Synthetic pesticide use has been the dominant form of pest control since the 1940s. However, biopesticides are emerging as sustainable pest control alternatives, with prevailing use in organic ...agricultural production systems. Foremost among botanical biopesticides is the limonoid azadirachtin, whose perceived environmental safety has come under debate and scrutiny in recent years. Coconut production, particularly organic coconut production, is one of the agricultural systems in which azadirachtin is used as a primary method of pest control for the management of the invasive coconut mite, Aceria guerreronis Keifer (Acari: Eriophyidae). The management of this mite species also greatly benefits from predation by Neoseiulus baraki (Athias-Henriot) (Acari: Phytoseiidae). Here, we assessed the potential behavioral impacts of azadirachtin on the coconut mite predator, N. baraki. We explored the effects of this biopesticide on overall predator activity, female searching time, and mating behavior and fecundity. Azadirachtin impairs the overall activity of the predator, reducing it to nearly half; however, female searching was not affected. In contrast, mating behavior was compromised by azadirachtin exposure particularly when male predators were exposed to the biopesticide. Consequently, predator fecundity was also compromised by azadirachtin, furthering doubts about its environmental safety and selectivity towards biological control agents.
The dose distribution of a proton beam stopping in water has components due to basic physics and may have others from beam contamination. We propose the concise terms core for the primary beam, halo ...(see Pedroni et al 2005 Phys. Med. Biol. 50 541-61) for the low dose region from charged secondaries, aura for the low dose region from neutrals, and spray for beam contamination. We have measured the dose distribution in a water tank at 177 MeV under conditions where spray, therefore radial asymmetry, is negligible. We used an ADCL calibrated thimble chamber and a Faraday cup calibrated integral beam monitor so as to obtain immediately the absolute dose per proton. We took depth scans at fixed distances from the beam centroid rather than radial scans at fixed depths. That minimizes the signal range for each scan and better reveals the structure of the core and halo. Transitions from core to halo to aura are already discernible in the raw data. The halo has components attributable to coherent and incoherent nuclear reactions. Due to elastic and inelastic scattering by the nuclear force, the Bragg peak persists to radii larger than can be accounted for by Molière single scattering. The radius of the incoherent component, a dose bump around midrange, agrees with the kinematics of knockout reactions. We have fitted the data in two ways. The first is algebraic or model dependent (MD) as far as possible, and has 25 parameters. The second, using 2D cubic spline regression, is model independent. Optimal parameterization for treatment planning will probably be a hybrid of the two, and will of course require measurements at several incident energies. The MD fit to the core term resembles that of the PSI group (Pedroni et al 2005), which has been widely emulated. However, we replace their T(w), a mass stopping power which mixes electromagnetic (EM) and nuclear effects, with one that is purely EM, arguing that protons that do not undergo hard single scatters continue to lose energy according to the Beth-Bloch formula. If that is correct, it is no longer necessary to measure T(w), and the dominant role played by the 'Bragg peak chamber' vanishes. For mathematical and other details we will refer to Gottschalk et al (2014, arXiv: 1409.1938v1), a long technical report of this project.
Plasma biomarkers for Alzheimer's disease (AD) have broad potential as screening tools in primary care and disease-modifying trials. Detecting elevated amyloid-β (Aβ) pathology to support trial ...recruitment or initiating Aβ-targeting treatments would be of critical value. In this study, we aimed to examine the robustness of plasma biomarkers to detect elevated Aβ pathology at different stages of the AD continuum. Beyond determining the best biomarker-or biomarker combination-for detecting this outcome, we also simulated increases in inter-assay coefficient of variability (CV) to account for external factors not considered by intra-assay variability. With this, we aimed to determine whether plasma biomarkers would maintain their accuracy if applied in a setting which anticipates higher variability (i.e., clinical routine).
We included 118 participants (cognitively unimpaired CU, n = 50, cognitively impaired CI, n = 68) from the ADNI study with a full plasma biomarker profile (Aβ42/40, GFAP, p-tau181, NfL) and matched amyloid imaging. Initially, we investigated how simulated CV variations impacted single-biomarker discriminative performance of amyloid status. Then, we evaluated the predictive performance of models containing different biomarker combinations, based both on original and simulated measurements. Plasma Aβ42/40 was represented by both immunoprecipitation mass spectrometry (IP-MS) and single molecule array (Simoa) methods in separate analyses. Model selection was based on a decision tree which incorporated Akaike information criterion value, likelihood ratio tests between the best-fitting models and, finally, and Schwartz's Bayesian information criterion.
Increasing variation greatly impacted the performance of plasma Aβ42/40 in discriminating Aβ status. In contrast, the performance of plasma GFAP and p-tau181 remained stable with variations >20%. When biomarker models were compared, the models "AG" (Aβ42/40 + GFAP; AUC = 86.5), "A" (Aβ42/40; AUC = 82.3), and "AGP" (Aβ42/40 + GFAP + p-tau181; AUC = 93.5) were superior in determining Aβ burden in all participants, within-CU, and within-CI groups, respectively. In the robustness analyses, when repeating model selection based on simulated measurements, models including IP-MS Aβ42/40 were also most often selected. Simoa Aβ42/40 did not contribute to any selected model when used as an immunoanalytical alternative to IP-MS Aβ42/40.
Plasma Aβ42/40, as quantified by IP-MS, shows high performance in determining Aβ positivity at all stages of the AD continuum, with GFAP and p-tau181 further contributing at CI stage. However, between-assay variations greatly impacted the performance of Aβ42/40 but not that of GFAP and p-tau181. Therefore, when dealing with between-assay CVs that exceed 5%, plasma GFAP and p-tau181 should be considered for a more robust determination of Aβ burden in CU and CI participants, respectively.
Geographic atrophy (GA) is a vision-threatening manifestation of age-related macular degeneration (AMD), one of the leading causes of blindness globally. Objective, rapid, reliable, and scalable ...quantification of GA from optical coherence tomography (OCT) retinal scans is necessary for disease monitoring, prognostic research, and clinical endpoints for therapy development. Such automatically quantified biomarkers on OCT are likely to further elucidate structure-function correlation in GA and thus the pathophysiological mechanisms of disease development and progression. In this work, we aimed to predict visual function with machine-learning applied to automatically acquired quantitative imaging biomarkers in GA. A post-hoc analysis of data from a clinical trial and routine clinical care was conducted. A deep-learning automated segmentation model was applied on OCT scans from 476 eyes (325 patients) with GA. A separate machine learning prediction model (Random Forest) used the resultant quantitative OCT (qOCT) biomarkers to predict cross-sectional visual acuity under standard (VA) and low luminance (LLVA). The primary outcome was regression coefficient (r
) and mean absolute error (MAE) for cross-sectional VA and LLVA in Early Treatment Diabetic Retinopathy Study (ETDRS) letters. OCT parameters were predictive of VA (r
0.40 MAE 11.7 ETDRS letters) and LLVA (r
0.25 MAE 12.1). Normalised random forest feature importance, as a measure of the predictive value of the three constituent features of GA; retinal pigment epithelium (RPE)-loss, photoreceptor degeneration (PDR), hypertransmission and their locations, was reported both on voxel-level heatmaps and ETDRS-grid subfields. The foveal region (46.5%) and RPE-loss (31.1%) had greatest predictive importance for VA. For LLVA, however, non-foveal regions (74.5%) and PDR (38.9%) were most important. In conclusion, automated qOCT biomarkers demonstrate predictive significance for VA and LLVA in GA. LLVA is itself predictive of GA progression, implying that the predictive qOCT biomarkers provided by our model are also prognostic.
We examine the effect of patenting on the survival prospects of 356 Internet-related firms that made an initial public offering on the NASDAQ at the height of the stock market bubble of the late ...1990s. By March 2005, almost 2/3 of these firms had delisted from the exchange. Changes in the legal environment in the US in the 1990s made it much easier to obtain patents on software, and ultimately, on business methods, though less than 1/2 of the firms in our sample obtained, or attempted to obtain, patents. For those that did, we hypothesize that patents conferred competitive advantages that translate into higher probability of survival, though they may also simply be a signal of firm quality. Controlling for other determinants of firm survival, patenting is positively associated with survival. Quite different processes appear to govern exit via acquisition compared to exit via delisting from the exchange due to business failure. Firms that applied for more patents were less likely to be acquired, though if they obtain unusually highly cited patents they may be a more attractive acquisition target. These findings do generally not hold true for “business method” patents, which do not appear to confer a survival advantage.
Synaptic dysfunction and degeneration is likely the key pathophysiology for the progression of cognitive decline in various dementia disorders. Synaptic status can be monitored by measurement of ...synaptic proteins in cerebrospinal fluid (CSF). In the current study, the aim was to investigate and compare both known and new synaptic proteins as potential biomarkers of synaptic dysfunction, especially in the context of Alzheimer's disease (AD). Seventeen synaptic proteins were quantified in CSF using two different targeted mass spectrometry assays in the prospective Swedish BioFINDER-2 study. The study included 958 individuals, characterized as having mild cognitive impairment (MCI, n = 205), AD dementia (n = 149), and a spectrum of other neurodegenerative diseases (n = 171), as well as cognitively unimpaired (CU, n = 443). Synaptic protein levels were compared between diagnostic groups and their associations with cognitive decline and key neuroimaging measures (Aβ-PET, tau-PET, and cortical thickness) were assessed. Among the 17 synaptic proteins examined, 14 were specifically elevated in the AD continuum. SNAP-25, 14-3-3 zeta/delta, beta-synuclein, and neurogranin exhibited the highest discriminatory accuracy to differentiate AD dementia from controls (AUCs = 0.81-0.93). SNAP-25 and 14-3-3 zeta/delta also had the strongest associations with tau-PET, Aβ-PET, and cortical thickness at baseline, and were associated with longitudinal changes in these imaging biomarkers (β(SE)=-0.056(0.0006) to 0.058(0.005), p < 0.0001). SNAP-25 was the strongest predictor of progression to AD dementia in non-demented individuals (Hazard ratio = 2.11). In contrast, neuronal pentraxins were decreased in all neurodegenerative diseases (except for Parkinson's disease), and NPTX2 showed the strongest associations with subsequent cognitive decline (longitudinal MMSE; β(SE) = 0.57(0.1), p ≤ 0.0001 and mPACC; β(SE) = 0.095(0.024), p ≤ 0.001) across the AD continuum. Interestingly, utilizing a ratio of the proteins that displayed higher levels in AD, such as SNAP-25 or 14-3-3 zeta/delta, over NPTX2 improved the biomarkers' association with cognitive decline and brain atrophy. We found that especially 14-3-3 zeta/delta and SNAP-25 are promising synaptic biomarkers of pathophysiological changes in AD. Neuronal pentraxins were identified as general indicators of neurodegeneration and associated with cognitive decline across various neurodegenerative dementias. The ratios of SNAP-25/NPTX2 and 14-3-3 zeta/delta/NPTX2 were found to best predict cognitive decline and brain atrophy.
In late 2016 and early 2017, the flat spectrum radio quasar CTA 102 exhibited a very strong and long-lasting outburst. The event can be described by a roughly two-month long increase of the baseline ...flux in the monitored energy bands (optical to γ-rays) by a factor 8, and a subsequent decrease over another two months back to pre-flare levels. The long-term trend was superseded by short but very strong flares, resulting in a peak flux that was a factor 50 above pre-flare levels in the γ-ray domain and almost a factor 100 above pre-flare levels in the optical domain. In this paper, we explain the long-term evolution of the outburst by the ablation of a gas cloud penetrating the relativistic jet. The slice-by-slice ablation results in a gradual increase of the particle injection until the center of the cloud is reached, after which the injected number of particles decreases again. With reasonable cloud parameters, we obtain excellent fits of the long-term trend.
A scannable laser beam is used to generate local thermal gradients in metallic (Co2FeAl) or insulating (Y3Fe5O12) ferromagnetic thin films. We study the resulting local charge and spin currents that ...arise due to the anomalous Nernst effect (ANE) and the spin Seebeck effect (SSE), respectively. In the local ANE experiments, we detect the voltage in the Co2FeAl thin film plane as a function of the laser-spot position and external magnetic field magnitude and orientation. The local SSE effect is detected in a similar fashion by exploiting the inverse spin Hall effect in a Pt layer deposited on top of the Y3Fe5O12. Our findings establish local thermal spin and charge current generation as well as spin caloritronic domain imaging.
Purpose
The fibroblast activation protein (FAP) is an emerging target for molecular imaging and therapy in cancer. OncoFAP is a novel small organic ligand for FAP with very high affinity. In this ...translational study, we establish
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GaGa-OncoFAP-DOTAGA (
68
Ga-OncoFAP) radiolabeling, benchmark its properties in preclinical imaging, and evaluate its application in clinical PET scanning.
Methods
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Ga-OncoFAP was synthesized in a cassette-based fully automated labeling module. Lipophilicity, affinity, and serum stability of
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Ga-OncoFAP were assessed by determining log
D
7.4
, IC
50
values, and radiochemical purity.
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Ga-OncoFAP tumor uptake and imaging properties were assessed in preclinical dynamic PET/MRI in murine subcutaneous tumor models. Finally, biodistribution and uptake in a variety of tumor types were analyzed in 12 patients based on individual clinical indications that received 163 ± 50 MBq
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Ga-OncoFAP combined with PET/CT and PET/MRI.
Results
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Ga-OncoFAP radiosynthesis was accomplished with high radiochemical yields. Affinity for FAP, lipophilicity, and stability of
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Ga-OncoFAP measured are ideally suited for PET imaging. PET and gamma counting–based biodistribution demonstrated beneficial tracer kinetics and high uptake in murine FAP-expressing tumor models with high tumor-to-blood ratios of 8.6 ± 5.1 at 1 h and 38.1 ± 33.1 at 3 h p.i. Clinical
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Ga-OncoFAP-PET/CT and PET/MRI demonstrated favorable biodistribution and kinetics with high and reliable uptake in primary cancers (SUV
max
12.3 ± 2.3), lymph nodes (SUV
max
9.7 ± 8.3), and distant metastases (SUV
max
up to 20.0).
Conclusion
Favorable radiochemical properties, rapid clearance from organs and soft tissues, and intense tumor uptake validate
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Ga-OncoFAP as a powerful alternative to currently available FAP tracers.
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