BATAL Vernier, J.-P.; Fairlie, T. D.; Deshler, T. ...
Bulletin of the American Meteorological Society,
05/2018, Letnik:
99, Številka:
5
Journal Article
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We describe and show results from a series of field campaigns that used balloonborne instruments launched from India and Saudi Arabia during the summers 2014–17 to study the nature, formation, and ...impacts of the Asian Tropopause Aerosol Layer (ATAL). The campaign goals were to i) characterize the optical, physical, and chemical properties of the ATAL; ii) assess its impacts on water vapor and ozone; and iii) understand the role of convection in its formation. To address these objectives, we launched 68 balloons from four locations, one in Saudi Arabia and three in India, with payload weights ranging from 1.5 to 50 kg. We measured meteorological parameters; ozone; water vapor; and aerosol backscatter, concentration, volatility, and composition in the upper troposphere and lower stratosphere (UTLS) region. We found peaks in aerosol concentrations of up to 25 cm–3 for radii > 94 nm, associated with a scattering ratio at 940 nm of ∼1.9 near the cold-point tropopause. During medium-duration balloon flights near the tropopause, we collected aerosols and found, after offline ion chromatography analysis, the dominant presence of nitrate ions with a concentration of about 100 ng m–3. Deep convection was found to influence aerosol loadings 1 km above the cold-point tropopause. The Balloon Measurements of the Asian Tropopause Aerosol Layer (BATAL) project will continue for the next 3–4 years, and the results gathered will be used to formulate a future National Aeronautics and Space Administration–Indian Space Research Organisation (NASA–ISRO) airborne campaign with NASA high-altitude aircraft.
The Systolic Blood Pressure Intervention (SPRINT) randomized trial demonstrated that intensive blood pressure management resulted in slower progression of cerebral white matter hyperintensities, ...compared with standard therapy. We assessed longitudinal changes in brain functional connectivity to determine whether intensive treatment results in less decline in functional connectivity and how changes in brain functional connectivity relate to changes in brain structure.
Five hundred forty-eight participants completed longitudinal brain MR imaging, including resting-state fMRI, during a median follow-up of 3.84 years. Functional brain networks were identified using independent component analysis, and a mean connectivity score was calculated for each network. Longitudinal changes in mean connectivity score were compared between treatment groups using a 2-sample
test, followed by a voxelwise
test. In the full cohort, adjusted linear regression analysis was performed between changes in the mean connectivity score and changes in structural MR imaging metrics.
Four hundred six participants had longitudinal imaging that passed quality control. The auditory-salience-language network demonstrated a significantly larger decline in the mean connectivity score in the standard treatment group relative to the intensive treatment group (
= .014), with regions of significant difference between treatment groups in the cingulate and right temporal/insular regions. There was no treatment group difference in other networks. Longitudinal changes in mean connectivity score of the default mode network but not the auditory-salience-language network demonstrated a significant correlation with longitudinal changes in white matter hyperintensities (
= .013).
Intensive treatment was associated with preservation of functional connectivity of the auditory-salience-language network, while mean network connectivity in other networks was not significantly different between intensive and standard therapy. A longitudinal increase in the white matter hyperintensity burden is associated with a decline in mean connectivity of the default mode network.
Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by expression of SS18-SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic ...dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells with those in >130 non-SS tumor cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR. Clinical ATR inhibitors (ATRi) elicited a synthetic lethal effect in SS tumor cells and impaired growth of SS patient-derived xenografts. Oncogenic SS18-SSX family fusion genes are known to alter the composition of the BAF chromatin-remodeling complex, causing ejection and degradation of wild-type SS18 and the tumor suppressor SMARCB1. Expression of oncogenic SS18-SSX fusion proteins caused profound ATRi sensitivity and a reduction in SS18 and SMARCB1 protein levels, but an SSX18-SSX1 Δ71-78 fusion containing a C-terminal deletion did not. ATRi sensitivity in SS was characterized by an increase in biomarkers of replication fork stress (increased γH2AX, decreased replication fork speed, and increased R-loops), an apoptotic response, and a dependence upon cyclin E expression. Combinations of cisplatin or PARP inhibitors enhanced the antitumor cell effect of ATRi, suggesting that either single-agent ATRi or combination therapy involving ATRi might be further assessed as candidate approaches for SS treatment.
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Global observations and model studies indicate that new particle formation (NPF) in the upper troposphere (UT) and subsequent particles supply 40 %-60 % of cloud condensation nuclei (CCN) in the ...lower troposphere, thus affecting the Earth's radiative budget. There are several plausible nucleation mechanisms and precursor species in this atmospheric region, which, in the absence of observational constraints, lead to uncertainties in modeled aerosols. In particular, the type of nucleation mechanism and concentrations of nucleation precursors, in part, determine the spatial distribution of new particles and resulting spatial distribution of CCN from this source. Although substantial advances in understanding NPF have been made in recent years, NPF processes in the UT in pristine marine regions are still poorly understood and are inadequately represented in global models.
Microbiological and molecular tools were used to monitor Streptococcus uberis populations on farm tracks and paddocks on a dairy farm during different seasons of a year to identify and profile ...potential environmental niches of Strep. uberis in a pasture-based dairying system. Farm tracks of high or low cow traffic were sampled every 2 wk for an entire year and Strep. uberis numbers were enumerated from a selective medium. During each season of the year, paddocks were sampled for the presence of Strep. uberis before and after grazing by dairy cows. Farm tracks of high cow traffic generally had greater concentrations of Strep. uberis isolated compared with tracks with less cow traffic, but there was also significant variation in the concentrations of Strep. uberis contamination among seasons, being highest in winter and lowest in summer. The bacterium was detected in paddocks only after cow grazing had occurred, but the bacteria could still be detected in soil for up to 2 wk following grazing in winter. Multilocus sequence typing showed great heterogeneity, with some commonality between farm track and milk isolates, which may help explain cow-to-environment or environment-to-cow transmission of the bacterium in the dairy setting.
Summary Background Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with ...seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. Methods SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. Findings For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1·57 95% CI 1·19–2·08), but there was no significant difference between valproate and lamotrigine (1·25 0·94–1·68). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1·55 1·07–2·24 and topiramate (1·89 1·32–2·70). For time to 12-month remission valproate was significantly better than lamotrigine overall (0·76 0·62–0·94), and for the subgroup with an idiopathic generalised epilepsy 0·68 (0·53–0·89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. Interpretation Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.
Myelination of axons by oligodendrocytes enables fast saltatory conduction. Oligodendrocytes are responsive to neuronal activity, which has been shown to induce changes to myelin sheaths, potentially ...to optimize conduction and neural circuit function. However, the cellular bases of activity-regulated myelination in vivo are unclear, partly due to the difficulty of analyzing individual myelinated axons over time. Activity-regulated myelination occurs in specific neuronal subtypes and can be mediated by synaptic vesicle fusion, but several questions remain: it is unclear whether vesicular fusion occurs stochastically along axons or in discrete hotspots during myelination and whether vesicular fusion regulates myelin targeting, formation, and/or growth. It is also unclear why some neurons, but not others, exhibit activity-regulated myelination. Here, we imaged synaptic vesicle fusion in individual neurons in living zebrafish and documented robust vesicular fusion along axons during myelination. Surprisingly, we found that axonal vesicular fusion increased upon and required myelination. We found that axonal vesicular fusion was enriched in hotspots, namely the heminodal non-myelinated domains into which sheaths grew. Blocking vesicular fusion reduced the stable formation and growth of myelin sheaths, and chemogenetically stimulating neuronal activity promoted sheath growth. Finally, we observed high levels of axonal vesicular fusion only in neuronal subtypes that exhibit activity-regulated myelination. Our results identify a novel “feedforward” mechanism whereby the process of myelination promotes the neuronal activity-regulated signal, vesicular fusion that, in turn, consolidates sheath growth along specific axons selected for myelination.
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•Live-imaged synaptic vesicular fusion during myelination of zebrafish spinal axons•Neuron-subtype specific differences in axonal vesicular fusion•Onset of myelination coincides with and promotes axonal vesicular fusion•Activity and vesicular fusion promote sheath stability and growth
Almeida et al. show that fusion of synaptic vesicles along axons in the developing zebrafish spinal cord is as frequent as at presynaptic terminals in some neuronal subtypes. In these neurons, axonal vesicular fusion is promoted by myelination and in turn consolidates sheath formation and growth.
The eradication of Helicobacter pylori has become the focus of much attention since the first attempts at developing effective therapies some 10 years ago. This review focuses on ranitidine bismuth ...citrate (RBC), the first new drug to be introduced for use in the eradication of H. pylori. RBC when combined with clarithromycin gives consistently high eradication rates (above 80% intention-to-treat assessment in double-blind, international studies) as a simple dual therapy for 14 days or when combined with two antibiotics as a triple therapy for 7 days. RBC enhances the in vitro killing of H. pylori by antibiotics, such as clarithromycin, metronidazole or tetracycline, in a synergistic manner. This effect is seen even when the H. pylori strains are 'resistant' to the antibiotics. Such a synergistic effect probably explains the increased efficacy of RBC-clarithromycin dual therapies compared with clarithromycin dosed with acid-suppressive agents such as H 2-receptor antagonists or proton-pump inhibitors.
Results are presented from a semicoherent search for continuous gravitational waves from the brightest low-mass X-ray binary, Scorpius X-1, using data collected during the first Advanced LIGO ...observing run. The search combines a frequency domain matched filter (Bessel-weighted F-statistic) with a hidden Markov model to track wandering of the neutron star spin frequency. No evidence of gravitational waves is found in the frequency range 60–650 Hz. Frequentist 95% confidence strain upper limits, h095%=4.0×10−25, 8.3×10−25, and 3.0×10−25 for electromagnetically restricted source orientation, unknown polarization, and circular polarization, respectively, are reported at 106 Hz. They are ≤10 times higher than the theoretical torque-balance limit at 106 Hz.
Purpose
Meningiomas are a frequent tumor of the central nervous system. Although mostly benign, approximately 5% present as atypical or malignant tumors. Treatments for atypical meningiomas include ...gross total resection and radiotherapy, but about 33% of patients have recurrent tumors, sometimes as a higher grade. Recently, the brain penetrant anthelmintic drug, mebendazole, has shown promise as an anticancer agent in rodent models of glioblastoma and medulloblastoma.
Methods
The half maximal inhibitory concentration (IC
50
) effect on colony formation, cell proliferation, and caspase-3/7 markers of apoptosis of mebendazole with and without radiation was measured in vitro. Mice intracranially implanted with KT21MG1 human meningioma were administered mebendazole alone or in combination with radiation. Survival benefit was evaluated, while tumors were investigated by immunohistochemical staining for apoptosis, cell proliferation, and vascular density.
Results
In vitro experiments on meningioma cell lines showed the IC
50
for mebendazole in the range of 0.26–0.42 µM. Mebendazole alone induced cytotoxicity, however the combination had a greater reduction in colony formation and resulted in higher levels of cleaved caspase-3. The in vivo study showed both, mebendazole alone and the combination, to have a survival benefit with an increase in apoptosis, and decreases in tumor cell and vascular proliferation.
Conclusion
These preclinical findings indicate that mebendazole alone or in combination with radiation can be considered for the treatment of malignant meningioma. The mechanism of action for this combination may include an increase in apoptosis, a reduction in proliferation and angiogenesis, or a combination of these effects.
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