Showing papers by "Dartmouth College published in 2023"

Nutritional compensation of the circadian clock is a conserved process influenced by gene expression regulation and mRNA stability

Abstract: Compensation is a defining principle of a true circadian clock, where its approximately 24-hour period length is relatively unchanged across environmental conditions. Known compensation effectors directly regulate core clock factors to buffer the oscillator's period length from variables in the environment. Temperature Compensation mechanisms have been experimentally addressed across circadian model systems, but much less is known about the related process of Nutritional Compensation, where circadian period length is maintained across physiologically relevant nutrient levels. Using the filamentous fungus Neurospora crassa, we performed a genetic screen under glucose and amino acid starvation conditions to identify new regulators of Nutritional Compensation. Our screen uncovered 16 novel mutants, and together with 4 mutants characterized in prior work, a model emerges where Nutritional Compensation of the fungal clock is achieved at the levels of transcription, chromatin regulation, and mRNA stability. However, eukaryotic circadian Nutritional Compensation is completely unstudied outside of Neurospora. To test for conservation in cultured human cells, we selected top hits from our fungal genetic screen, performed siRNA knockdown experiments of the mammalian orthologs, and characterized the cell lines with respect to compensation. We find that the wild-type mammalian clock is also compensated across a large range of external glucose concentrations, as observed in Neurospora, and that knocking down the mammalian orthologs of the Neurospora compensation-associated genes CPSF6 or SETD2 in human cells also results in nutrient-dependent period length changes. We conclude that, like Temperature Compensation, Nutritional Compensation is a conserved circadian process in fungal and mammalian clocks and that it may share common molecular determinants.

Factor Momentum

Abstract: Abstract Factors display strong cross-sectional momentum that subsumes momentum in industries and other portfolio characteristics. The profits of all these momentum strategies—based on factors, industries, and other characteristics—significantly correlate with each other and therefore likely emanate from the same source. If factors display momentum, so will any set of portfolios with cross-sectional variation in factor loadings. Consistent with factors being at the root of momentum, we find that momentum in industry-neutral factors explains industry momentum, but industry momentum explains none of the factor momentum. Cross-sectional factor momentum concentrates in the first few highest-eigenvalue factors and is distinct from time-series factor momentum.

Identification of Spatial Proteomic Signatures of Colon Tumor Metastasis

Abstract: Over 150,000 Americans are diagnosed with colorectal cancer (CRC) every year, and annually >50,000 individuals are estimated to die of CRC, necessitating improvements in screening, prognostication, disease management, and therapeutic options. CRC tumors are removed en bloc with surrounding vasculature and lymphatics. Examination of regional lymph nodes at the time of surgical resection is essential for prognostication. Developing alternative approaches to indirectly assess recurrence risk would have utility in cases where lymph node yield is incomplete or inadequate. Spatially dependent, immune cell-specific (eg, tumor-infiltrating lymphocytes), proteomic, and transcriptomic expression patterns inside and around the tumor-the tumor immune microenvironment-can predict nodal/distant metastasis and probe the coordinated immune response from the primary tumor site. The comprehensive characterization of tumor-infiltrating lymphocytes and other immune infiltrates is possible using highly multiplexed spatial omics technologies, such as the GeoMX Digital Spatial Profiler. In this study, machine learning and differential co-expression analyses helped identify biomarkers from Digital Spatial Profiler-assayed protein expression patterns inside, at the invasive margin, and away from the tumor, associated with extracellular matrix remodeling (eg, granzyme B and fibronectin), immune suppression (eg, forkhead box P3), exhaustion and cytotoxicity (eg, CD8), Programmed death ligand 1-expressing dendritic cells, and neutrophil proliferation, among other concomitant alterations. Further investigation of these biomarkers may reveal independent risk factors of CRC metastasis that can be formulated into low-cost, widely available assays.

Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer–Risk Factors

Abstract: Abstract Background: DNA methylation patterning is cell-type–specific and altered DNA methylation is well established to occur early in breast carcinogenesis, affecting non-cancerous, histopathologically normal breast tissue. Previous work assessing risk factor–associated alterations to DNA methylation in breast tissue has been limited, with even less published research in breast milk, a noninvasively obtained biospecimen containing sloughed mammary epithelial cells that may identify early alterations indicative of cancer risk. Methods: Here, we present a novel library for the estimation of the cellular composition of breast tissue and milk and subsequent assessment of cell-type–independent alterations to DNA methylation associated with established breast cancer–risk factors in solid breast tissue (n = 95) and breast milk (n = 48) samples using genome-scale DNA methylation measures from the Illumina HumanMethylation450 array. Results: We identified 772 hypermethylated CpGs (P < 0.01) associated with age consistent between breast tissue and breast milk samples. Age-associated hypermethylated CpG loci were significantly enriched for CpG island shore regions known to be important for regulating gene expression. Among the overlapping hypermethylated loci mapping to genes, a differentially methylated region was identified in the promoter region of SFRP2, a gene observed to undergo promoter hypermethylation in breast cancer. Conclusions: Our findings suggest the potential to identify epigenetic biomarkers of breast cancer risk in noninvasively obtained, tissue-specific breast milk specimens. Impact: This work demonstrates the potential of using breast milk as a noninvasive biomarker of breast cancer risk, improving our ability to detect early-stage disease and lowering the overall disease burden.

Mechanisms of adjustments to different types of uncertainty in the reward environment across mice and monkeys

Abstract: Despite being unpredictable and uncertain, reward environments often exhibit certain regularities, and animals navigating these environments try to detect and utilize such regularities to adapt their behavior. However, successful learning requires that animals also adjust to uncertainty associated with those regularities. Here, we analyzed choice data from two comparable dynamic foraging tasks in mice and monkeys to investigate mechanisms underlying adjustments to different types of uncertainty. In these tasks, animals selected between two choice options that delivered reward probabilistically, while baseline reward probabilities changed after a variable number (block) of trials without any cues to the animals. To measure adjustments in behavior, we applied multiple metrics based on information theory that quantify consistency in behavior, and fit choice data using reinforcement learning models. We found that in both species, learning and choice were affected by uncertainty about reward outcomes (in terms of determining the better option) and by expectation about when the environment may change. However, these effects were mediated through different mechanisms. First, more uncertainty about the better option resulted in slower learning and forgetting in mice, whereas it had no significant effect in monkeys. Second, expectation of block switches accompanied slower learning, faster forgetting, and increased stochasticity in choice in mice, whereas it only reduced learning rates in monkeys. Overall, while demonstrating the usefulness of metrics based on information theory in examining adaptive behavior, our study provides evidence for multiple types of adjustments in learning and choice behavior according to uncertainty in the reward environment.

Hierarchical categorization learning is associated with representational changes in the dorsal striatum and posterior frontal and parietal cortex

Abstract: Learning and recognition can be improved by sorting novel items into categories and subcategories. Such hierarchical categorization is easy when it can be performed according to learned rules (e.g., “if car, then automatic or stick shift” or “if boat, then motor or sail”). Here, we present results showing that human participants acquire categorization rules for new visual hierarchies rapidly, and that, as they do, corresponding hierarchical representations of the categorized stimuli emerge in patterns of neural activation in the dorsal striatum and in posterior frontal and parietal cortex. Participants learned to categorize novel visual objects into a hierarchy with superordinate and subordinate levels based on the objects' shape features, without having been told the categorization rules for doing so. On each trial, participants were asked to report the category and subcategory of the object, after which they received feedback about the correctness of their categorization responses. Participants trained over the course of a one-hour-long session while their brain activation was measured using functional magnetic resonance imaging. Over the course of training, significant hierarchy learning took place as participants discovered the nested categorization rules, as evidenced by the occurrence of a learning trial, after which performance suddenly increased. This learning was associated with increased representational strength of the newly acquired hierarchical rules in a corticostriatal network including the posterior frontal and parietal cortex and the dorsal striatum. We also found evidence suggesting that reinforcement learning in the dorsal striatum contributed to hierarchical rule learning.

Streaming algorithms for the missing item finding problem

Abstract: Many problems on data streams have been studied at two extremes of difficulty: either allowing randomized algorithms, in the static setting (where they should err with bounded probability on the worst case stream); or when only deterministic and infallible algorithms are required. Some recent works have considered the adversarial setting, in which a randomized streaming algorithm must succeed even on data streams provided by an adaptive adversary that can see the intermediate outputs of the algorithm.In order to better understand the differences between these models, we study a streaming task called “Missing Item Finding”. In this problem, for r < n, one is given a data stream a1,…, ar of elements in [n], (possibly with repetitions), and must output some x ∈ [n] which does not equal any of the ai. We prove that, for r = n Θ (1) and δ = 1/poly(n), the space required for randomized algorithms that solve this problem in the static setting with error δ is Θ(polylog(n)); for algorithms in the adversarial setting with error δ, Θ((1 + r2/n)polylog(n)); and for deterministic algorithms, Θ(r/polylog(n)). Because our adversarially robust algorithm relies on free access to a string of O(r log n) random bits, we investigate a “random start” model of streaming algorithms where all random bits used are included in the space cost. Here we find a conditional lower bound on the space usage, which depends on the space that would be needed for a pseudo-deterministic algorithm to solve the problem. We also prove an Ω(r/polylog(n)) lower bound for the space needed by a streaming algorithm with < 1/2polylog(n) error against “white-box” adversaries that can see the internal state of the algorithm, but not predict its future random decisions.

Data from Alternating 17β-Estradiol and Aromatase Inhibitor Therapies Is Efficacious in Postmenopausal Women with Advanced Endocrine-Resistant ER&lt;sup&gt;+&lt;/sup&gt; Breast Cancer

Abstract: <div>AbstractPurpose:<p>Strategies to implement estrogen therapy for advanced estrogen receptor–positive (ER⁺) breast cancer are underdeveloped. Preclinical data suggest that cycling treatment with 17β-estradiol followed by estrogen deprivation can control tumor growth long-term.</p>Patients and Methods:<p>Postmenopausal women with advanced ER⁺/HER2⁻ breast cancer with recurrence or progression on ≥ 1 antiestrogen or aromatase inhibitor (AI)-based therapy were eligible. Patients received 17β-estradiol (2 mg orally, three times a day) for 8 weeks followed by AI (physician's choice) for 16 weeks, alternating treatments on an 8-week/16-week schedule until disease progression. Patients then optionally received continuous single-agent treatment until a second instance of disease progression. Endpoints included 24-week clinical benefit and objective response per RECIST, and tumor genetic alterations.</p>Results:<p>Of 19 evaluable patients, clinical benefit rate was 42.1% [95% confidence interval (CI), 23.1%–63.9%] and objective response rate (ORR) was 15.8% (95% CI, 5.7%–37.9%). One patient experienced a grade 3 adverse event related to 17β-estradiol. Among patients who received continuous single-agent treatment until a second instance of disease progression, clinical benefit was observed in 5 of 12 (41.7%) cases. Tumor ER (<i>ESR1</i>) mutations were found by whole-exome profiling in 4 of 7 (57.1%) versus 2 of 9 (22.2%) patients who did versus did not experience clinical benefit from alternating 17β-estradiol/AI therapy. The only two patients to experience objective responses to initial 17β-estradiol had tumor <i>ESR1</i> mutations.</p>Conclusions:<p>Alternating 17β-estradiol/AI therapy may be a promising treatment for endocrine-refractory ER⁺ breast cancer, including following progression on CDK4/6 inhibitors or everolimus. Further study is warranted to determine whether the antitumor activity of 17β-estradiol differs according to <i>ESR1</i> mutation status.</p></div>

Sea-level rise projections of Petermann Glacier, Greenland, modeled using synchronously coupled subglacial hydrology and ice flow dynamics

Abstract: Greenland ice shelves are known to display seasonal speedups of ice velocity which can be attributed to ice front position or to meltwater runoff, depending on which glacier is being examined. However, it remains uncertain if the seasonality of glacier speed will be impacted by climate change in the coming century. Current projections of glacier dynamics under 21st century climate forcings do not include subglacial hydrology, so it also remains unknown if it will play any important role in evolving glacier dynamics under different climate change scenarios, or ultimately have an impact on sea-level rise projections. Here we present a model with synchronous coupling of ice dynamics and subglacial hydrology applied to Petermann Glacier in northern Greenland. Petermann exhibits a summer-time acceleration of roughly 15% as compared to its baseline winter velocity, which is likely the result of subglacial hydrology. Although it has been relatively stable in recent years, as one of the largest marine terminating glaciers in northern Greenland, whether or not Petermann remains stable will have a significant impact on the sea-level contribution of the northern sector of the ice-sheet. We use climate through 2100 to investigate how the subglacial hydrologic system may evolve in a warmer climate and to test if including hydrology changes the stability of Petermann under future climate scenarios using the Ice-sheet and Sea-level System Model (ISSM) which includes the Glacier Drainage System (GlaDS) model. We compare glacier evolution and projected sea-level rise for three model configurations: one with synchronously coupled subglacial hydrology and ice dynamics, a second with asynchronous coupling where subglacial hydrology is calculated with static ice geometry and velocity but ice dynamics are calculated using effective pressure from GlaDS output, and a third where subglacial hydrology is excluded entirely from the model setup.&#160; Results show a significant increase in projected sea-level rise by the end of the century and differing patterns of grounding line migration and ice thinning when subglacial hydrology is included in the model configuration for Petermann.

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Beyond the Limits: Medicine, Healing, and Medical Anthropology

Abstract: This collection contemplates that which resides at the limits of the anthropology of health and medicine. By “limit,” we mean that “outside which there is nothing to be found” and “inside of which everything is to be found” (de la Cadena 2015: 14, citing Ranajit Guha 2002: 7). Our work takes place within many kinds of limits: epistemological frameworks, ethical and moral commitments, disciplinary norms, ontological certainties, political economies, writing conventions, and the ends of life, to name a few. In this collection of essays and accompanying conversations, we consider how medicine and health are performed in ways that appear beyond such limits—as impossible, unreal, unscientific, irresponsible, unthinkable, nonacademic, non-replicable, fictitious, unethical, unruly, or untrue—but which, nonetheless, are. In so doing, this collection moves toward the speculative to examine the potential it holds for displacing our sedimented ways of thinking and producing knowledge in and about medicine, health, and healing. Our speculative orientation draws on and augments broader anthropological interventions that experiment with doing, thinking, and writing otherwise.1,2 This collection also attends to how multiplicity takes shape by following and tracing relations, tensions, convergences, and divergences between worlds of health and healing. We maintain that recognizing such multiplicity requires that we create conditions for tellability that “push up against familiar understandings of ‘reality’ and take us beyond a division of the world into rational/irrational, real/imagined, and either/or” (Mittermaier 2011: 29). The essays in this collection draw on disqualified types of knowledge and minor practices (including incantations, oracles, and witchcraft, care and gentleness, and fugitive science) and “play them out against the regimes of knowledge on whose terms we have come to understand them as anomalous, irrational, unrealistic, or simply implausible” (Palmie 2002: 20, see also Klima 2019; McLean 2017). Such interventions have been important for thinking more capaciously about medicine, health, and healing, yet they do little, directly, to unsettle medical anthropology itself—to help us rethink how we tell stories that are legible to the subdiscipline and the institutions in which we are employed. To do that work—of storying otherwise—our collection takes the form of a conversation, quite literally. This conversation took place among all the authors as we explored the various limits that shape our fieldwork and writing. In producing this collection, one of the trickiest limits we came up against is that of the conventional journal article, with its norms of discrete vignette followed by separate analysis. In this convention—and there are some examples of this form among our essays—authors build on the work of others through citational practices. As critical recent interventions by groups like #CiteBlackWomen (Cite Black Women Collective 2022) and The Ancestors Project (Pouchet 2020) have demonstrated, these citational practices have a politics; one that frequently excludes and marginalizes (Smith and Garrett-Scott 2021; Vaughn et al. 2021). Changing our citational practices is one way to disrupt conventional scholarly practices within our discipline, dismantling the norms that reproduce patriarchy and white supremacy (Mariner 2022; Ogden 2021: 130–32; Yates-Doerr 2020). Allied with this move, our intervention here seeks not merely to broaden the conversation, but rather to shift it: to change how we recognize and value the collaborative co-laboring and co-thinking that is often hidden by the conventions of academic publishing. This Introduction also resists normative academic conventions according to which we would be expected to condense, outline, synthesize, and capture the multifarious speculations that follow. Instead, we invite readers to join us in conversation, to sit with its excesses and unruly (undisciplined) meanderings, and to relinquish the idea of closure. As co-authors of this Introduction, we opt not to grant ourselves the authority to write that closure. Instead, our approach with this collection's structure is to make our collective conversation explicit, transcribed, and interspersed among the pieces that follow. This conversation is not linear and is not meant to speak specifically to the pieces it bookends, but rather to offer a space to speculate together about the possibilities and limitations of our work in medical anthropology. Together, our conversation examines the core concepts that our individually authored pieces grapple with—limits, multiplicity, and the speculative—building, learning, and thinking collectively about what our contributions do and do not do, can and cannot do, given the structures of the discipline and the situated nature of our individual experiences and positionalities. These limits include—but are not limited to—how we produce knowledge; give credit; join and exist within disciplinary hierarchies; assess, take, and bear the costs of risks; divide and parse the work of medical anthropology; attend to our interlocutors honestly and ethically; interpret (or not) what we learn in our field sites; and write for medical anthropology and beyond. Our aim is to foreground the collaborative and dialogic nature of knowledge making, the thinking together that goes into all of our work. We hope that this unconventional and undisciplined approach opens up ideas, conversations, and provocations that unsettle the current limits of medicine, healing, and medical anthropology.

Data from CD122-Selective IL2 Complexes Reduce Immunosuppression, Promote Treg Fragility, and Sensitize Tumor Response to PD-L1 Blockade

Abstract: <div>Abstract<p>The IL2 receptor (IL2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Treg) and antitumor T cells. Here we used IL2Rβ-selective IL2/anti-IL2 complexes (IL2c) to stimulate effector T cells preferentially in the orthotopic mouse ID8agg ovarian cancer model. Despite strong tumor rejection, IL2c unexpectedly lowered the tumor microenvironmental CD8⁺/Treg ratio. IL2c reduced tumor microenvironmental Treg suppression and induced a fragile Treg phenotype, helping explain improved efficacy despite numerically increased Tregs without affecting Treg in draining lymph nodes. IL2c also reduced Treg-mediated, high-affinity IL2R signaling needed for optimal Treg functions, a likely mechanism for reduced Treg suppression. Effector T-cell IL2R signaling was simultaneously improved, suggesting that IL2c inhibits Treg functions without hindering effector T cells, a limitation of most Treg depletion agents. Anti-PD-L1 antibody did not treat ID8agg, but adding IL2c generated complete tumor regressions and protective immune memory not achieved by either monotherapy. Similar anti-PD-L1 augmentation of IL2c and degradation of Treg functions were seen in subcutaneous B16 melanoma. Thus, IL2c is a multifunctional immunotherapy agent that stimulates immunity, reduces immunosuppression in a site-specific manner, and combines with other immunotherapies to treat distinct tumors in distinct anatomic compartments.</p>Significance:<p>These findings present CD122-targeted IL2 complexes as an advancement in cancer immunotherapy, as they reduce Treg immunosuppression, improve anticancer immunity, and boost PD-L1 immune checkpoint blockade efficacy in distinct tumors and anatomic locations.</p></div>

Large‐scale validation study of an improved semiautonomous urine cytology assessment tool: AutoParis‐X

Abstract: Background Adopting a computational approach for the assessment of urine cytology specimens has the potential to improve the efficiency, accuracy, and reliability of bladder cancer screening, which has heretofore relied on semisubjective manual assessment methods. As rigorous, quantitative criteria and guidelines have been introduced for improving screening practices (e.g., The Paris System for Reporting Urinary Cytology), algorithms to emulate semiautonomous diagnostic decision-making have lagged behind, in part because of the complex and nuanced nature of urine cytology reporting. Methods In this study, the authors report on the development and large-scale validation of a deep-learning tool, AutoParis-X, which can facilitate rapid, semiautonomous examination of urine cytology specimens. Results The results of this large-scale, retrospective validation study indicate that AutoParis-X can accurately determine urothelial cell atypia and aggregate a wide variety of cell-related and cluster-related information across a slide to yield an atypia burden score, which correlates closely with overall specimen atypia and is predictive of Paris system diagnostic categories. Importantly, this approach accounts for challenges associated with the assessment of overlapping cell cluster borders, which improve the ability to predict specimen atypia and accurately estimate the nuclear-to-cytoplasm ratio for cells in these clusters. Conclusions The authors developed a publicly available, open-source, interactive web application that features a simple, easy-to-use display for examining urine cytology whole-slide images and determining the level of atypia in specific cells, flagging the most abnormal cells for pathologist review. The accuracy of AutoParis-X (and other semiautomated digital pathology systems) indicates that these technologies are approaching clinical readiness and necessitates full evaluation of these algorithms in head-to-head clinical trials.

Arctic Cyclone Cloud and Boundary-Layer Features Producing Thermodynamic and Dynamic Impacts on Arctic Sea Ice During MOSAiC

Abstract: MOSAiC was a rare opportunity to obtain observational data on Arctic cyclones (ACs), with at least 22 ACs sampled during four of the five legs.&#160; This presentation will illustrate how some of the AC cloud and boundary-layer characteristics produce both thermodynamic and dynamic impacts on the sea ice in the non-melt seasons.&#160; Deep clouds associated with the ACs enhanced the downwelling radiation, with the surface radiation dependent on cloud height, temperature, and liquid water layers.&#160; Underneath the warm fronts ahead of the ACs, this effect directly warmed the surface, sometimes to the extent of destabilizing the near-surface boundary layer.&#160; Synoptically induced low-level jets (LLJs) found within AC warm sectors between the surface warm front and cold front often also provided warm-air advection down to a few hundred meters above the surface, which, in many cases, produced a stable lower boundary layer and enhanced downward sensible heat flux in these AC regions. &#160;These effects in some mid-winter ACs produced near-surface temperature increases of 20&#176; C or more compared to the surface temperatures prior to the ACs, with some, but not all, winter cases also producing strong thermal waves penetrating through the snow and ice and reducing sea-ice growth.&#160;In some ACs, a quasi-axisymmetric LLJ near the top of the boundary layer in the warm sector and then wrapping around the low center as a &#8220;bent-back&#8221; feature produces the appearance of two successive LLJs with greatly differing wind directions at the MOSAiC site.&#160; The rapid change in wind speed and direction between these LLJ pairs produces a rapid change in the surface stress vector and imparts strong forcing on the sea ice.&#160; During MOSAiC, strong ice deformation, lead formation, etc., was observed during the time periods between the two LLJs.&#160; Hence, these LLJs not only play a role in the atmospheric thermal impacts on sea ice from ACs, but also on the dynamic impacts.The broad relevance of Arctic Cyclone mesoscale features, such as low-level jets, warm-sector warm-air advection, and cloud macro and microstructure, to the sea-ice thermodynamic and dynamic environment during the MOSAiC field program will be illustrated with MOSAiC case-study observations, including basic meteorological measurements, rawinsondes, ARM remote sensors, surface energy budget measurements, and ice motion measurements.

Above- and Belowground Plant Mercury Dynamics in a Salt Marsh Estuary in Massachusetts, USA

Abstract: Abstract. Estuaries are dominant conduits of mercury (Hg) to the coastal ocean and the salt marshes within play an important role in coastal Hg cycling. While Hg cycling in upland terrestrial systems has been well studied, processes in salt marsh ecosystems are poorly characterized. We investigated Hg dynamics in vegetation and soils in the Plum Island Sound estuary in Massachusetts, USA and specifically assessed the role of marsh vegetation for Hg deposition and turnover. Monthly quantitative harvesting of aboveground biomass showed strong linear seasonal increases in plant Hg, with a four-fold increase in Hg concentration and an eight-fold increase in standing Hg mass between June (3.9±0.2 µg kg-1 and 0.7±0.4 µg m-2, respectively) and November (16.2±2.0 µg kg-1 and 5.7±2.1 µg m-2, respectively). Hg ceased to increase in aboveground biomass after plant senescence, indicating physiological controls of vegetation Hg uptake in salt marsh plants. Hg concentrations in live roots and live rhizomes were 11 times and two times higher than concentrations in aboveground live biomass, respectively. Furthermore, live belowground biomass Hg pools (roots and rhizomes, 108.1±83.4 μg m-2) is more than ten times larger than peak standing aboveground Hg pools (9.0±3.3 μg m-2). A ternary mixing model suggests Hg sources in marsh aboveground tissues originates from a mix of root uptake (~35 %), precipitation uptake (~33 %), and atmospheric gaseous elemental mercury (GEM) uptake (~32 %). The results suggest a more important role of Hg transport from belowground (i.e., roots) to aboveground tissues in salt marsh vegetation compared to upland vegetation, where GEM uptake is generally the dominant Hg source. GEM deposition via uptake and subsequent senescence (5.9 µg m-2 yr-1) and throughfall (1.0 µg m-2 yr-1) hence is lower in this salt marsh ecosystem compared to upland vegetation and is similar to open field wet and dry deposition (6.2 µg m-2 yr-1). Hg contained in salt marsh aboveground tissues leads to direct Hg export to tidal water and oceans via wrack (tidal flushing of vegetation), which accounts for ~1.6 µg m-2 yr-1. Hg consumption by herbivory ranges between 0.5 and 2.4 µg Hg m-2 yr-1. The similarity in isotopic signatures between roots and soils suggest that belowground plant tissues mostly take up Hg directly from soils. Annual root turnover results in large internal Hg recycling between soils and plants accounting for 58.6 µg m-2 yr-1. An initial mass balance of Hg in this whole estuarine salt marsh ecosystem considering atmospheric inputs (atmospheric GEM and precipitation Hg(II), throughfall, including plants) and losses (wrack export and lateral exchange of dissolved and particulate Hg) shows that the salt marsh presently serves as a small net Hg sink for environmental Hg of 5.2 µg m-2 yr-1.

Radiometric characterization methods for fluorescence guidance imaging systems using a calibrated solid-state emitter

Abstract: Methods for radiometric characterization of fluorescence-guided imaging systems using a calibrated solid-state emitter are introduced. Used alongside fluorescence phantoms, we demonstrate quantitative fluorescence imaging that can facilitate cross-system comparisons and multi-center reproducibility.

Alpelisib Efficacy without Cherry-PI3King Mutations

Abstract: Summary The PI3K inhibitor alpelisib is clinically approved for the treatment of metastatic estrogen receptor–positive breast cancers harboring hotspot mutations in PIK3CA, which encodes a subunit of PI3K. Prospective clinical trial results demonstrated benefit from alpelisib for the treatment of advanced ER+ breast cancers harboring PIK3CA mutations in the hotspots of exons 7, 9, and 20. However, 20% of PIK3CA mutations occur in non-hotspot regions. A recent article demonstrated that patients with cancers bearing non-hotspot PIK3CA mutations also derived benefit from alpelisib, which will inform clinical decision-making moving forward. See related article by Rugo et al., p. 1056

Towards stability results for global radial basis function based quadrature formulas

Abstract: Cubature formulas (CFs) based on radial basis functions (RBFs) have become an important tool for multivariate numerical integration of scattered data. Although numerous works have been published on such RBF-CFs, their stability theory can still be considered as underdeveloped. Here, we strive to pave the way towards a more mature stability theory for RBF-CFs. In particular, we prove stability for RBF-CFs based on compactly supported RBFs under certain conditions on the shape parameter and the data points. Moreover, it is shown that asymptotic stability of many RBF-CFs is independent of polynomial terms, which are often included in RBF approximations. While our findings provide some novel conditions for stability of RBF-CFs, the present work also demonstrates that there are still many gaps to fill in future investigations.

Challenges to Brain Death in Revising the Uniform Determination of Death Act

Abstract: Brain death, more recently called death determination by neurologic criteria,1 is at the nexus of current controversy as the US Uniform Law Commission (ULC) seeks to revise the Uniform Determination of Death Act (UDDA). The UDDA was developed in 1980 by the ULC, then called the National Conference of Commissioners for Uniform State Laws, in conjunction with the American Bar Association, the American Medical Association, and the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research.2 The UDDA was designed with 2 principal goals: to enhance the uniformity of death determination among states and to codify the new determination of death based on the irreversible cessation of all functions of the brain, a condition that had been concisely and popularly, though infelicitously, termed “brain death.”3 The President's Commission's first report in 1981, Defining Death , provided the conceptual justification for the UDDA and showed how brain death determination should be best incorporated into a model statute of death.4 The ULC effort was extremely successful because a large majority of states enacted the UDDA verbatim or with only minor modifications.5

The emergence of Continental Crust Revealed by Machine Learning

Abstract: Reconstructing the emergence of the modern continental crust is crucial to understand the evolution of the crust, the onset of plate tectonics, elemental cycling, and long-term climate. However, it remains highly contentious about when and how the major subaerial continental crust emerged over time. Here, we used a machine learning (ML) model (XGBoost) to reveal the exposed history of continental crust over the last 3.8 billion years ago (Ga). First, we compiled ~10,000 modern subaerial or submarine basalts with major and trace elements to train the ML model. Then, the trained ML model (with resampling) was utilized to predict and calculate the mean proportions of subaerially erupted continental basaltic rocks since 3.8 Ga. The result suggested that the subaerial proportion only reached about 50% at ~2.5 Ga, indicating the exposure of the continental crust was far from the present-day level at the end of the Archean era. On the other hand, since ~1.8 Ga, the subaerial proportion of the continental crust exhibited a dynamic balance between ~60% and 80%, reaching the present-day level.

Geometry of Freezing Impacts Ice Composition: Implications for Icy Satellites

Abstract: Non-ice impurities within the ice shells of ocean worlds (e.g., Europa, Enceladus, Titan, Ganymede) are believed to play a fundamental role in their geophysics and habitability and may become a surface expression of subsurface ocean properties. Heterogeneous entrainment and distribution of impurities within planetary ice shells have been proposed as mechanisms that can drive ice shell overturns, generate diverse geological features, and facilitate ocean-surface material transport critical for maintaining a habitable subsurface ocean. However, current models of ice shell composition suggest that impurity rejection at the ice-ocean interface of thick contemporary ice shells will be exceptionally efficient, resulting in relatively pure, homogeneous ice. As such, additional mechanisms capable of facilitating enhanced and heterogeneous impurity entrainment are needed to reconcile the observed physicochemical diversity of planetary ice shells. Here we investigate the potential for hydrologic features within planetary ice shells (sills and basal fractures), and the unique freezing geometries they promote, to provide such a mechanism. By simulating the two-dimensional thermal and physicochemical evolution of these hydrological features as they solidify, we demonstrate that bottom-up solidification at sill floors and horizontal solidification at fracture walls generate distinct ice compositions and provide mechanisms for both enhanced and heterogeneous impurity entrainment. We compare our results with magmatic and metallurgic analogs that exhibit similar micro- and macroscale chemical zonation patterns during solidification. Our results suggest variations in ice-ocean/brine interface geometry could play a fundamental role in introducing compositional heterogeneities into planetary ice shells and cryoconcentrating impurities in (re)frozen hydrologic features.

Seneca

Abstract: Seneca stands apart from other philosophers of Greece and Rome not only for his interest in practical ethics, but also for the beauty and liveliness of his writing. These twelve in-depth essays take up a series of interrelated topics in his works, from his relation to Stoicism, Epicureanism, and other schools of thought; to the psychology of emotion and action and the management of anger and grief; to letter-writing, gift-giving, friendship, and kindness; to Seneca's innovative use of genre, style, and humor. Recalling Socrates's critique of philosophical writing in Plato's Phaedrus, this volume gives particular attention to Seneca's ideas about the techniques of reading, writing, and study that make philosophy beneficial to the individual and to society. Clear explanations and careful translations make the volume accessible to a wide range of readers.

The Future of Thwaites Glacier, West Antarctica.

Abstract: We use numerical modelling to address several questions related to the future evolution of Thwaites Glacier over the next 50 years. The importance of Thwaites Ice Shelf for upstream grounded flow is investigated by quantifying the buttressing stresses along the grounding line. Removing the ice shelf changes the stress regime along the grounding line by less than 20%. This change is small compared to many, if not most, grounding lines of the Antarctic Ice Sheet, and much smaller than corresponding changes for the neighboring Pine Island and Pope, Smith and Kohler glaciers.&#160; Transient ice-flow modelling experiments show that mass loss from Thwaites Glacier over the next 50 years is insignificantly affected by removal of the ice shelf. We then explore the consequences of the proposed marine ice-cliff instability for Thwaites Glacier. For recently proposed calving laws, where the calving rate increases sharply with cliff height, we do not observe an onset of an unstable calving front retreat. Further numerical modelling experiments for future climatic forcing scenarios will be presented, including uncertainty quantification. Interactions between the ice and the ocean are studied using a coupled ice+ocean modelling framework. As shown before in several studies, we find when simulating its future evolution, that Thwaites Glacier can enter unstable periods of self-enhancing retreat. This appears to be a very robust result, and this behavior is found in all model runs, including coupled ice+ocean simulations.

Intraoperative plasma proteomic changes in cardiac surgery: In search of biomarkers of post‐operative delirium

Abstract: Delirium presents a significant healthcare burden. It complicates post-operative care in up to 50% of cardiac surgical patients with worse outcomes, longer hospital stays and higher cost of care. Moreover, the nature of delirium following cardiac surgery with cardiopulmonary bypass (CPB) remains unclear, the underlying pathobiology is poorly understood, status quo diagnostic methods are subjective, and diagnostic biomarkers are currently lacking.To identify diagnostic biomarkers of delirium and for insights into possible neuronal pathomechanisms.Comparative proteomic analyses were performed on plasma samples from a nested matched cohort of patients who underwent cardiac surgery. Validation by targeted proteomics was performed in an independent set of samples. Biomarkers were assessed for biological functions and diagnostic accuracy.Forty-seven percent of subjects demonstrated delirium. Of 3803 proteins identified from patient samples by multiplexed quantitative proteomics, 16 were identified as signatures of exposure to CPB, and 11 biomarkers distinguished delirium cases from non-cases (AuROC = 93%). Notable among these biomarkers are C-reactive protein, serum amyloid A-1 and cathepsin-B.The interplay of systemic and central inflammatory markers sheds new light on delirium pathogenesis. This work suggests that accurate identification of cases may be achievable using panels of biomarkers.

Modelling the future evolution of an alpine debris-covered glacier

Abstract: Debris-covered glaciers can react differently to external forcings than clean-surface glaciers. Depending on its thickness, a supraglacial debris layer impacts the glacier mass balance by either enhancing the surface melt or protecting the underlying ice. Based on previous works focusing on simple flowline geometries, we extended the model setup to three-dimensional complex geometries. The framework is implemented using the Ice-sheet and Sea-level System Model (ISSM) and applied to a typical alpine glacier geometry. Ice dynamics are solved on high-resolution with full-Stokes and coupled to the surface debris transport equation. The employed surface mass balance (SMB) model is capable of describing the melt rate for all debris thicknesses by including turbulent fluxes within the upper debris cover. This SMB formulation resolves the enhanced melt rates for a thin debris cover as well as the decreasing melt rates for thickening debris. To test the sensitivity of future projections of alpine glaciers on the debris layer, simulations are forced with high-resolution regional climate model (RCM) data from the EURO-CORDEX ensemble (RCP2.6 and RCP8.5).