Learning from crowds in digital pathology using scalable variational Gaussian processes

This work was supported by the Agencia Estatal de Investigacion of the Spanish Ministerio de Ciencia e Innovacion under contract PID2019-105142RB-C22/AEI/10.13039/501100011033, and the United States National Institutes of Health National Cancer Institute Grants U01CA220401 and U24CA19436201. P.M. contribution was mostly before joining Microsoft Research, when he was supported by La Caixa Banking Foundation (ID 100010434, Barcelona, Spain) through La Caixa Fellowship for Doctoral Studies LCF/BQ/ES17/11600011.The volume of labeled data is often the primary determinant of success in developing machine learning algorithms. This has increased interest in methods for leveraging crowds to scale data labeling efforts, and methods to learn from noisy crowd-sourced labels. The need to scale labeling is acute but particularly challenging in medical applications like pathology, due to the expertise required to generate quality labels and the limited availability of qualified experts. In this paper we investigate the application of Scalable Variational Gaussian Processes for Crowdsourcing (SVGPCR) in digital pathology. We compare SVGPCR with other crowdsourcing methods using a large multi-rater dataset where pathologists, pathology residents, and medical students annotated tissue regions breast cancer. Our study shows that SVGPCR is competitive with equivalent methods trained using goldstandard pathologist generated labels, and that SVGPCR meets or exceeds the performance of other crowdsourcing methods based on deep learning. We also show how SVGPCR can effectively learn the class-conditional reliabilities of individual annotators and demonstrate that Gaussian-process classifiers have comparable performance to similar deep learning methods. These results suggest that SVGPCR can meaningfully engage non-experts in pathology labeling tasks, and that the classconditional reliabilities estimated by SVGPCR may assist in matching annotators to tasks where they perform well.Agencia Estatal de Investigacion of the Spanish Ministerio de Ciencia e Innovacion PID2019-105142RB-C22/AEI/10.13039/501100011033United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) U01CA220401 U24CA19436201La Caixa Banking Foundation (Barcelona, Spain) Barcelona, Spain) through La Caixa Fellowship 100010434 LCF/BQ/ES17/1160001

RAG2's non-core domain contributes to the ordered regulation of V(D)J recombination

Variable (diversity) joining [V(D)J] recombination of immune gene loci proceeds in an ordered manner with D to J portions recombining first and then an upstream V joins that recombinant. We present evidence that the non-core domain of recombination activating gene (RAG) protein 2 is involved in the regulation of recombinatorial order. In mice lacking the non-core domain of RAG2 the ordered rearrangement is disturbed and direct V to D rearrangements are 10- to 1000-times increased in tri-partite immune gene loci. Some forms of inter-chromosomal translocations between TCRβ and TCRδ D gene segments are also increased in the core RAG2 animals as compared with their wild-type (WT) counterparts. In addition, the concise use of proper recombination signal sequences (RSSs) appears to be disturbed in the core RAG2 mice as compared with WT RAG2 animals

Gas emissions from five volcanoes in northern Chile, and implications for the volatiles budget of the Central Volcanic Zone

This study performed the first assessment of the volcanic gas output from the Central Volcanic Zone (CVZ) of northern Chile. We present the fluxes and compositions of volcanic gases (H2O, CO2, H2, HCl, HF, and HBr) from five of the most actively degassing volcanoes in this region—Láscar, Lastarria, Putana, Ollagüe, and San Pedro—obtained during field campaigns in 2012 and 2013. The inferred gas plume compositions for Láscar and Lastarria (CO2/Stot = 0.9–2.2; Stot/HCl = 1.4–3.4) are similar to those obtained in the Southern Volcanic Zone of Chile, suggesting uniform magmatic gas fingerprint throughout the Chilean arc. Combining these compositions with our own UV spectroscopy measurements of the SO2 output (summing to ~1800 t d−1 for the CVZ), we calculate a cumulative CO2 output of 1743–1988 t d−1 and a total volatiles output of >20,200 t d−1

Anthelmintic activity of trans-cinnamaldehyde and A- and B-type proanthocyanidins derived from cinnamon (Cinnamomum verum)

Cinnamon (Cinnamomum verum) has been shown to have anti-inflammatory and antimicrobial properties, but effects on parasitic worms of the intestine have not been investigated. Here, extracts of cinnamon bark were shown to have potent in vitro anthelmintic properties against the swine nematode Ascaris suum. Analysis of the extract revealed high concentrations of proanthocyanidins (PAC) and trans-cinnamaldehyde (CA). The PAC were subjected to thiolysis and HPLC-MS analysis which demonstrated that they were exclusively procyanidins, had a mean degree of polymerization of 5.2 and 21% of their inter-flavan-3-ol links were A-type linkages. Purification of the PAC revealed that whilst they had activity against A. suum, most of the potency of the extract derived from CA. Trichuris suis and Oesophagostomum dentatum larvae were similarly susceptible to CA. To test whether CA could reduce A. suum infection in pigs in vivo, CA was administered daily in the diet or as a targeted, encapsulated dose. However, infection was not significantly reduced. It is proposed that the rapid absorption or metabolism of CA in vivo may prevent it from being present in sufficient concentrations in situ to exert efficacy. Therefore, further work should focus on whether formulation of CA can enhance its activity against internal parasites

Structure and serpentinization of the subducting Cocos plate offshore Nicaragua and Costa Rica

Author Posting. © American Geophysical Union, 2011. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 12 (2011): Q06009, doi:10.1029/2011GC003592.The Cocos plate experiences extensional faulting as it bends into the Middle American Trench (MAT) west of Nicaragua, which may lead to hydration of the subducting mantle. To estimate the along strike variations of volatile input from the Cocos plate into the subduction zone, we gathered marine seismic refraction data with the R/V Marcus Langseth along a 396 km long trench parallel transect offshore of Nicaragua and Costa Rica. Our inversion of crustal and mantle seismic phases shows two notable features in the deep structure of the Cocos plate: (1) Normal oceanic crust of 6 km thickness from the East Pacific Rise (EPR) lies offshore Nicaragua, but offshore central Costa Rica we find oceanic crust from the northern flank of the Cocos Nazca (CN) spreading center with more complex seismic velocity structure and a thickness of 10 km. We attribute the unusual seismic structure offshore Costa Rica to the midplate volcanism in the vicinity of the Galápagos hot spot. (2) A decrease in Cocos plate mantle seismic velocities from ∼7.9 km/s offshore Nicoya Peninsula to ∼6.9 km/s offshore central Nicaragua correlates well with the northward increase in the degree of crustal faulting outboard of the MAT. The negative seismic velocity anomaly reaches a depth of ∼12 km beneath the Moho offshore Nicaragua, which suggests that larger amounts of water are stored deep in the subducting mantle lithosphere than previously thought. If most of the mantle low velocity zone can be interpreted as serpentinization, the amount of water stored in the Cocos plate offshore central Nicaragua may be about 2.5 times larger than offshore Nicoya Peninsula. Hydration of oceanic lithosphere at deep sea trenches may be the most important mechanism for the transfer of aqueous fluids to volcanic arcs and the deeper mantle.This work was funded by the U.S. National Science Foundation MARGINS program under grants OCE0405556, OCE 0405654, and OCE 0625178

TRPA1 Contributes to the Acute Inflammatory Response and Mediates Carrageenan-Induced Paw Edema in the Mouse

Transient receptor potential ankyrin 1 (TRPA1) is an ion channel involved in thermosensation and nociception. TRPA1 is activated by exogenous irritants and also by oxidants formed in inflammatory reactions. However, our understanding of its role in inflammation is limited. Here, we tested the hypothesis that TRPA1 is involved in acute inflammatory edema. The TRPA1 agonist allyl isothiocyanate (AITC) induced inflammatory edema when injected intraplantarly to mice, mimicking the classical response to carrageenan. Interestingly, the TRPA1 antagonist HC-030031 and the cyclo-oxygenase (COX) inhibitor ibuprofen inhibited not only AITC but also carrageenan-induced edema. TRPA1-deficient mice displayed attenuated responses to carrageenan and AITC. Furthermore, AITC enhanced COX-2 expression in HEK293 cells transfected with human TRPA1, a response that was reversed by HC-030031. This study demonstrates a hitherto unknown role of TRPA1 in carrageenan-induced inflammatory edema. The results also strongly suggest that TRPA1 contributes, in a COX-dependent manner, to the development of acute inflammation