated for use in these patients; hence, early diagnosis remains difficult. Evidence regarding the benefits of cholinesterase inhibitors and other therapeutic options to treat or delay progressive cognitive decline or dementia is very scarce. Despite close similarities with late-onset Alzheimer's disease, individuals with Down's syndrome respond differently to treatment, and a targeted approach to drug development is thus necessary. Genetic and preclinical studies offer opportunities for treatment development, and potential therapies have been identified using these approaches.
Journal Article