A productivity collapse to end earth's great oxidation

Author Posting. © National Academy of Sciences, 2019. This article is posted here by permission of National Academy of Sciences for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences 116 (35), (2019): 17207-17212, doi:10.1073/pnas.1900325116.It has been hypothesized that the overall size of—or efficiency of carbon export from—the biosphere decreased at the end of the Great Oxidation Event (GOE) (ca. 2,400 to 2,050 Ma). However, the timing, tempo, and trigger for this decrease remain poorly constrained. Here we test this hypothesis by studying the isotope geochemistry of sulfate minerals from the Belcher Group, in subarctic Canada. Using insights from sulfur and barium isotope measurements, combined with radiometric ages from bracketing strata, we infer that the sulfate minerals studied here record ambient sulfate in the immediate aftermath of the GOE (ca. 2,018 Ma). These sulfate minerals captured negative triple-oxygen isotope anomalies as low as ∼ −0.8‰. Such negative values occurring shortly after the GOE require a rapid reduction in primary productivity of >80%, although even larger reductions are plausible. Given that these data imply a collapse in primary productivity rather than export efficiency, the trigger for this shift in the Earth system must reflect a change in the availability of nutrients, such as phosphorus. Cumulatively, these data highlight that Earth’s GOE is a tale of feast and famine: A geologically unprecedented reduction in the size of the biosphere occurred across the end-GOE transition.Olivia M. J. Dagnaud assisted during fieldwork. S. V. Lalonde and E. A. Sperling provided helpful comments on an early version of the manuscript. We thank N. J. Planavsky and an anonymous reviewer for their constructive feedback. M.S.W.H. was supported by an NSERC PGS-D and student research grants from National Geographic, the APS Lewis and Clark Fund, Northern Science Training Program, McGill University Graduate Research Enhancement and Travel Awards, Geological Society of America, Mineralogical Association of Canada, and Stanford University. P.W.C. acknowledges support from the University of Colorado Boulder, the Agouron Institute Geobiology postdoctoral Fellowship program, a Natural Sciences and Engineering Council of Canada Postgraduate Scholarship–Doctoral Program scholarship, and the NSTP. Y.P. was supported by the Strategic Priority Research Program of CAS (XDB26000000). T.J.H. thanks Maureen E. Auro for laboratory assistance and the NSF for supporting isotope research in the NIRVANA Labs.2020-02-1

Study of heterogeneous nucleation of eutectic Si in high-purity Al-Si alloys with Sr addition

The official published version can be accessed from the link below - Copyright @ 2010 The Minerals, Metals & Materials Society and ASM InternationalAl-5 wt pct Si master-alloys with controlled Sr and/or P addition/s were produced using super purity Al 99.99 wt pct and Si 99.999 wt pct materials in an arc melter. The master-alloy was melt-spun resulting in the production of thin ribbons. The Al matrix of the ribbons contained entrained Al-Si eutectic droplets that were subsequently investigated. Differential scanning calorimetry, thermodynamic calculations, and transmission electron microscopy techniques were employed to examine the effect of the Sr and P additions on eutectic undercoolings and nucleation phenomenon. Results indicate that, unlike P, Sr does not promote nucleation. Increasing Sr additions depressed the eutectic nucleation temperature. This may be a result of the formation of a Sr phase that could consume or detrimentally affect potent AlP nucleation sites.This work is financially supported by the Higher Education Commission of Pakistan and managerially supported from the OAD

Effects of Anti-VEGF on Predicted Antibody Biodistribution: Roles of Vascular Volume, Interstitial Volume, and Blood Flow

BACKGROUND: The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences. METHODOLOGY/PRINCIPAL FINDINGS: Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naïve or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naïve versus anti-VEGF-administered mice. CONCLUSIONS/SIGNIFICANCE: These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF

Pelagic barite precipitation at micromolar ambient sulfate

The question of how significant barite deposits were able to form from early Earth’s low-sulfate seas remains controversial. Here, the authors show pelagic barite precipitation within a strongly barite-undersaturated ecosystem, highlighting the importance of particle-associated microenvironments

Publisher Correction : Pelagic barite precipitation at micromolar ambient sulfate

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Nature Communications 9 (2018): 305, doi:10.1038/s41467-017-02701-y.Correction to: Nature Communications https://doi.org/10.1038/s41467-017-01229-5, Article published online 07 November 201

Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state

Abstract Treatment of BRAF‐mutant melanomas with MAP kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live‐cell imaging, single‐cell analysis, and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest, and the remainder adapt to drug. Drug‐adapted cells up‐regulate markers of the neural crest (e.g., NGFR), a melanocyte precursor, and grow slowly. This phenotype is transiently stable, reverting to the drug‐naïve state within 9 days of drug withdrawal. Transcriptional profiling of cell lines and human tumors implicates a c‐Jun/ECM/FAK/Src cascade in de‐differentiation in about one‐third of cell lines studied; drug‐induced changes in c‐Jun and NGFR levels are also observed in xenograft and human tumors. Drugs targeting the c‐Jun/ECM/FAK/Src cascade as well as BET bromodomain inhibitors increase the maximum effect (E max) of RAF/MEK kinase inhibitors by promoting cell killing. Thus, analysis of reversible drug resistance at a single‐cell level identifies signaling pathways and inhibitory drugs missed by assays that focus on cell populations

Search for CP Violation in the Decay Z -> b (b bar) g

About three million hadronic decays of the Z collected by ALEPH in the years 1991-1994 are used to search for anomalous CP violation beyond the Standard Model in the decay Z -> b \bar{b} g. The study is performed by analyzing angular correlations between the two quarks and the gluon in three-jet events and by measuring the differential two-jet rate. No signal of CP violation is found. For the combinations of anomalous CP violating couplings, ${\hat{h}}_b = {\hat{h}}_{Ab}g_{Vb}-{\hat{h}}_{Vb}g_{Ab}$ and $h^{\ast}_b = \sqrt{\hat{h}_{Vb}^{2}+\hat{h}_{Ab}^{2}}$, limits of \hat{h}_b < 0.59$and$h^{\ast}_{b} < 3.02$ are given at 95\% CL.Comment: 8 pages, 1 postscript figure, uses here.sty, epsfig.st

Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism

Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as a therapeutic target in several cancers because it has many reported substrates with a role in cancer progression, including FOXO4, MDM2, N-Myc, and PTEN. The multisubstrate nature of USP7, combined with the modest potency and selectivity of early generation USP7 inhibitors, has presented a challenge in defining predictors of response to USP7 and potential patient populations that would benefit most from USP7-targeted drugs. Here, we describe the structureguided development of XL177A, which irreversibly inhibits USP7 with sub-nM potency and selectivity across the human proteome. Evaluation of the cellular effects of XL177A reveals that selective USP7 inhibition suppresses cancer cell growth predominantly through a p53-dependent mechanism: XL177A specifically upregulates p53 transcriptional targets transcriptome-wide, hotspot mutations in TP53 but not any other genes predict response to XL177A across a panel of similar to 500 cancer cell lines, and TP53 knockout rescues XL177A-mediated growth suppression of TP53 wild-type (WT) cells. Together, these findings suggest TP53 mutational status as a biomarker for response to USP7 inhibition. We find that Ewing sarcoma and malignant rhabdoid tumor (MRT), two pediatric cancers that are sensitive to other p53-dependent cytotoxic drugs, also display increased sensitivity to XL177A

The clinical course of acute otitis media in high-risk Australian Aboriginal children: a longitudinal study

BACKGROUND: It is unclear why some children with acute otitis media (AOM) have poor outcomes. Our aim was to describe the clinical course of AOM and the associated bacterial nasopharyngeal colonisation in a high-risk population of Australian Aboriginal children. METHODS: We examined Aboriginal children younger than eight years who had a clinical diagnosis of AOM. Pneumatic otoscopy and video-otoscopy of the tympanic membrane (TM) and tympanometry was done every weekday if possible. We followed children for either two weeks (AOM without perforation), or three weeks (AOM with perforation), or for longer periods if the infection persisted. Nasopharyngeal swabs were taken at study entry and then weekly. RESULTS: We enrolled 31 children and conducted a total of 219 assessments. Most children had bulging of the TM or recent middle ear discharge at diagnosis. Persistent signs of suppurative OM (without ear pain) were present in most children 7 days (23/30, 77%), and 14 days (20/26, 77%) later. Episodes of AOM did not usually have a sudden onset or short duration. Six of the 14 children with fresh discharge in their ear canal had an intact or functionally intact TM. Perforation size generally remained very small (<2% of the TM). Healing followed by re-perforation was common. Ninety-three nasophyngeal swabs were taken. Most swabs cultured Streptococcus pneumoniae (82%), Haemophilus influenzae (71%), and Moraxella catarrhalis (95%); 63% of swabs cultured all three pathogens. CONCLUSION: In this high-risk population, AOM was generally painless and persistent. These infections were associated with persistent bacterial colonisation of the nasopharynx and any benefits of antibiotics were modest at best. Systematic follow up with careful examination and review of treatment are required and clinical resolution cannot be assumed

Geographic Variations in Retention in Care among HIV-Infected Adults in the United States

ObjectiveTo understand geographic variations in clinical retention, a central component of the HIV care continuum and key to improving individual- and population-level HIV outcomes.DesignWe evaluated retention by US region in a retrospective observational study.MethodsAdults receiving care from 2000–2010 in 12 clinical cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) contributed data. Individuals were assigned to Centers for Disease Control and Prevention (CDC)-defined regions by residential data (10 cohorts) and clinic location as proxy (2 cohorts). Retention was ≥2 primary HIV outpatient visits within a calendar year, >90 days apart. Trends and regional differences were analyzed using modified Poisson regression with clustering, adjusting for time in care, age, sex, race/ethnicity, and HIV risk, and stratified by baseline CD4+ count.ResultsAmong 78,993 adults with 444,212 person-years of follow-up, median time in care was 7 years (Interquartile Range: 4–9). Retention increased from 2000 to 2010: from 73% (5,000/6,875) to 85% (7,189/8,462) in the Northeast, 75% (1,778/2,356) to 87% (1,630/1,880) in the Midwest, 68% (8,451/12,417) to 80% (9,892/12,304) in the South, and 68% (5,147/7,520) to 72% (6,401/8,895) in the West. In adjusted analyses, retention improved over time in all regions (p<0.01, trend), although the average percent retained lagged in the West and South vs. the Northeast (p<0.01).ConclusionsIn our population, retention improved, though regional differences persisted even after adjusting for demographic and HIV risk factors. These data demonstrate regional differences in the US which may affect patient care, despite national care recommendations