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"Cunningham, Douglas W. (Douglas William)"
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Experimental design : from user studies to psychophysics
This book explains the basic terminology used to discuss experiments and takes a brief look at the more than 150 year history of experiments in psychology. It covers how to generalize from a few people to the whole population. The largest part of the book is dedicated to the most flexible, and arguably the most central, aspect of an experiment: What do the participants do? Each chapter follows the same structure and includes two examples, one from traditional psychophysics and one using computer animated facial expressions as stimuli.
eBook
Effects of long-term testosterone treatment on cardiovascular outcomes in men with hypogonadism: Rationale and design of the TRAVERSE study
Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an adequately-powered randomized trial.
The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study is a randomized, double-blind, placebo-controlled, parallel group, non-inferiority, multicenter study. Eligible participants are men, 45 to 80 years, with serum testosterone concentration <300 ng/dL and hypogonadal symptoms, who have evidence pre-existing CV disease or increased risk of CV disease. Approximately 6,000 subjects will be randomized to either 1.62% transdermal testosterone gel or a matching placebo gel daily for an anticipated duration of up to 5 years. The primary outcome is CV safety defined by the major adverse CV event composite of nonfatal myocardial infarction, nonfatal stroke, or death due to CV causes. The trial will continue until at least 256 adjudicated major adverse CV event endpoints have occurred to assess whether the 95% (2-sided) upper confidence limit for a hazard ratio of 1.5 can be ruled out. Secondary endpoints include prostate safety defined as the incidence of adjudicated high grade prostate cancer and efficacy in domains of sexual function, bone fractures, depression, anemia, and diabetes.
As of July 1, 2021, 5,076 subjects had been randomized.
The TRAVERSE study will determine the CV safety and long-term efficacy of testosterone treatment in middle-aged and older men with hypogonadism with or at increased risk of CV disease.
Journal Article
Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss
Christopher Klein and colleagues report that DNMT1 is disrupted in hereditary sensory neuropathy with dementia and hearing loss. The mutations lead to reduced methyltransferase activity, leading to global hypomethylation and site-specific hypermethylation.
DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability
1
,
2
,
3
. DNA mismatch repair, cell cycle regulation in post-mitotic neurons
4
,
5
and neurogenesis
6
are influenced by DNA methylation. Here we show that mutations in
DNMT1
cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss
7
,
8
. Exome sequencing led to the identification of
DNMT1
mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470–1472TCC>ATA (p.Asp490Glu–Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of
DNMT1
. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that
DNMT1
mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered
DNMT1
mutations provide a new framework for the study of neurodegenerative diseases.
Journal Article
Anthrax Lethal Factor Inhibition
The primary virulence factor of Bacillus anthracis is a secreted zinc-dependent metalloprotease toxin known as lethal factor (LF) that is lethal to the host through disruption of signaling pathways, cell destruction, and circulatory shock. Inhibition of this proteolytic-based LF toxemia could be expected to provide therapeutic value in combination with an antibiotic during and immediately after an active anthrax infection. Herein is shown the crystal structure of an intimate complex between a hydroxamate, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, and LF at the LF-active site. Most importantly, this molecular interaction between the hydroxamate and the LF active site resulted in (i) inhibited LF protease activity in an enzyme assay and protected macrophages against recombinant LF and protective antigen in a cell-based assay, (ii) 100% protection in a lethal mouse toxemia model against recombinant LF and protective antigen, (iii) ≈50% survival advantage to mice given a lethal challenge of B. anthracis Sterne vegetative cells and to rabbits given a lethal challenge of B. anthracis Ames spores and doubled the mean time to death in those that died in both species, and (iv) 100% protection against B. anthracis spore challenge when used in combination therapy with ciprofloxacin in a rabbit \"point of no return\" model for which ciprofloxacin alone provided 50% protection. These results indicate that a small molecule, hydroxamate LF inhibitor, as revealed herein, can ameliorate the toxemia characteristic of an active B. anthracis infection and could be a vital adjunct to our ability to combat anthrax.
Journal Article
Development and verification of a novel tiling PCR method for long-range HIV-1 sequencing in a diagnostic setting
New HIV-1 infections are genotyped as part of standard of care testing to ensure that antiretroviral treatment will be efficacious against the virus. Historically this has been performed by sequencing the
pol
region of the HIV-1 genome only. The popularity of next-generation sequencing (NGS) methods during the SARS-CoV-2 pandemic has resulted in a shift towards using NGS in diagnostic sequencing, but there remain limited methodologies utilising the strengths of NGS for robust diagnostic sequencing of longer regions of the HIV-1 genome. Given the acceptance and success of tiling PCR methodologies during the SARS-CoV-2 pandemic, we aimed to design and verify a novel tiling PCR method for routine HIV-1 sequencing. A set of tiling PCR primers was designed to amplify the 5’ half of HIV-1 in six overlapping segments of 1,000 bp in only two PCR reactions. The assay can move from sample to sequencer in under a day. The tiling PCR was able to generate HIV-1 sequences from 90 (100%) samples in a comparison panel, and complete
protease-reverse transcriptase
and
integrase
regions were amplified in > 90% of samples with a viral load > 5000 copies/mL. Seven additional drug resistance mutations were identified when using this novel method. As such, this novel designer tiling PCR is a promising method for the routine NGS-based diagnostic sequencing of HIV-1.
Journal Article
The Care of HIV-Infected Adults in the United States
Although much has been learned about the care of persons with human immunodeficiency virus (HIV) infection, there are persistent questions about the population under care, how much care they receive, where they get it, what it costs, and who pays for it. Unbiased answers to questions such as these are crucial to understanding the care of HIV-infected people, whether new research is being translated into practice, and where future clinical and policy challenges will lie. The generalizability of available studies has been limited by the use of patient groups selected because of location, convenience of sampling, or some other arbitrary . . .
Journal Article
Readers Respond Saturday Talk
I am sick and tired of the race baiting and bigotry surrounding the efforts to change the Georgia state flag. Don't confuse African- Americans' discomfort with the Confederate symbol as an attack on the \"South.\" Most African-Americans understand and respect feelings of pride and heritage surrounding the memory of those who died for the Confederacy. For most African-Americans, however, the Confederate symbol is equivalent to the swastika. The symbol was so embraced by those with violent hatred toward African-Americans that it becomes impossible for us to separate the good history from the bad history when we see the St. Andrew's cross with stars. It is a constant reminder that many African-Americans suffered or died needlessly at the hands of people cloaked in the Confederate symbol.
Newspaper Article
