863 research outputs found
Carbonic Anhydrase Activators: Gold Nanoparticles Coated with Derivatized Histamine, Histidine, and Carnosine Show Enhanced Activatory Effects on Several Mammalian Isoforms.
International audienc
Glycosyl Coumarin Carbonic Anhydrase IX and XII Inhibitors Strongly Attenuate the Growth of Primary Breast Tumors.
International audienc
Artificial intelligence-based recurrence prediction outperforms classical histopathological methods in pulmonary adenocarcinoma biopsies
Introduction: Between 10 and 50% of early-stage lung adenocarcinoma patients experience local or distant recurrence. Histological parameters such as a solid or micropapillary growth pattern are well-described risk factors for recurrence. However, not every patient presenting with such a pattern will develop recurrence. Designing a model which can more accurately predict recurrence on small biopsy samples can aid the stratification of patients for surgery, (neo-)adjuvant therapy, and follow-up. Material and Methods: In this study, a statistical model on biopsies fed with histological data from early and advanced-stage lung adenocarcinomas was developed to predict recurrence after surgical resection. Additionally, a convolutional neural network (CNN)-based artificial intelligence (AI) classification model, named AI-based Lung Adenocarcinoma Recurrence Predictor (AILARP), was trained to predict recurrence, with an ImageNet pre-trained EfficientNet that was fine-tuned on lung adenocarcinoma biopsies using transfer learning. Both models were validated using the same biopsy dataset to ensure that an accurate comparison was demonstrated. Results: The statistical model had an accuracy of 0.49 for all patients when using histology data only. The AI classification model yielded a test accuracy of 0.70 and 0.82 and an area under the curve (AUC) of 0.74 and 0.87 on patch-wise and patient-wise hematoxylin and eosin (H&E) stained whole slide images (WSIs), respectively. Conclusion: AI classification outperformed the traditional clinical approach for recurrence prediction on biopsies by a fair margin. The AI classifier may stratify patients according to their recurrence risk, based only on small biopsies. This model warrants validation in a larger lung biopsy cohort.</p
Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors.
The X-ray crystal structure of the adduct between the zinc metalloenzyme carbonic anhydrase II (CA, EC 4.2.1.1) with the recently discovered natural product coumarin derivative 6-(1S-hydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one showed the coumarin hydrolysis product, a cis-2-hydroxy-cinnamic acid derivative, and not the parent coumarin, bound within the enzyme active site. The bound inhibitor exhibits an extended, two-arm conformation that effectively plugs the entrance to the enzyme active site with no interactions with the catalytically crucial zinc ion. The inhibitor is sandwiched between Phe131, with which it makes an edge-to-face stacking, and Asn67/Glu238sym, with which it makes several polar and hydrogen bonding interactions. This unusual binding mode, with no interactions between the inhibitor molecule and the active site metal ion is previously unobserved for this enzyme class and presents a new opportunity for future drug design campaigns to target a mode of inhibition that differs substantially from classical inhibitors such as the clinically used sulfonamides and sulfamates. Several structurally simple coumarin scaffolds were also shown to inhibit all 13 catalytically active mammalian CA isoforms, with inhibition constants ranging from nanomolar to millimolar. The inhibition is time dependent, with maximum inhibition being observed after 6 h.No Full Tex
Carbonic anhydrase inhibitor coated gold nanoparticles selectively inhibit the tumor-associated isoform IX over the cytosolic isozymes I and II.
International audienc
Search for the Weak Decay of an H Dibaryon
We have searched for a neutral dibaryon decaying via and
. Our search has yielded two candidate events from which we set
an upper limit on the production cross section. Normalizing to the
inclusive production cross section, we find at 90% C.L., for an of mass
2.15 GeV/.Comment: 11 pages, 6 postscript figures, epsfig, aps, preprint, revte
On the importance of grain size in luminescence dating using quartz
There are two major problems commonly encountered when applying Optically Stimulated Luminescence (OSL) dating in the high dose range: (i) age discrepancy between different grain sizes, and (ii) age underestimation. A marked and systematic discrepancy between fine-grain (4–11 μm) and coarse-grain (63–90 μm) quartz single aliquot regeneration protocol (SAR) ages has been reported previously for Romanian and Serbian loess >40 ka (De of ∼100 Gy), generally with fine-grain ages underestimating the depositional age. In this paper, we show a similar age pattern for two grain size fractions from Chinese loess, thus pointing to a potential worldwide phenomenon. While age underestimation is often attributed to signal saturation problems, this is not the case for fine grain material, which saturates at higher doses than coarse grains, yet begins to underestimate true ages earlier. Here we examine the dose response curves of quartz from different sedimentary contexts around the world, using a range of grain sizes (diameters of 4–11 μm, 11–30 μm, 35–50 μm, 63–90 μm, 90–125 μm, 125–180 μm, and 180–250 μm). All dose response curves can be adequately described by a sum of two saturating exponential functions, whose saturation characteristics (D0 values) are clearly anticorrelated with grain diameter (φ) through an inverse square root relationship, D0 = A/√φ, where A is a scaling factor. While the mechanism behind this grain-size dependency of saturation characteristics still needs to be understood, our results show that the observation of an extended SAR laboratory dose response curve does not necessarily enable high doses to be recorded accurately, or provide a corresponding extended age range
Effect of the distal histidine on the peroxidatic activity of monomeric cytoglobin
The reaction of hydrogen peroxide with ferric human cytoglobin and a number of distal histidine variants were studied. The peroxidase activity of the monomeric wildtype protein with an internal disulfide bond, likely to be the form of the protein in vivo, exhibits a high peroxidase-like activity above that of other globins such as myoglobin. Furthermore, the peroxidatic activity of wildtype cytoglobin shows increased resistance to radical-based degradation compared to myoglobin. The ferryl form of wildtype cytoglobin is unstable, but is able to readily oxidize substrates such as guaiacol. In contrast distal histidine mutants of cytoglobin (H81Y and H81V) show very low peroxidase activity but enhanced radical-induced degradation. Therefore, the weakly bound distal histidine appears to modulate ferryl stability and limit haem degradation. These data are consistent with a role of a peroxidase activity of cytoglobin in cell stress response mechanisms.</ns4:p
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