UKESM1: Description and Evaluation of the U.K. Earth System Model Sellar, Alistair A.; Jones, Colin G.; Mulcahy, Jane P. ...
Journal of advances in modeling earth systems,
December 2019, 2019-12-00, 20191201, 2019-12-01, Letnik:
11, Številka:
12
Journal Article
Recenzirano
Odprti dostop
We document the development of the first version of the U.K. Earth System Model UKESM1. The model represents a major advance on its predecessor HadGEM2‐ES, with enhancements to all component models ...and new feedback mechanisms. These include a new core physical model with a well‐resolved stratosphere; terrestrial biogeochemistry with coupled carbon and nitrogen cycles and enhanced land management; tropospheric‐stratospheric chemistry allowing the holistic simulation of radiative forcing from ozone, methane, and nitrous oxide; two‐moment, five‐species, modal aerosol; and ocean biogeochemistry with two‐way coupling to the carbon cycle and atmospheric aerosols. The complexity of coupling between the ocean, land, and atmosphere physical climate and biogeochemical cycles in UKESM1 is unprecedented for an Earth system model. We describe in detail the process by which the coupled model was developed and tuned to achieve acceptable performance in key physical and Earth system quantities and discuss the challenges involved in mitigating biases in a model with complex connections between its components. Overall, the model performs well, with a stable pre‐industrial state and good agreement with observations in the latter period of its historical simulations. However, global mean surface temperature exhibits stronger‐than‐observed cooling from 1950 to 1970, followed by rapid warming from 1980 to 2014. Metrics from idealized simulations show a high climate sensitivity relative to previous generations of models: Equilibrium climate sensitivity is 5.4 K, transient climate response ranges from 2.68 to 2.85 K, and transient climate response to cumulative emissions is 2.49 to 2.66 K TtC−1.
Plain Language Summary
We describe the development and behavior of UKESM1, a novel climate model that includes improved representations of processes in the atmosphere, ocean, and on land. These processes are inter‐related: For example, dust is produced on the land and blown up into the atmosphere where it affects the amount of sunlight falling on Earth. Dust can also be dissolved in the ocean, where it affects marine life. This in turn changes both the amount of carbon dioxide absorbed by the ocean and the material emitted from the surface into the atmosphere, which has an affect on the formation of clouds. UKESM1 includes many processes and interactions such as these, giving it a high level of complexity. Ensuring realistic process behavior is a major challenge in the development of our model, and we have carefully tested this. UKESM1 performs well, correctly exhibiting stable results from a continuous pre‐industrial simulation (used to provide a reference for future experiments) and showing good agreement with observations toward the end of its historical simulations. Results for some properties—including the degree to which average surface temperature changes with increased amounts of carbon dioxide in the atmosphere—are examined in detail.
Key Points
UKESM1 represents a major advance over its predecessor HadGEM2‐ES, both in the complexity of its components and its internal coupling
The complex coupling presents challenges to the model development; we document the tuning process employed to obtain acceptable performance
UKESM1 performs well, having a stable pre‐industrial state and showing good agreement with observations in a wide variety of contexts
The ability of the pathogenic yeast Candida albicans to interconvert between budded and hyphal growth states, herein termed the budded-to-hyphal transition (BHT), is important for C. albicans ...development and virulence. The BHT is under the control of multiple cell signaling pathways that respond to external stimuli, including nutrient availability, high temperature, and pH. Previous studies identified 21 small molecules that could inhibit the C. albicans BHT in response to carbon limitation in Spider media. However, the studies herein show that the BHT inhibitors had varying efficacies in other hyphal-inducing media, reflecting their varying abilities to block signaling pathways associated with the different media. Chemical epistasis analyses suggest that most, but not all, of the BHT inhibitors were acting through either the Efg1 or Cph1 signaling pathways. Notably, the BHT inhibitor clozapine, a FDA-approved drug used to treat atypical schizophrenia by inhibiting G-protein-coupled dopamine receptors in the brain, and several of its functional analogs were shown to act at the level of the Gpr1 G-protein-coupled receptor. These studies are the first step in determining the target and mechanism of action of these BHT inhibitors, which may have therapeutic anti-fungal utility in the future.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Douglas Fir Group proposes a transdisciplinary framework for second language acquisition (SLA), offering four objectives to this proposal: (a) to advance fundamental understandings of language ...learning and teaching, including understandings of linguistic development in an additional language, taking into account forces beyond individual learners, (b) to promote the development of innovative research agendas for SLA in the 21st century, (c) to serve as a platform for the development of practical, innovative, and sustainable solutions that are responsive to the challenges of language teaching and learning in our increasingly networked, technologized, and mobile worlds, and (d) to improve communication with a wider range of audiences, especially any and all stakeholders that SLA investigates or whom it hopes to benefit, so they can use SLA work to improve their material and social conditions.
Background and purpose
Elevated blood pressure (BP) is prevalent and modifiable and has been hypothesized to lead to increased risk of dementia.
Data
Data on 2 593 629 people from the UK Clinical ...Practice Research Database aged ≥40 years with a BP measurement between 1992 and 2011 and no prior record of dementia were collected.
Methods
Poisson regression models were used to study the association between BP and physician‐diagnosed dementia. BP is believed to fall during the prodromal phase of dementia development, so associations were investigated by categories of time since BP measurement (<5, 5–10, >10 years) and by subtypes of dementia.
Results
During a median follow‐up of 8.2 years, 65 618 cases of dementia were observed: 49 161 Alzheimer's, 13 816 vascular dementia and 2541 other subtypes. For each 10 mmHg higher systolic BP, the future dementia risk was 9.2% (95% confidence interval 8.4%–10.0%) lower, but this association varied markedly by time since BP measurement. Short‐term associations with dementia were inverse with a 15.8% (15.5%–17.0%) lower risk 0–5 years after BP measurement and a 5.8% (7.7%–4.4%) lower risk 5–10 years after BP measurement. During the period >10 years after BP measurement, dementia risk was only 1.6% (0.1%–3.0%) lower, with a 4.3% (2.5%–6.0%) lower risk of Alzheimer's disease and a 7.0% (3.8%–10.2%) higher risk of vascular dementia.
Conclusions
Elevated BP is associated with decreased risk of dementia in the short term, possibly due to reverse causation. Long‐term associations of BP with dementia are less marked and differ by dementia subtype.
Abstract Background Collecting duct carcinoma (CDC) is a rare type of renal cell carcinoma (RCC) originating from the renal medulla. Clinical outcomes are poor, and there are no consensus guidelines ...to guide therapy. Objective To determine genomic alterations (GAs) in a series of patients with locally advanced or metastatic CDC for whom genomic profiling was performed during the course of clinical care. Design, setting, and participants Formalin-fixed, paraffin-embedded blocks or slides were obtained for 17 patients with CDC. DNA was extracted and comprehensive genomic profiling was performed in a laboratory certified under the Clinical Laboratory Improvement Amendments. Outcome measurements and statistical analysis Bayesian algorithms and local alignment algorithms were used to detect substitutions and insertions/deletions, respectively. A comparison to normal control samples was used to detect copy number alterations. Clinically relevant GAs (CRGAs) were defined as those linked to approved or investigational targeted therapies. Results and limitations The median age in the cohort was 53 yr (range 26–73), and 14 primary tumors and three metastatic sites assessed. A total of 36 GAs were detected in this series of patients, with an average of 2.1 GAs per case. The most common GAs were in NF2 (5/17, 29%), SETD2 (4/17, 24%), SMARCB1 (3/17, 18%), and CDKN2A (2/17, 12%). Of nine cases assessed for FH GAs, two patients had FH homozygous loss. A limitation is that targeted interrogation of genes known to be implicated in other cancers was performed, so mutations outside of these cannot be excluded. Conclusions Recurrent CRGAs were detected in this series of CDC cases and suggest a possible benefit from targeted therapy. In particular, mTOR inhibitors may be of interest in patients with NF2 alterations. Alterations in FH and SMARCB1 also occurred in a mutually exclusive manner to NF2 alterations. Patient summary This report provides important genomic insights into collecting duct carcinoma, a rare type of renal cell carcinoma with a very aggressive course. These insights could further rationalize the use of targeted therapies for rare tumors according to the individual genomic alterations harbored.
Purpose
Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer’s disease. Human imaging studies have begun to investigate its use in chronic ...traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players.
Methods
Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs).
Results
Four brain donors had autopsy-confirmed CTE, all with high stage disease (
n
= 3 stage III,
n
= 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical (
ρ
= 0.71) and limbic (
ρ
= 0.77) ROIs. Although there was a strong association in the thalamic ROI (
ρ
= 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions.
Conclusions
Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed.
Abstract
The proper storage and release of monoamines contributes to a wide range of neuronal activity. Here, we examine the effects of altered vesicular monoamine transport in the nematode ...Caenorhabditis elegans. The gene cat-1 is responsible for the encoding of the vesicular monoamine transporter (VMAT) in C. elegans and is analogous to the mammalian vesicular monoamine transporter 2 (VMAT2). Our laboratory has previously shown that reduced VMAT2 activity confers vulnerability on catecholamine neurons in mice. The purpose of this article was to determine whether this function is conserved and to determine the impact of reduced VMAT activity in C. elegans. Here we show that deletion of cat-1/VMAT increases sensitivity to the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) as measured by enhanced degeneration of dopamine neurons. Reduced cat-1/VMAT also induces changes in dopamine-mediated behaviors. High-resolution mass spectrometry-based metabolomics in the whole organism reveals changes in amino acid metabolism, including tyrosine metabolism in the cat-1/VMAT mutants. Treatment with MPP+ disrupted tryptophan metabolism. Both conditions altered glycerophospholipid metabolism, suggesting a convergent pathway of neuronal dysfunction. Our results demonstrate the evolutionarily conserved nature of monoamine function in C. elegans and further suggest that high-resolution mass spectrometry-based metabolomics can be used in this model to study environmental and genetic contributors to complex human disease.
Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral ...dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals.
Our cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES.
CSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations.
Specific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.
Power transformers can experience large inrush currents upon energization, the severity of which depends on the source strength, the leakage impedance and residual flux of the transformer, and the ...angle of the applied voltage at energization. A novel inrush current reduction strategy has been implemented which involves setting a single-phase transformer's residual flux to a known polarity after the transformer has been de-energized, a process called "prefluxing," and controlling the instant of transformer energization based on the flux polarity, seeking not to eliminate inrush current but to substantially reduce it. Unlike a popular suggested solution, this strategy does not require prior knowledge of the transformer's flux. The device used for prefluxing is simple in construction and operates at substantially lower voltage levels when compared to the transformer's rated voltage. The presented strategy has been successfully implemented on an 18-kVA laboratory transformer with inrush current levels reduced below the rated current of the transformer even when accounting for typical breaker deviations. This paper describes the operation of the reduction strategy, including theory, device sizing, and implementation, and presents the successful laboratory results, all of which provide the basis for implementing inrush current reduction in three-phase transformers using a three-pole circuit breaker.
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