792 research outputs found
Machine Learning for Localizing Epileptogenic-Zone in the Temporal Lobe: Quantifying the Value of Multimodal Clinical-Semiology and Imaging Concordance
Background: Epilepsy affects 50 million people worldwide and a third are refractory to medication. If a discrete cerebral focus or network can be identified, neurosurgical resection can be curative. Most excisions are in the temporal-lobe, and are more likely to result in seizure-freedom than extra-temporal resections. However, less than half of patients undergoing surgery become entirely seizure-free. Localizing the epileptogenic-zone and individualized outcome predictions are difficult, requiring detailed evaluations at specialist centers. Methods: We used bespoke natural language processing to text-mine 3,800 electronic health records, from 309 epilepsy surgery patients, evaluated over a decade, of whom 126 remained entirely seizure-free. We investigated the diagnostic performances of machine learning models using set-of-semiology (SoS) with and without hippocampal sclerosis (HS) on MRI as features, using STARD criteria. Findings: Support Vector Classifiers (SVC) and Gradient Boosted (GB) decision trees were the best performing algorithms for temporal-lobe epileptogenic zone localization (cross-validated Matthews correlation coefficient (MCC) SVC 0.73 ± 0.25, balanced accuracy 0.81 ± 0.14, AUC 0.95 ± 0.05). Models that only used seizure semiology were not always better than internal benchmarks. The combination of multimodal features, however, enhanced performance metrics including MCC and normalized mutual information (NMI) compared to either alone (p < 0.0001). This combination of semiology and HS on MRI increased both cross-validated MCC and NMI by over 25% (NMI, SVC SoS: 0.35 ± 0.28 vs. SVC SoS+HS: 0.61 ± 0.27). Interpretation: Machine learning models using only the set of seizure semiology (SoS) cannot unequivocally perform better than benchmarks in temporal epileptogenic-zone localization. However, the combination of SoS with an imaging feature (HS) enhance epileptogenic lobe localization. We quantified this added NMI value to be 25% in absolute terms. Despite good performance in localization, no model was able to predict seizure-freedom better than benchmarks. The methods used are widely applicable, and the performance enhancements by combining other clinical, imaging and neurophysiological features could be similarly quantified. Multicenter studies are required to confirm generalizability. Funding: Wellcome/EPSRC Center for Interventional and Surgical Sciences (WEISS) (203145Z/16/Z)
Imaging of Four Planetary Nebulae in the Magellanic Clouds Using the Hubble Space Telescope Faint Object Camera
Using the Faint Object Camera on-board the Hubble Space Telescope, we have obtained images of four planetary nebulae (PNe) in the Magellanic Clouds, namely N2 and N5 in the SMC and N66 and N201 in the LMC. Each nebula was imaged through two narrow-band filters isolating [O III] λ5007 and Hβ, for a nominal exposure time of 1000 s in each filter. Significant detail is evident on the raw images and, after deconvolution using the Richardson-Lucy algorithm, structures as small as 0.06" are easily discernible. In [O III], SMC N5 shows a circular ring structure, with a peak-to-peak diameter of 0.26" and a FWHM of 0.35", while SMC N2 shows an elliptical ring structure with a peak-to-peak diameter of 0.26" x 0.21" (FWHM 0.40" x 0.35"). The expansion ages corresponding to the observed structures in SMC N2 and N5 are of the order of 3000 yr. Such low ages appear more easy to reconcile with helium-burning rather than hydrogen-burning central star evolutionary tracks. LMC N201 is very compact, with a FWHM of 0.21" in Hβ. The Type I PN LMC N66 is a multipolar nebula, with the brightest part having an extent of about 2" and with fainter structures extending over 4". The [O III] image reveals structures unprecedented for a planetary nebula, with several bright knots and faint loops visible outside the two main bright lobes
Baryonic symmetries and M5 branes in the AdS_4/CFT_3 correspondence
We study U(1) symmetries dual to Betti multiplets in the AdS_4/CFT_3
correspondence for M2 branes at Calabi-Yau four-fold singularities. Analysis of
the boundary conditions for vector fields in AdS_4 allows for a choice where
wrapped M5 brane states carrying non-zero charge under such symmetries can be
considered. We begin by focusing on isolated toric singularities without
vanishing six-cycles, and study in detail the cone over Q^{111}. The boundary
conditions considered are dual to a CFT where the gauge group is U(1)^2 x
SU(N)^4. We find agreement between the spectrum of gauge-invariant
baryonic-type operators in this theory and wrapped M5 brane states. Moreover,
the physics of vacua in which these symmetries are spontaneously broken
precisely matches a dual gravity analysis involving resolutions of the
singularity, where we are able to match condensates of the baryonic operators,
Goldstone bosons and global strings. We also argue more generally that theories
where the resolutions have six-cycles are expected to receive non-perturbative
corrections from M5 brane instantons. We give a general formula relating the
instanton action to normalizable harmonic two-forms, and compute it explicitly
for the Q^{222} example. The holographic interpretation of such instantons is
currently unclear.Comment: 92 pages, 10 figure
Climate and southern Africa's water-energy-food nexus
In southern Africa, the connections between climate and the water-energy-food nexus are strong. Physical and socioeconomic exposure to climate is high in many areas and in crucial economic sectors. Spatial interdependence is also high, driven for example, by the regional extent of many climate anomalies and river basins and aquifers that span national boundaries. There is now strong evidence of the effects of individual climate anomalies, but associations between national rainfall and Gross Domestic Product and crop production remain relatively weak. The majority of climate models project decreases in annual precipitation for southern Africa, typically by as much as 20% by the 2080s. Impact models suggest these changes would propagate into reduced water availability and crop yields. Recognition of spatial and sectoral interdependencies should inform policies, institutions and investments for enhancing water, energy and food security. Three key political and economic instruments could be strengthened for this purpose; the Southern African Development Community, the Southern African Power Pool, and trade of agricultural products amounting to significant transfers of embedded water
The Reproducibility of Blood Acid Base Responses in Male Collegiate Athletes Following Individualised Doses of Sodium Bicarbonate: A Randomised Controlled Crossover Study
Background: Current evidence suggests sodium bicarbonate (NaHCO3) should be ingested based upon the individualised alkalotic peak of either blood pH or bicarbonate (HCO3−) because of large inter-individual variations (10–180 min). If such a strategy is to be practical, the blood analyte response needs to be reproducible. Objective: This study aimed to evaluate the degree of reproducibility of both time to peak (TTP) and absolute change in blood pH, HCO3− and sodium (Na+) following acute NaHCO3 ingestion. Methods: Male participants (n = 15) with backgrounds in rugby, football or sprinting completed six randomised treatments entailing ingestion of two doses of 0.2 g·kg−1 body mass (BM) NaHCO3 (SBC2a and b), two doses of 0.3 g·kg−1 BM NaHCO3 (SBC3a and b) or two control treatments (CON1a and b) on separate days. Blood analysis included pH, HCO3− and Na+ prior to and at regular time points following NaHCO3 ingestion over a 3-h period. Results: HCO3− displayed greater reproducibility than pH in intraclass correlation coefficient (ICC) analysis for both TTP (HCO3− SBC2 r = 0.77, P = 0.003; SBC3 r = 0.94, P < 0.001; pH SBC2 r = 0.62, P = 0.044; SBC3 r = 0.71, P = 0.016) and absolute change (HCO3− SBC2 r = 0.89, P < 0.001; SBC3 r = 0.76, P = 0.008; pH SBC2 r = 0.84, P = 0.001; SBC3 r = 0.62, P = 0.041). Conclusion: Our results indicate that both TTP and absolute change in HCO3− is more reliable than pH. As such, these data provide support for an individualised NaHCO3 ingestion strategy to consistently elicit peak alkalosis before exercise. Future work should utilise an individualised NaHCO3 ingestion strategy based on HCO3− responses and evaluate effects on exercise performance
The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a.
p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate
Post-depositional fracturing and subsidence of pumice flow deposits: Lascar Volcano, Chile
Unconsolidated pyroclastic flow deposits of the
1993 eruption of Lascar Volcano, Chile, have, with time,
become increasingly dissected by a network of deeply
penetrating fractures. The fracture network comprises
orthogonal sets of decimeter-wide linear voids that form a
pseudo-polygonal grid visible on the deposit surface. In this
work, we combine shallow surface geophysical imaging
tools with remote sensing observations and direct field
measurements of the deposit to investigate these fractures
and their underlying causal mechanisms. Based on ground
penetrating radar images, the fractures are observed to have
propagated to depths of up to 10 m. In addition, orbiting radar interferometry shows that deposit subsidence of up to
1 cm/year occurred between 1993 and 1996 with continued
subsidence occurring at a slower rate thereafter. In situ
measurements show that 1 m below the surface, the 1993
deposits remain 5°C to 15°C hotter, 18 years after
emplacement, than adjacent deposits. Based on the observed
subsidence as well as estimated cooling rates, the fractures are
inferred to be the combined result of deaeration, thermal
contraction, and sedimentary compaction in the months to
years following deposition. Significant environmental factors,
including regional earthquakes in 1995 and 2007, accelerated
settling at punctuated moments in time. The spatially variable
fracture pattern relates to surface slope and lithofacies
variations as well as substrate lithology. Similar fractures
have been reported in other ignimbrites but are generally
exposed only in cross section and are often attributed to
formation by external forces. Here we suggest that such
interpretations should be invoked with caution, and deformation
including post-emplacement subsidence and fracturing of
loosely packed ash-rich deposits in the months to years postemplacement
is a process inherent in the settling of pyroclastic
material
Pre-eruptive magmatic processes re-timed using a non-isothermal approach to magma chamber dynamics
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Hydrothermal alteration of andesitic lava domes can lead to explosive volcanic behaviour
Dome-forming volcanoes are among the most hazardous volcanoes on Earth. Magmatic outgassing can be hindered if the permeability of a lava dome is reduced, promoting pore pressure augmentation and explosive behaviour. Laboratory data show that acid-sulphate alteration, common to volcanoes worldwide, can reduce the permeability on the sample lengthscale by up to four orders of magnitude and is the result of pore- and microfracture-filling mineral precipitation. Calculations using these data demonstrate that intense alteration can reduce the equivalent permeability of a dome by two orders of magnitude, which we show using numerical modelling to be sufficient to increase pore pressure. The fragmentation criterion shows that the predicted pore pressure increase is capable of fragmenting the majority of dome-forming materials, thus promoting explosive volcanism. It is crucial that hydrothermal alteration, which develops over months to years, is monitored at dome-forming volcanoes and is incorporated into real-time hazard assessments
Remodeling Lipid Metabolism and Improving Insulin Responsiveness in Human Primary Myotubes
OBJECTIVE: Disturbances in lipid metabolism are strongly associated with insulin resistance and type 2 diabetes (T2D). We hypothesized that activation of cAMP/PKA and calcium signaling pathways in cultured human myotubes would provide further insight into regulation of lipid storage, lipolysis, lipid oxidation and insulin responsiveness. METHODS: Human myoblasts were isolated from vastus lateralis, purified, cultured and differentiated into myotubes. All cells were incubated with palmitate during differentiation. Treatment cells were pulsed 1 hour each day with forskolin and ionomycin (PFI) during the final 3 days of differentiation to activate the cAMP/PKA and calcium signaling pathways. Control cells were not pulsed (control). Mitochondrial content, (14)C lipid oxidation and storage were measured, as well as lipolysis and insulin-stimulated glycogen storage. Myotubes were stained for lipids and gene expression measured. RESULTS: PFI increased oxidation of oleate and palmitate to CO(2) (p<0.001), isoproterenol-stimulated lipolysis (p = 0.01), triacylglycerol (TAG) storage (p<0.05) and mitochondrial DNA copy number (p = 0.01) and related enzyme activities. Candidate gene and microarray analysis revealed increased expression of genes involved in lipolysis, TAG synthesis and mitochondrial biogenesis. PFI increased the organization of lipid droplets along the myofibrillar apparatus. These changes in lipid metabolism were associated with an increase in insulin-mediated glycogen storage (p<0.001). CONCLUSIONS: Activation of cAMP/PKA and calcium signaling pathways in myotubes induces a remodeling of lipid droplets and functional changes in lipid metabolism. These results provide a novel pharmacological approach to promote lipid metabolism and improve insulin responsiveness in myotubes, which may be of therapeutic importance for obesity and type 2 diabetes
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