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"Lewis, C. M."
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Coherent elastic neutrino-nucleus scattering at the European Spallation Source
A
bstract
The European Spallation Source (ESS), presently well on its way to completion, will soon provide the most intense neutron beams for multi-disciplinary science. Fortuitously, it will also generate the largest pulsed neutrino flux suitable for the detection of Coherent Elastic Neutrino-Nucleus Scattering (CE
ν
NS), a process recently measured for the first time at ORNL’s Spallation Neutron Source. We describe innovative detector technologies maximally able to profit from the order-of-magnitude increase in neutrino flux provided by the ESS, along with their sensitivity to a rich particle physics phenomenology accessible through high-statistics, precision CE
ν
NS measurements.
Journal Article
Wild cards III : Jokers Wild
\"The journey into high adventure soars on! Let the secret history of the world be told--of the alien virus that struck Earth after World War II, and of the handful of survivors who found they now possessed superhuman powers. Some were called Aces, endowed with powerful mental and physical prowess. The others were Jokers, tormented by bizarre mind or body disfigurements. Some served humanity. Others wreaked terror. Now, forty years later, under the streets of Manhattan an evil genius unleashes the powers of darkness--and Aces and Jokers alike must fight for their lives. Here, in the third volume of the Wild Cards series, seven of science fiction's most gifted writers take you on a journey of wonder and excitement.Includes stories by:Edward Bryant, Leanne C. Harper, George R. R. Martin, John J. Miller, Lewis Shiner ,Walter Simons, Melinda M. Snodgrass\"-- Provided by publisher.
Book
GAD1 alternative transcripts and DNA methylation in human prefrontal cortex and hippocampus in brain development, schizophrenia
Genetic variations and adverse environmental events in utero or shortly after birth can lead to abnormal brain development and increased risk of schizophrenia. γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, plays a vital role in normal brain development. GABA synthesis is controlled by enzymes derived from two glutamic acid decarboxylase (GAD) genes, GAD1 and GAD2, both of which produce transcript isoforms. While the full-length GAD1 transcript (GAD67) has been implicated in the neuropathology of schizophrenia, the transcript structure of GAD1 in the human brain has not been fully characterized. In this study, with the use of RNA sequencing and PCR technologies, we report the discovery of 10 novel transcripts of GAD1 in the human brain. Expression levels of four novel GAD1 transcripts (8A, 8B, I80 and I86) showed a lifespan trajectory expression pattern that is anticorrelated with the expression of the full-length GAD1 transcript. In addition, methylation levels of two CpG loci within the putative GAD1 promoter were significantly associated with the schizophrenia-risk SNP rs3749034 and with the expression of GAD25 in dorsolateral prefrontal cortex (DLPFC). Moreover, schizophrenia patients who had completed suicide and/or were positive for nicotine exposure had significantly higher full-length GAD1 expression in the DLPFC. Alternative splicing of GAD1 and epigenetic state appear to play roles in the developmental profile of GAD1 expression and may contribute to GABA dysfunction in the PFC and hippocampus of patients with schizophrenia.
Journal Article
Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity
Background:
Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity.
Methods:
Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables,
DPYD, DPYS, TYMS, MTHFR, CDA
genotypes, and toxicity were analysed using logistic regression models.
Results:
Four
DPYD
sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3–4 toxicity (
P
<0.0001). The
TYMS
3′-untranslated region del/del genotype substantially increased the risk of severe toxicity (
P
=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38–6.87). For patients treated with capecitabine, a
MTHFR
c.1298CC homozygous variant genotype predicted hand–foot syndrome (
P
=4.1 × 10
−6
, OR=9.99, 95% CI: 3.84–27.8). The linked
CDA
c.−92A>G and
CDA
c.−451C>T variants predicted grade 2–4 diarrhoea (
P
=0.0055, OR=2.3, 95% CI: 1.3–4.2 and
P
=0.0082, OR=2.3, 95% CI: 1.3–4.2, respectively).
Conclusion:
We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.
Journal Article
Diurnal fuel moisture content variations of live and dead Calluna vegetation in a temperate peatland
The increasing frequency and severity of UK wildfires, attributed in part to the effects of climate change, highlights the critical role of fuel moisture content (FMC) of live and dead vegetation in shaping wildfire behaviour. However, current models used to assess wildfire danger do not perform well in shrub-type fuels such as
Calluna vulgaris,
requiring in part an improved understanding of fuel moisture dynamics on diurnal and seasonal scales. To this end, 554 samples of upper live
Calluna
canopy, live
Calluna
stems, upper dead
Calluna
canopy, dead
Calluna
stems, moss, litter and organic layer (top 5 cm of organic material above mineral soil) were sampled hourly between 10:00 and 18:00 on seven days from March-August. Using a novel statistical method for investigating diurnal patterns, we found distinctive diurnal and seasonal trends in FMC for all fuel layers. Notably, significant diurnal patterns were evident in dead
Calluna
across nearly all sampled months, while diurnal trends in live
Calluna
canopy were pronounced in March, June, and August, coinciding with the peak occurrence of UK wildfires. In addition, the moisture content of moss and litter was found to fluctuate above and below their relative ignition thresholds throughout the day on some sampling days. These findings underscore the impact of diurnal FMC variations on wildfire danger during early spring and late summer in
Calluna
dominated peatlands and the need to consider such fluctuations in management and fire suppression strategies.
Journal Article
Estimating accelerated biological ageing using machine learning and metabolomics data in people with mental disorders
IntroductionAccelerated biological ageing might contribute to the higher prevalence of age-related diseases and excess mortality amongst individuals with mental disorders. Recent advances in machine learning and the collection of high-dimensional molecular “omics” data allow for the quantification of biological age.ObjectivesThe aim of this study was to use machine learning methods to predict biological age from nuclear magnetic resonance spectroscopy metabolomics data and to identify psychiatric traits associated with accelerated biological ageing.MethodsThe UK Biobank is a multicentre community-based observational study that recruited >500,000 middle-aged and older adults. 168 metabolomic measures were quantified using the Nightingale Health platform. Phase 1 release of these data included a random subset of 118,462 UK Biobank participants. Metabolomic age delta (MetaboAgeΔ) was defined as the difference between predicted biological age and observed chronological age. We estimated group differences in MetaboAgeΔ between individuals with and without mental disorders and examined whether polygenic scores for mental disorders predicted MetaboAgeΔ.ResultsUp to 110,780 participants with complete data on all metabolomic measures were included in the analysis. Individuals with a history of mental disorders had higher MetaboAgeΔ values than people without a mental illness. For example, MetaboAgeΔ suggested that the difference between predicted biological age and observed chronological age was about two-years greater amongst individuals with bipolar disorder than amongst people without mental illness. Polygenic scores for mental disorders were positively correlated with MetaboAgeΔ.ConclusionsThese findings suggest that individuals with a history of mental disorders or with higher polygenic scores for mental disorders were biologically older than their chronological age.Disclosure of InterestNone Declared
Journal Article
Understanding the Scientific Basis of Post-traumatic Stress Disorder (PTSD): Precision Behavioral Management Overrides Stigmatization
Post-traumatic stress disorder (PTSD) is a severe polygenic disorder triggered by environmental factors. Many polymorphic genes, particularly the genetic determinants of hypodopaminergia (low dopamine function), associate with a predisposition to PTSD as well as substance use disorder. Support from the National Institutes of Health for neuroimaging research and molecular, genetic applied technologies has improved understanding of brain reward circuitry functions that have inspired the development of new innovative approaches to their early diagnosis and treatment of some PTSD symptomatology and addiction. This review presents psychosocial and genetic evidence that vulnerability or resilience to PTSD can theoretically be impacted by dopamine regulation. From a neuroscience perspective, dopamine is widely accepted as a major neurotransmitter. Questions about how to modulate dopamine clinically in order to treat and prevent PTSD and other types of reward deficiency disorders remain. Identification of genetic variations associated with the relevant genotype–phenotype relationships can be characterized using the Genetic Addiction Risk Score (GARS®) and psychosocial tools. Development of an advanced genetic panel is under study and will be based on a new array of genes linked to PTSD. However, for now, the recommendation is that enlistees for military duty be given the opportunity to voluntarily pre-test for risk of PTSD with GARS, before exposure to environmental triggers or upon return from deployment as part of PTSD management. Dopamine homeostasis may be achieved via customization of neuronutrient supplementation “Precision Behavioral Management” (PBM™) based on GARS test values and other pro-dopamine regulation interventions like exercise, mindfulness, biosensor tracking, and meditation.
Journal Article
Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1–PAK3 signaling in neuroplasticity
Although the pathogenesis of schizophrenia (SCZ) is proposed to involve alterations of neural circuits via synaptic dysfunction, the underlying molecular mechanisms remain poorly understood. Recent exome sequencing studies of SCZ have uncovered numerous single-nucleotide variants (SNVs); however, the majority of these SNVs have unknown functional consequences, leaving their disease relevance uncertain. Filling this knowledge gap requires systematic application of quantitative and scalable assays to assess known and novel biological functions of genes. Here we demonstrate loss-of-function effects of multiple rare coding SNVs found in SCZ subjects in the
GIT1
(
G protein-coupled receptor kinase interacting ArfGAP 1
) gene using functional cell-based assays involving coexpression of GIT1 and PAK3 (p21 protein (Cdc42/Rac)-activated kinase 3). Most notably, a GIT1-R283W variant reported in four independent SCZ cases was defective in activating PAK3 as well as MAPK (mitogen-activated protein kinase). Similar functional deficits were found for a
de novo
SCZ variant GIT1-S601N. Additional assays revealed deficits in the capacity of GIT1-R283W to stimulate PAK phosphorylation in cultured hippocampal neurons. In addition, GIT1-R283W showed deficits in the induction of GAD1 (glutamate decarboxylase 1) protein expression. Extending these functional assays to 10 additional rare GIT1 variants revealed the existence of an allelic series with the majority of the SCZ case variants exhibiting loss of function toward MAPK activation in a manner correlated with loss of PAK3 activation. Taken together, we propose that rare variants in GIT1, along with other genetic and environmental factors, cause dysregulation of PAK3 leading to synaptic deficits in SCZ.
Journal Article