Abstract Peripheral neuropathy is a common and major complication of diabetes, the underlying mechanisms of which are not fully understood. Using a mouse model of type II diabetes, the present study ...investigated the role of phosphodiesterase-5 (PDE5) in peripheral neuropathy. BKS.Cg-m+/+Leprdb/J (db/db) mice were treated with sildenafil, a specific inhibitor of PDE5, at doses of 2 and 10 mg/kg or saline. Levels of PDE5 and morphometric parameters in sciatic nerve tissue as well as the motor and sensory function were measured in these mice. In diabetic mice, PDE5 expression in sciatic nerve tissue was significantly upregulated, whereas the myelin sheath thickness, myelin basic protein (MBP), and subcutaneous nerve fibers were significantly reduced. Treatment with sildenafil significantly improved neurological function, assayed by motor and sensory conducting velocities and thermal and mechanical noxious stimuli, concomitantly with increases in myelin sheath thickness, MBP levels, and subcutaneous nerve fibers. In vitro , hyperglycemia upregulated PDE5 in Schwann cells and reduced Schwann cell proliferation, migration, and expression of brain-derived neurotrophic factor (BDNF). Blockage of PDE5 with sildenafil increased cyclic guanosine monophosphate (cGMP) and completely abolished the effect of hyperglycemia on Schwann cells. Sildenafil upregulated cGMP-dependent protein kinase G I (PKGI), whereas inhibition of PKGI with a PKG inhibitor, KT5823, suppressed the inhibitory effect of sildenafil on Schwann cells. These data indicate that hyperglycemia substantially upregulates PDE5 expression and that the cGMP/PKG signaling pathway activated by sildenafil mediates the beneficial effects of sildenafil on diabetic peripheral neuropathy.
The Energy Exascale Earth System Model Atmosphere Model version 1, the atmospheric component of the Department of Energy's Energy Exascale Earth System Model is described. The model began as a fork ...of the well‐known Community Atmosphere Model, but it has evolved in new ways, and coding, performance, resolution, physical processes (primarily cloud and aerosols formulations), testing and development procedures now differ significantly. Vertical resolution was increased (from 30 to 72 layers), and the model top extended to 60 km (~0.1 hPa). A simple ozone photochemistry predicts stratospheric ozone, and the model now supports increased and more realistic variability in the upper troposphere and stratosphere. An optional improved treatment of light‐absorbing particle deposition to snowpack and ice is available, and stronger connections with Earth system biogeochemistry can be used for some science problems. Satellite and ground‐based cloud and aerosol simulators were implemented to facilitate evaluation of clouds, aerosols, and aerosol‐cloud interactions. Higher horizontal and vertical resolution, increased complexity, and more predicted and transported variables have increased the model computational cost and changed the simulations considerably. These changes required development of alternate strategies for tuning and evaluation as it was not feasible to “brute force” tune the high‐resolution configurations, so short‐term hindcasts, perturbed parameter ensemble simulations, and regionally refined simulations provided guidance on tuning and parameterization sensitivity to higher resolution. A brief overview of the model and model climate is provided. Model fidelity has generally improved compared to its predecessors and the CMIP5 generation of climate models.
Plain Language Summary
This study provides an overview of a new computer model of the Earth's atmosphere that is used as one component of the Department of Energy's latest Earth system model. The model can be used to help understand past, present, and future changes in Earth's behavior as the system responds to changes in atmospheric composition (like pollution and greenhouse gases), land, and water use and to explore how the atmosphere interacts with other components of the Earth system (ocean, land, biology, etc.). Physical, chemical, and biogeochemical processes treated within the atmospheric model are described, and pointers to previous and recent work are listed to provide additional information. The model is compared to present‐day observations and evaluated for some important tests that provide information about what could happen to clouds and the environment as changes occur. Strengths and weaknesses of the model are listed, as well as opportunities for future work.
Key Points
A brief description and evaluation is provided for the atmospheric component of the Department of Energy's Energy Exascale Earth System Model
Model fidelity has generally improved compared to predecessors and models participating in past international model evaluations
Strengths and weaknesses of the model, as well as opportunities for future work, are described
Progenitor cells in the subventricular zone of the lateral ventricle and in the dentate gyrus of the hippocampus can proliferate throughout the life of the animal. To examine the proliferation and ...fate of progenitor cells in the subventricular zone and dentate gyrus after focal cerebral ischemia, we measured the temporal and spatial profiles of proliferation of cells and the phenotypic fate of proliferating cells in ischemic brain in a model of embolic middle cerebral artery occlusion in the adult rat. Proliferating cells were labeled by injection of bromodeoxyuridine (BrdU) in a pulse or a cumulative protocol. To determine the temporal profile of proliferating cells, ischemic rats were injected with BrdU every 4 h for 12 h on the day preceding death. Rats were killed 2–14 days after ischemia. We observed significant increases in numbers of proliferating cells in the ipsilateral cortex and subventricular zone 2–14 days with a peak at 7 days after ischemia compared with the control group. To maximize labeling of proliferating cells, a single daily injection of BrdU was administered over a 14-day period starting the day after ischemia. Rats were killed either 2 h or 28 days after the last injection of BrdU. A significant increase in numbers of BrdU immunoreactive cells in the subventricular zone was coincident with a significant increase in numbers of BrdU immunoreactive cells in the olfactory bulb 14 days after ischemia and numbers of BrdU immunoreactive cells did not significantly increase in the dentate gyrus. However, 28 days after the last labeling, the number of BrdU labeled cells decreased by 90% compared with number at 14 days. Clusters of BrdU labeled cells were present in the cortex distal to the infarction. Numerous cells immunostained for the polysialylated form of the neuronal cell adhesion molecule were detected in the ipsilateral subventricular zone. Only 6% of BrdU labeled cells exhibited glial fibrillary acidic protein immunoreactivity in the cortex and subcortex and no BrdU labeled cells expressed neuronal protein markers (neural nuclear protein and microtubule associated protein-2).
From these data we suggest that focal cerebral ischemia induces transient and regional specific increases in cell proliferation in the ipsilateral hemisphere and that proliferating progenitor cells may exist in the adult cortex.
Background. Algorithms for the diagnosis of syphilis continue to be a source of great controversy, and numerous test interpretations have perplexed many clinicians. Methods. We conducted a ...cross-sectional study of 24 124 subjects to analyze 3 syphilis testing algorithms: traditional algorithm, reverse algorithm, and the European Centre for Disease Prevention and Control (ECDC) algorithm. Every serum sample was simultaneously evaluated using the rapid plasma reagin, Treponema pallidum particle agglutination, and chemiluminescence immunoassay tests. With the results of clinical diagnoses of syphilis as a gold standard, we evaluated the diagnostic accuracy of the 3 syphilis testing algorithms. The κ coefficient was used to compare the concordance between the reverse algorithm and the ECDC algorithm. Results. Overall, 2749 patients in our cohort were diagnosed with syphilis. The traditional algorithm had the highest negative likelihood ratio (0.24), a missed diagnosis rate of 24.2%, and only 75.81% sensitivity. However, both the reverse and ECDC algorithms had higher diagnostic efficacy than the traditional algorithm. Their sensitivity, specificity, and accuracy were 99.38%–99.85%, 99.98%–100.00%, and 99.93%–99.96%, respectively. Moreover, the overall percentage of agreement and κ value between the reverse and the ECDC algorithms were 99.9% and 0.996, respectively. Conclusions. Our research supported use of the ECDC algorithm, in which syphilis screening begins with a treponemal immunoassay that is followed by a second, different treponemal assay as a confirmatory test in high-prevalence populations. In addition, our results indicated that nontreponemal assay is unnecessary for syphilis diagnosis but can be recommended for determining serological activity and the effect of syphilis treatment.
It is well accepted that the propagation of electromagnetic ion cyclotron (EMIC) waves are bidirectional near their source regions and unidirectional when away from these regions. The generally ...believed source region for EMIC waves is around the magnetic equatorial plane. Here we describe a series of EMIC waves in the Pc1 (0.2–5 Hz) frequency band above the local He+ cyclotron frequency observed in situ by all four Cluster spacecraft on 9 April 2005 at midmagnetic latitudes (MLAT = ~33°–49°) with L = 10.7–11.5 on the dayside (MLT = 10.3–10.4). A Poynting vector spectrum shows that the wave packets consist of multiple groups of packets propagating bidirectionally, rather than unidirectionally, away from the equator, while the local plasma conditions indicate that the spacecraft are entering into a region sufficient for local wave excitation. One possible interpretation is that, while part of the observed waves are inside their source region, the others are either close enough to the source region, or mixed with the wave packets from multiple source regions at different latitudes.
Key Points
Multiple bidirectional EMIC wave packets at midlatitude are investigated
Plasma conditions indicate that spacecraft are entering into source region
This wave event is compared to a similar event by expanding on a recent study
Abstract
We compute the spherically averaged power spectrum from four seasons of data obtained for the Epoch of Reionization (EoR) project observed with the Murchison Widefield Array (MWA). We ...measure the EoR power spectrum over k = 0.07–3.0 h Mpc−1 at redshifts $z$ = 6.5–8.7. The largest aggregation of 110 h on EoR0 high band (3340 observations), yields a lowest measurement of (43 mK)2 = 1.8 × 103 mK2 at k = 0.14 h Mpc−1 and $z$ = 6.5 (2σ thermal noise plus sample variance). Using the Real-Time System to calibrate and the CHIPS pipeline to estimate power spectra, we select the best observations from the central five pointings within the 2013–2016 observing seasons, observing three independent fields and in two frequency bands. This yields 13 591 2-min snapshots (453 h), based on a quality assurance metric that measures ionospheric activity. We perform another cut to remove poorly calibrated data, based on power in the foreground-dominated and EoR-dominated regions of the two-dimensional power spectrum, reducing the set to 12 569 observations (419 h). These data are processed in groups of 20 observations, to retain the capacity to identify poor data, and used to analyse the evolution and structure of the data over field, frequency, and data quality. We subsequently choose the cleanest 8935 observations (298 h of data) to form integrated power spectra over the different fields, pointings, and redshift ranges.
We report a novel plastic deformation mechanism of bulk metallic glass composites (BMGCs) containing metastable β − Ti dendrites. Plastic deformation of the BMGCs beyond the ultimate tensile strength ...is mediated by cooperative shear events, which comprise a shear band in the glassy matrix and a continuous ω − Ti band with a thickness of ∼ 10 nm in the β − Ti dendrite. The cooperative shear leads to serrated shear avalanches. The formation of narrow ω − Ti bands is caused by high local strain rates during the cooperative shear. The cooperative shear mechanism enriches the deformation mechanisms of BMGCs and also deepens the understanding of ω − Ti formation.
Amino-functionalized graphene oxide (GO-NH2) was directly grafted onto carbon fiber surface by covalent bonding in an attempt to improve the mechanical properties of carbon fiber composites. The ...effect of surface modification on the properties of carbon fiber and the resulting carbon fiber composites was investigated by X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and interfacial shear strength (IFSS). As revealed by Fourier transform infrared spectroscopy (FT-IR), GO-NH2 was successfully grafted on the carbon fiber surface. From dynamic contact angle analysis (DCAT) and XPS values, such GO-NH2 grafted carbon fiber exhibited significant improvements in surface energy and functional groups of the carbon fiber surface, which lead to an increase of 36.4% in the IFSS of its composites. Such hierarchical reinforcement shows great potential for enhancing interfacial properties in carbon fiber-reinforced composites.
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•Amino-functionalized graphene oxide was grafted onto carbon fibers by covalent bonding.•The functionalized carbon fiber exhibited enhanced mechanical properties and interfacial adhesion.•The functional groups on the hierarchical reinforcement are tunable to meet different demands.
Abstract Molecular mechanisms by which stroke increases neurogenesis have not been fully investigated. Using neural progenitor cells isolated from the subventricular zone (SVZ) of the adult rat ...subjected to focal cerebral ischemia, we investigated the Notch pathway in regulating proliferation and differentiation of adult neural progenitor cells after stroke. During proliferation of neural progenitor cells, ischemic neural progenitor cells exhibited substantially increased levels of Notch, Notch intracellular domain (NICD), and hairy enhancer of split (Hes) 1, which was associated with a significant increase of proliferating cells. Blockage of the Notch pathway by short interfering ribonucleic acid (siRNA) against Notch or a γ secretase inhibitor significantly reduced Notch, NICD and Hes1 expression and cell proliferation induced by stroke. During differentiation of neural progenitor cells, Notch and Hes1 expression was downregulated in ischemic neural progenitor cells, which was coincident with a significant increase of neuronal population. Inhibition of the Notch pathway with a γ secretase inhibitor further substantially increased neurons, but did not alter astrocyte population in ischemic neural progenitor cells. These data suggest that the Notch signaling pathway mediates adult SVZ neural progenitor cell proliferation and differentiation after stroke.
Highlights ► We assessed the effect of HDAC inhibitor–VPA on post-stroke recovery. ► The administration of VPA starting 24 h after stroke improved neurological outcome. ► The VPA treatment enhances ...white matter repair and neurogenesis after stroke. ► The upregulation of GLT-1 by VPA may lead to increased oligodendrocyte survival.
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