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Fodor's essential Great Britain
Presents a travel guide to England, Scotland, and Wales, providing recommendations on hotels, restaurants, shopping, local transportation, sights of interest, and nightlife.
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Garnet sand reveals rock recycling processes in the youngest exhumed high- and ultrahigh-pressure terrane on Earth
Rock recycling within the forearcs of subduction zones involves subduction of sediments and hydrated lithosphere into the upper mantle, exhumation of rocks to the surface, and erosion to form new sediment. The compositions of, and inclusions within detrital minerals revealed by electron microprobe analysis and Raman spectroscopy preserve petrogenetic clues that can be related to transit through the rock cycle. We report the discovery of the ultrahigh-pressure (UHP) indicator mineral coesite as inclusions in detrital garnet from a modern placer deposit in the actively exhuming Late Miocene–Recent high- and ultrahigh-pressure ((U)HP) metamorphic terrane of eastern Papua New Guinea. Garnet compositions indicate the coesite-bearing detrital garnets are sourced from felsic protoliths. Carbonate, graphite, and CO₂ inclusions also provide observational constraints for geochemical cycling of carbon and volatiles during subduction. Additional discoveries include polyphase inclusions of metastable polymorphs of SiO₂ (cristobalite) and K-feldspar (kokchetavite) that we interpret as rapidly cooled former melt inclusions. Application of elastic thermobarometry on coexisting quartz and zircon inclusions in six detrital garnets indicates elastic equilibration during exhumation at granulite and amphibolite facies conditions. The garnet placer deposit preserves a record of the complete rock cycle, operative on < 10-My geologic timescales, including subduction of sedimentary protoliths to UHP conditions, rapid exhumation, surface uplift, and erosion. Detrital garnet geochemistry and inclusion suites from both modern sediments and stratigraphic sections can be used to decipher the petrologic evolution of plate boundary zones and reveal recycling processes throughout Earth’s history.
Journal Article
CathAI: fully automated coronary angiography interpretation and stenosis estimation
Coronary angiography is the primary procedure for diagnosis and management decisions in coronary artery disease (CAD), but ad-hoc visual assessment of angiograms has high variability. Here we report a fully automated approach to interpret angiographic coronary artery stenosis from standard coronary angiograms. Using 13,843 angiographic studies from 11,972 adult patients at University of California, San Francisco (UCSF), between April 1, 2008 and December 31, 2019, we train neural networks to accomplish four sequential necessary tasks for automatic coronary artery stenosis localization and estimation. Algorithms are internally validated against criterion-standard labels for each task in hold-out test datasets. Algorithms are then externally validated in real-world angiograms from the University of Ottawa Heart Institute (UOHI) and also retrained using quantitative coronary angiography (QCA) data from the Montreal Heart Institute (MHI) core lab. The CathAI system achieves state-of-the-art performance across all tasks on unselected, real-world angiograms. Positive predictive value, sensitivity and F1 score are all ≥90% to identify projection angle and ≥93% for left/right coronary artery angiogram detection. To predict obstructive CAD stenosis (≥70%), CathAI exhibits an AUC of 0.862 (95% CI: 0.843–0.880). In UOHI external validation, CathAI achieves AUC 0.869 (95% CI: 0.830–0.907) to predict obstructive CAD. In the MHI QCA dataset, CathAI achieves an AUC of 0.775 (95%. CI: 0.594–0.955) after retraining. In conclusion, multiple purpose-built neural networks can function in sequence to accomplish automated analysis of real-world angiograms, which could increase standardization and reproducibility in angiographic coronary stenosis assessment.
Journal Article
First evaluation of stiff-in-soft host–inclusion systems: experimental synthesis of zircon inclusions in quartz crystals
Quartz crystals with zircon inclusions were synthesized using a piston-cylinder apparatus to experimentally evaluate the use of inclusions in “soft” host minerals for elastic thermobarometry. Synthesized zircon inclusion strains and, therefore, pressures (
P
inc
) were measured using Raman spectroscopy and then compared with the expected inclusion strains and pressures calculated from elastic models. Measured inclusion strains and inclusion pressures are systematically more tensile than the expected values and, thus, re-calculated entrapment pressures are overestimated. These discrepancies are not caused by analytical biases or assumptions in the elastic models and strain calculations. Analysis shows that inclusion strain discrepancies progressively decrease with decreasing experimental temperature in the α-quartz field. This behavior is consistent with inelastic deformation of the host–inclusion pairs induced by the development of large differential stresses during experimental cooling. Therefore, inclusion strains are more reliable for inclusions trapped at lower temperature conditions in the α-quartz field where there is less inelastic deformation of the host–inclusion systems. On the other hand, entrapment isomekes of zircon inclusions entrapped in the β-quartz stability field plot along the α–β quartz phase boundary, suggesting that the inclusion strains were mechanically reset at the phase boundary during experimental cooling and decompression. Therefore, inclusions contained in soft host minerals can be used for elastic thermobarometry and inclusions contained in β-quartz may provide constraints on the
P
–
T
at which the host–inclusion system crossed the phase boundary during exhumation.
Journal Article
Developing an Interactive Environment through the Teaching of Mathematics with Small Robots
The article is the product of the study “Development of innovative resources to improve logical-mathematical skills in primary school, through educational robotics”, developed during the 2019 school year in three public schools in the province of Chiriquí, Republic of Panama. The teaching-learning process in students is influenced by aspects inside and outside the classroom, since not all schools have the necessary resources to deliver content or teaching material. The general objective of the project is to design, develop and implement educational robotics to improve logical-mathematical skills aimed at preschool and first grade students in public schools, using programmable educational robots. For this, a set of resources and activities were developed to improve the logical-mathematical skills of the initial stages, in public schools, obtaining significant results. Playful activities favor the teaching-learning process. Considering the analysis of the results made on the data obtained through the applied collection instruments, it can be argued that in general terms the values indicate that the students obtained a favorable level of performance in the different challenges proposed. The project has allowed the academic community to have an application of great value that allows teaching about the conservation of natural sites. The project only covers the area of mathematics in preschool and first grade.
Journal Article
Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity
Innate pattern recognition receptor agonists, including Toll-like receptors (TLRs), alter the tumor microenvironment and prime adaptive antitumor immunity. However, TLR agonists present toxicities associated with widespread immune activation after systemic administration. To design a TLR-based therapeutic suitable for systemic delivery and capable of safely eliciting tumor-targeted responses, we developed immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 dual agonist conjugated to tumor-targeting antibodies. Systemically administered human epidermal growth factor receptor 2 (HER2)-targeted ISACs were well tolerated and triggered a localized immune response in the tumor microenvironment that resulted in tumor clearance and immunological memory. Mechanistically, ISACs required tumor antigen recognition, Fcγ-receptor-dependent phagocytosis and TLR-mediated activation to drive tumor killing by myeloid cells and subsequent T-cell-mediated antitumor immunity. ISAC-mediated immunological memory was not limited to the HER2 ISAC target antigen since ISAC-treated mice were protected from rechallenge with the HER2
parental tumor. These results provide a strong rationale for the clinical development of ISACs.
Journal Article
Remembering for the right reasons: Explanations reduce catastrophic forgetting
The goal of continual learning (CL) is to learn a sequence of tasks without suffering from the phenomenon of catastrophic forgetting. Previous work has shown that leveraging memory in the form of a replay buffer can reduce performance degradation on prior tasks. We hypothesize that forgetting can be further reduced when the model is encouraged to remember the evidence for previously made decisions. As a first step towards exploring this hypothesis, we propose a simple novel training paradigm, called Remembering for the Right Reasons (RRR), that additionally stores visual model explanations for each example in the buffer and ensures the model has “the right reasons” for its predictions by encouraging its explanations to remain consistent with those used to make decisions at training time. Without this constraint, there is a drift in explanations and increase in forgetting as conventional continual learning algorithms learn new tasks. We demonstrate how RRR can be easily added to any memory or regularization‐based approach and results in reduced forgetting, and more importantly, improved model explanations. We have evaluated our approach in the standard and few‐shot settings and observed a consistent improvement across various CL approaches using different architectures and techniques to generate model explanations and demonstrated our approach showing a promising connection between explainability and continual learning. Our code is available at https://github.com/SaynaEbrahimi/Remembering-for-the-Right-Reasons. We posit that the catastrophic forgetting phenomenon is due in part to not being able to rely on the same reasoning as was used for a previously seen observation. Therefore, we hypothesize that forgetting can be mitigated when the model is encouraged to remember the evidence for previously made decisions; in other words, a model which can remember its final decision and can reconstruct the same prior reasoning. Based on this approach, we develop a novel strategy to exploit explainable models for improving performance.
Journal Article
Impact of age and prior COVID-19 on the response to influenza a components in the 2020–2021 Fluzone vaccine
Understanding how age and prior COVID-19 infection influenced influenza vaccine responses during the early SARS-CoV-2 pandemic is important for identifying factors that affect vaccine efficacy and for optimizing immunization strategies in diverse populations amid co-circulating respiratory viruses. In this study, participants were enrolled during the 2020–2021 season to receive the Fluzone vaccine, and their humoral responses to the influenza A components were analyzed in relation to age and COVID-19 history. Anti-H1 hemagglutinin (HA) responses were assessed at baseline and multiple time points post-vaccination using neutralizing antibody assays against a contemporary H1-expressing pseudovirus, measurements of H1 HA-specific memory B cells, and profiling of anti-H1 IgG glycosylation. Anti-H3 antibody responses were evaluated using a hemagglutination inhibition (HI) assay. While prior COVID-19 infection was not associated with notable differences in the humoral response in this cohort, older age consistently correlated with reduced responses across multiple readouts. These findings highlight the need for targeted approaches to improve influenza vaccine effectiveness in older adults, who remain at elevated risk for severe outcomes from both influenza virus and SARS-CoV-2 infections.
Journal Article
Abnormal Mechanisms of Plasticity and Metaplasticity in Autism Spectrum Disorders and Fragile X Syndrome
Objectives:
Multiple lines of evidence from genetic linkage studies to animal models implicate aberrant cortical plasticity and metaplasticity in the pathophysiology of autism spectrum disorder (ASD) and fragile X syndrome (FXS). However, direct experimental evidence of these alterations in humans with these disorders is scarce. Transcranial magnetic stimulation (TMS) is a noninvasive tool for probing mechanisms of plasticity and metaplasticity in vivo, in humans. The aim of the current study was to examine mechanisms of plasticity and metaplasticity in humans with ASD and FXS. We employed a repetitive TMS protocol developed specifically to probe cortical plasticity, namely continuous theta burst stimulation (cTBS).
Methods:
We applied a 40-second train of cTBS to primary motor cortex (M1) to healthy control participants and individuals with ASD or FXS, and we measured the cTBS-induced modulation in motor-evoked potentials (MEPs) in a contralateral intrinsic hand muscle. Each participant completed two sessions of the same protocol on two consecutive days. The degree of modulation in MEPs after cTBS on the first day was evaluated as a putative index of cortical plasticity. Examination of the changes in the effects of cTBS on the second day, as conditioned by the effects on the first day, provided an index of metaplasticity, or the propensity of a given cortical region to undergo plastic change based on its recent history.
Results:
After a 40-second cTBS train, individuals with ASD show a significantly longer duration of suppression in MEP amplitude as compared with healthy controls, whereas individuals with FXS show a significantly shorter duration. After a second train of cTBS, 24 hours later, the ASD group was indistinguishable from the control group, and while in the FXS group MEPs were paradoxically facilitated by cTBS.
Conclusion:
These findings offer insights into the pathophysiology of ASD and FXS, specifically providing direct experimental evidence that humans with these disorders show distinct alterations in plasticity and metaplasticity, consistent with the findings in animal models. If confirmed in larger test–retest studies, repeated TMS measures of plasticity and metaplasticity may provide a valuable physiologic phenotype for ASD and FXS.
Journal Article
Investigating Polymer Flipping and Lattice Disruptions in TELSAM-Facilitated Protein Crystallization
TELSAM, the sterile alpha motif (SAM) domain of the human translocation ETS leukemia protein (TEL), spontaneously forms 6-fold helical polymers at low pH. Previously, TELSAM was fused to the CMG2 vWA domain via a Threonine–Valine linker to create the 1TEL-TV-vWA construct. This construct was crystallized, mounted in-house, and analyzed using synchrotron X-ray diffraction. Despite successful crystallization, structure solution consistently yielded high R-values. Reciprocal lattice analysis revealed three domains, indicating a break in lattice periodicity. The observed intensity pattern—normal reflections at h-k=3n and streaky reflections at h-k=3n±1—suggests a unit cell shift equivalent to one-third of the P65 unit cell’s h-k length. This aligns with the polymer packing seen in the solved structure, where regular crystals show a repeating pattern of two normal polymers followed by a flipped one. The disrupted lattice shows a shift due to sequences of three or four normal polymers before the next flipped polymer. These flips occur because TELSAM polymers form crystal contacts independent of orientation, a known behavior in TELSAM-mediated crystallization. To address this lattice disruption and improve crystal quality, we have developed a novel device aimed at reducing polymer flipping during crystallization.
Journal Article