Terrestrial carbon isotope stratigraphy and mammal turnover during post-PETM hyperthermals in the Bighorn Basin, Wyoming, USA

Paleogene hyperthermals, including the Paleocene–Eocene Thermal Maximum (PETM) and several other smaller events, represent global perturbations to Earth’s climate system and are characterized by warmer temperatures, changes in floral and faunal communities, and hydrologic changes. These events are identified in the geologic record globally by negative carbon isotope excursions (CIEs), resulting from the input of isotopically light carbon into Earth’s atmosphere. Much about the causes and effects of hyperthermals remains uncertain, including whether all hyperthermals were caused by the same underlying processes, how biotic effects scale with the magnitude of hyperthermals, and why CIEs are larger in paleosol carbonates relative to marine records. Resolving these questions is crucial for a full understanding of the causes of hyperthermals and their application to future climate scenarios. The primary purpose of this study was to identify early Eocene hyperthermals in the Fifteenmile Creek area of the south-central Bighorn Basin, Wyoming, USA. This area preserves a sequence of fluvial floodplain sedimentary rocks containing paleosol carbonates and an extensive record of fossil mammals. Previous analysis of faunal assemblages in this area revealed two pulses of mammal turnover and changes in diversity interpreted to correlate with the ETM2 and H2 hyperthermals that follow the PETM. This was, however, based on long-distance correlation of the fossil record in this area with chemostratigraphic records from elsewhere in the basin. We present new carbon isotope stratigraphies using micrite δ13C values from paleosol carbonate nodules preserved in and between richly fossiliferous mammal localities at Fifteenmile Creek to identify the stratigraphic positions of ETM2 and H2. Carbon isotope results show that the ETM2 and H2 hyperthermals, and possibly the subsequent I1 hyperthermal, are recorded at Fifteenmile Creek. ETM2 and H2 overlap with the two previously recognized pulses of mammal turnover. The CIEs for these hyperthermals are also somewhat smaller in magnitude than in more northerly Bighorn Basin records. We suggest that basin-wide differences in soil moisture and/or vegetation could contribute to variable CIE amplitudes in this and other terrestrial records

Teaching with Feminist Judgments: A Global Conversation

This conversational-style essay is an exchange among fourteen professors—representing thirteen universities across five countries—with experience teaching with feminist judgments. Feminist judgments are ‘shadow’ court decisions rewritten from a feminist perspective, using only the precedent in effect and the facts known at the time of the original decision. Scholars in Canada, England, the U.S., Australia, New Zealand, Scotland, Ireland, India, and Mexico have published (or are currently producing) written collections of feminist judgments that demonstrate how feminist perspectives could have changed the legal reasoning or outcome (or both) in important legal cases. This essay begins to explore the vast pedagogical potential of feminist judgments. The contributors to this conversation describe how they use feminist judgments in the classroom; how students have responded to the judgments; how the professors achieve specific learning objectives through teaching with feminist judgments; and how working with feminist judgments—whether studying them, writing them, or both—can help students excavate the multiple social, political, economic, and even personal factors that influence the development of legal rules, structures, and institutions. The primary takeaway of the essay is that feminist judgments are a uniquely enriching pedagogical tool that can broaden the learning experience. Feminist judgments invite future lawyers, and indeed any reader, to re-imagine what the law is, what the law can be, and how to make the law more responsive to the needs of all people

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient\u27s progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. ©2017 AACR

Grand Challenges in Global Health: Ethical, Social, and Cultural Issues Based on Key Informant Perspectives

The authors interviewed key informants from the developing world and the Grand Challenges investigators to explore their ethical, social, and cultural concerns about the program

Pyrite mega-analysis reveals modes of anoxia through geological time

The redox structure of the water column in anoxic basins through geological time remains poorly resolved despite its importance to biological evolution/extinction and biogeochemical cycling. Here, we provide a temporal record of bottom and pore water redox conditions by analyzing the temporal distribution and chemistry of sedimentary pyrite. We combine machine-reading techniques, applied over a large library of published literature, with statistical analysis of element concentrations in databases of sedimentary pyrite and bulk sedimentary rocks to generate a scaled analysis spanning the majority of Earth’s history. This analysis delineates the prevalent anoxic basin states from the Archaean to present day, which are associated with diagnostic combinations of five types of syngenetic pyrite. The underlying driver(s) for the pyrite types are unresolved but plausibly includes the ambient seawater inventory, precipitation kinetics, and the (co)location of organic matter degradation coupled to sulfate reduction, iron (oxyhydr)oxide dissolution, and pyrite precipitation

Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity

Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-α, IL17A–D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.Fil: Araya, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Waugh, Katherine A.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Sullivan, Kelly D.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Núñez, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Roselli, Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Smith, Keith P.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Granrath, Ross E.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Rachubinski, Angela L.. University of Colorado; Estados UnidosFil: Enriquez Estrada, Belinda. University Of Colorado. School Of Medicine.; Estados UnidosFil: Butcher, Eric T.. University of Colorado; Estados UnidosFil: Minter, Ross. University of Colorado; Estados UnidosFil: Tuttle, Kathryn D.. University of Colorado; Estados UnidosFil: Bruno, Tullia C.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Maccioni, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Espinosa, Joaquín M.. University Of Colorado. School Of Medicine.; Estados Unido

Environment Constrains Fitness Advantages of Division of Labor in Microbial Consortia Engineered for Metabolite Push or Pull Interactions

Fitness benefits from division of labor are well documented in microbial consortia, but the dependency of the benefits on environmental context is poorly understood. Two synthetic Escherichia coli consortia were built to test the relationships between exchanged organic acid, local environment, and opportunity costs of different metabolic strategies. Opportunity costs quantify benefits not realized due to selecting one phenotype over another. The consortia catabolized glucose and exchanged either acetic or lactic acid to create producer-consumer food webs. The organic acids had different inhibitory properties and different opportunity costs associated with their positions in central metabolism. The exchanged metabolites modulated different consortial dynamics. The acetic acid-exchanging (AAE) consortium had a “push” interaction motif where acetic acid was secreted faster by the producer than the consumer imported it, while the lactic acid-exchanging (LAE) consortium had a “pull” interaction motif where the consumer imported lactic acid at a comparable rate to its production. The LAE consortium outperformed wild-type (WT) batch cultures under the environmental context of weakly buffered conditions, achieving a 55% increase in biomass titer, a 51% increase in biomass per proton yield, an 86% increase in substrate conversion, and the complete elimination of by-product accumulation all relative to the WT. However, the LAE consortium had the trade-off of a 42% lower specific growth rate. The AAE consortium did not outperform the WT in any considered performance metric. Performance advantages of the LAE consortium were sensitive to environment; increasing the medium buffering capacity negated the performance advantages compared to WT

Effectiveness of a Community Program for Older Adults with Type 2 Diabetes and Multimorbidity: A Pragmatic Randomized Controlled Trial

Background Type II diabetes mellitus (T2DM) affects upwards of 25% of Canadian older adults and is associated with high comorbidity and burden. Studies show that lifestyle factors and self-management are associated with improved health outcomes, but many studies lack rigour or exclude older adults, particularly those with multimorbidity. More evidence is needed on the effectiveness of community-based self-management programs in older adults with T2DM and multimorbidity. The study purpose is to evaluate the effect of a community-based intervention versus usual care on physical functioning, mental health, depressive symptoms, anxiety, self-efficacy, self-management, and healthcare costs in older adults with T2DM and 2 or more comorbidities. Methods Community-living older adults with T2DM and two or more chronic conditions were recruited from three Primary Care Networks (PCNs) in Alberta, Canada. Participants were randomly allocated to the intervention or control group in this pragmatic randomized controlled trial comparing the intervention to usual care. The intervention involved up to three in-home visits, a monthly group wellness program, monthly case conferencing, and care coordination. The primary outcome was physical functioning. Secondary outcomes included mental functioning, anxiety, depressive symptoms, self-efficacy, self-management, and the cost of healthcare service use. Intention-to-treat analysis was performed using ANCOVA modeling. Results Of 132 enrolled participants (70-Intervention, 62-Control), 42% were 75 years or older, 55% were female, and over 75% had at least six chronic conditions (in addition to T2DM). No significant group differences were seen for the baseline to six-month change in physical functioning (mean difference: -0.74; 95% CI: − 3.22, 1.74; p-value: 0.56), mental functioning (mean difference: 1.24; 95% CI: − 1.12, 3.60; p-value: 0.30), or other secondary outcomes.. Conclusion No significant group differences were seen for the primary outcome, physical functioning (PCS). Program implementation, baseline differences between study arms and chronic disease management services that are part of usual care may have contributed to the modest study results. Fruitful areas for future research include capturing clinical outcome measures and exploring the impact of varying the type and intensity of key intervention components such as exercise and diet

Sites of vulnerability in HCV E1E2 identified by comprehensive functional screening

The E1 and E2 envelope proteins of hepatitis C virus (HCV) form a heterodimer that drives virus-host membrane fusion. Here, we analyze the role of each amino acid in E1E2 function, expressing 545 individual alanine mutants of E1E2 in human cells, incorporating them into infectious viral pseudoparticles, and testing them against 37 different monoclonal antibodies (MAbs) to ascertain full-length translation, folding, heterodimer assembly, CD81 binding, viral pseudoparticle incorporation, and infectivity. We propose a model describing the role of each critical residue in E1E2 functionality and use it to examine how MAbs neutralize infection by exploiting functionally critical sites of vulnerability on E1E2. Our results suggest that E1E2 is a surprisingly fragile protein complex where even a single alanine mutation at 92% of positions disrupts its function. The amino-acid-level targets identified are highly conserved and functionally critical and can be exploited for improved therapies and vaccines