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"Flanagan, John (John Anthony)"
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Royal ranger
\"Will Treaty is a shell of his former self, and his first apprentice may be the only one who can save him\"-- Provided by publisher.
Book
Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture
The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene
GBA
. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s disease and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
Whole-genome sequence analysis identifies five independent risk loci for Lewy body dementia and demonstrates overlapping genetic architecture with Alzheimer’s and Parkinson’s diseases.
Journal Article
The sorcerer of the north
Now a full-fledged Ranger responsible for a sleepy fief, Will finds a new adventure seeking the traitors who poisoned the king, investigating rumors of sorcery, and trying to rescue his friend Alyss, who is taken hostage.
Book
Association between birth weight and risk of overweight at adulthood in Labrador dogs
Several studies in humans indicate that low birth weight predisposes individuals to obesity in later life. Despite the constant increase in prevalence of obesity in the canine population and the major health consequences of this affection, few investigations have been carried out on the association between birth weight and the development of overweight in dogs. The purpose of the current study was to examine the association between birth weight and some other neonatal characteristics and overweight at adulthood in a population of purebred Labrador dogs. Information was collected about the sex, age, neuter status, birth weight, and growth rates (between 0–2 days and 2–15 days of age) in 93 Labrador dogs raised under similar environmental conditions until two months old. The body condition scores (BCS, scale of 1–9) of these dogs at adulthood were recorded, with BCS equal to or greater than 6 classified as overweight. Dogs were split into two groups based on the median birth weight in the population: lower than the median (LTM) and higher than the median (HTM). A logistic regression model was applied to analyse associations between the general characteristics of the dogs (sex, age, neuter status), early life parameters (birth weight, growth rates) and overweight at adulthood. Birth weight was the only early-life parameter found to be associated with overweight (p value = 0.032) with a prevalence of overweight of 70% among the dogs with LTM birth weight vs. 47% in dogs born with HTM birth weight. Overweight was also associated with age and neuter status (p value = 0.029 and 0.005 respectively). Our results suggest that, as in humans, dogs with the lowest birth weights are more likely to become overweight at adulthood. More studies are needed to further examine this relationship and to explore the underlying mechanisms. A subsequent objective could be to identify preventive strategies such as an adapted early nutrition programme for at-risk individuals.
Journal Article
The invaders
\"Hal and the other Herons face many perils as they track down the pirates who stole Skandia's most prized artifact, the Andomal\"-- Provided by publisher.
Book
Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes
Retrotransposons are DNA repeat sequences that are constantly on the move. By poaching certain cellular enzymes, they copy and insert themselves at new sites in the genome. Sometimes they carry along adjacent DNA sequences, a process called 3′ transduction. Tubio
et al.
found that 3′ transduction is a common event in human tumors. Because this process can scatter genes and regulatory sequences across the genome, it may represent yet another mechanism by which tumor cells acquire new mutations that help them survive and grow.
Science
, this issue p.
10.1126/science.1251343
Tumor genomes are peppered with mobile repeat sequences that carry along adjacent DNA when they insert into new genomic sites.
Long interspersed nuclear element–1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3′ transduction. Because 3′ transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3′ transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3′ transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3′ transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome.
Journal Article
Ranger's apprentice : the lost stories
In 1896, an archaeological dig unearths an ancient trunk containing manuscripts that confirm the existence of Araluen Rangers Will and Halt and tell of their first meeting and some of their previously unknown exploits.
Book
Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm
UNC13A
as the strongest overall FTLD-TDP risk factor and identify
TNIP1
as a novel FTLD-TDP risk factor. In subgroup analyzes, we further identify genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed
TBK1
and identified
C3AR1
,
SMG8
,
VIPR1
,
RBPJL
,
L3MBTL1
and
ANO9
, as novel subtype-specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signaling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.
Here the authors identify
TNIP1
as a risk factor for a fatal neurodegenerative disorder and discover specific genetic loci associated with the three main subtypes of this disorder. The findings highlight distinct disease mechanisms, emphasizing the roles of immunity and the notch signaling pathway.
Journal Article
The siege of Macindaw
Now a full-fledged Ranger, Will must rescue his friend Alyss from a rogue knight and uncover vital information needed to ward off a Scotti invasion.
Book
STAREE-Mind Imaging Study: a randomised placebo-controlled trial of atorvastatin for prevention of cerebrovascular decline and neurodegeneration in older individuals
IntroductionCerebrovascular disease and neurodegeneration are causes of cognitive decline and dementia, for which primary prevention options are currently lacking. Statins are well-tolerated and widely available medications that potentially have neuroprotective effects. The STAREE-Mind Imaging Study is a randomised, double-blind, placebo-controlled clinical trial that will investigate the impact of atorvastatin on markers of neurovascular health and brain atrophy in a healthy, older population using MRI. This is a nested substudy of the ‘Statins for Reducing Events in the Elderly’ (STAREE) primary prevention trial.MethodsParticipants aged 70 years or older (n=340) will be randomised to atorvastatin or placebo. Comprehensive brain MRI assessment will be undertaken at baseline and up to 4 years follow-up, including structural, diffusion, perfusion and susceptibility imaging. The primary outcome measures will be change in brain free water fraction (a composite marker of vascular leakage, neuroinflammation and neurodegeneration) and white matter hyperintensity volume (small vessel disease). Secondary outcomes will include change in perivascular space volume (glymphatic drainage), cortical thickness, hippocampal volume, microbleeds and lacunae, prefrontal cerebral perfusion and white matter microstructure.Ethics and disseminationAcademic publications from this work will address the current uncertainty regarding the impact of statins on brain structure and vascular integrity. This study will inform the utility of repurposing these well-tolerated, inexpensive and widely available drugs for primary prevention of neurological outcomes in older individuals. Ethics approval was given by Monash University Human Research Ethics Committee, Protocol 12206.Trial registration numberClinicalTrials.gov Identifier: NCT05586750.
Journal Article