The Coniacian–Santonian sedimentary record in southern Tanzania (Ruvuma Basin, East Africa): Planktonic foraminiferal evolutionary, geochemical and palaeoceanographic patterns

AbstractA 101 m thick stratigraphically complete late Coniacian–early Santonian (ca 89 to 83 Ma) sedimentary sequence drilled in Tanzania (Tanzania Drilling Project Site 39) allows, for the first time, examination of the planktonic foraminiferal biostratigraphy and evolution, the depositional history, and geochemical patterns of the subtropical–tropical Indian Ocean region. The sedimentary succession corresponds to an outer shelf to upper slope setting and is dominated by calcareous clayey siltstones and mudstones. The occurrences of Tethyan marker species enable application of the tropical biozonation including identification of the Dicarinella concavata and Dicarinella asymetrica Zones. In addition, Tanzania Drilling Project Site 39 is proposed as reference section for the Coniacian/Santonian boundary in the Indian Ocean with the boundary placed at the lowest occurrence of Globotruncana linneiana in agreement with the Global Stratotype Section and Point (Spain). The record at Tanzania Drilling Project Site 39 provides a unique opportunity to document the planktonic foraminiferal evolution in a subtropical marginal sea environment during a key period in their evolutionary history characterized by a major radiation among the deep‐dwelling taxa. Combined documentation of lithological and geochemical changes (%CaCO3, %Corg, δ13Ccarb and δ18Ocarb) reveals a setting influenced by continental‐derived nutrients in the Dicarinella concavata Zone (Lindi Formation) with a change to higher carbonate production and reduced surface water primary productivity in the overlying Dicarinella asymetrica Zone (Nangurukuru Formation). Planktonic foraminiferal assemblage changes mirror the depositional and geochemical trends and indicate a progressive shift from a more eutrophic to a more oligotrophic regime through time. At the local scale, this palaeoceanographic scenario is consistent with the deepening of coastal Tanzania in response to the Late Cretaceous marine transgression registered in south‐east Tanzania. Because the tectonic evolution and sea‐level rise along the East Africa continental margin is superimposed on the Coniacian–Campanian global long‐term sea‐level high, this study hypothesizes that the epicontinental invasion of blue waters may have favoured radiation among deep‐dwelling taxa

Late Cretaceous Paleoceanographic Evolution and the Onset of Cooling in the Santonian at Southern High Latitudes (IODP Site U1513, SE Indian Ocean)

The latest Cenomanian to Santonian sedimentary record recovered at IODP Expedition 369 Site U1513 in the Mentelle Basin (SE Indian Ocean, paleolatitude 60°S at 85 Ma) is studied to interpret the paleoceanographic evolution in the Southern Hemisphere. The planktonic foraminiferal assemblage changes, the depth ecology preferences of different species, and the surface and seafloor temperature inferred from the stable isotopic values measured on foraminiferal tests provide meaningful information to the understanding of the Late Cretaceous climate. The hothouse climate during the Turonian-Santonian, characterized by weak latitudinal temperature gradients and high atmospheric CO2 concentrations, is followed by a progressive cooling during the Campanian. At Site U1513 the beginning of this climatic transition is nicely recorded within the Santonian, as indicated by an ∼1‰ increase in δ18O values of planktonic foraminifera suggesting a decline in surface water paleotemperatures of 4°C. The onset of cooling is mirrored by changes in the planktonic foraminiferal assemblages including extinctions among surface and deep dwellers, appearances and diversification of newly evolving taxa, and changes from predominantly epifaunal oxic to infaunal dysoxic/ suboxic taxa among co-occurring benthic foraminifera. Overall, the data presented here document an interval in the Santonian during which the rate of southern high latitude cooling increased. Both surface and bottom waters were affected, although the cooling signal is more evident in the data for surface waters. This pattern of cooling ascribes the deterioration of the Late Cretaceous climate to decreased CO2 in the atmosphere and changes in the oceanic circulation correlated with enhanced meridional circulation

A Targeted<em> in Vivo</em> SILAC Approach for Quantification of Drug Metabolism Enzymes:Regulation by the Constitutive Androstane Receptor

The modulation of drug metabolism enzyme (DME) expression by therapeutic agents is a central mechanism of drug-drug interaction and should be assessed as early as possible in preclinical drug development. Direct measurement of DME levels is typically achieved by Western blotting, qPCR, or microarray, but these techniques have their limitations; antibody cross-reactivity among highly homologous subfamilies creates ambiguity, while discordance between mRNA and protein expression undermines observations. The aim of this study was to design a simple targeted workflow by combining in vivo SILAC and label-free proteomics approaches for quantification of DMEs in mouse liver, facilitating a rapid and comprehensive evaluation of metabolic potential at the protein level. A total of 197 peptides, representing 51 Phase I and Phase II DMEs, were quantified by LC-MS/MS using targeted high resolution single ion monitoring (tHR/SIM) with a defined mass-to-charge and retention time window for each peptide. In a constitutive androstane receptor (Car) activated mouse model, comparison of tHR/SIM-in vivo SILAC with Western blotting for analysis of the expression of cytochromes P450 was favorable, with agreement in fold-change values between methods. The tHR/SIM-in vivo SILAC approach therefore permits the robust analysis of multiple DME in a single protein sample, with clear utility for the assessment of the drug-drug interaction potential of candidate therapeutic compounds. </p

Testing the early Late Ordovician cool-water hypothesis with oxygen isotopes from conodont apatite

© 2017 Cambridge University Press. Latest Sandbian to early Katian sequences across Laurentia\u27s epicontinental sea exhibit a transition from lithologies characterized as \u27warm-water\u27 carbonates to those characterized as \u27cool-water\u27carbonates. This shift occurs across the regionally recognized M4/M5 sequence stratigraphic boundary and has been attributed to climatic cooling and glaciation, basin reorganization and upwelling of open ocean water, and/or increased water turbidity and terrigenous input associated with the Taconic tectophase. Documentation of oxygen isotopic trends across the M4/M5 and through bracketing strata provides a potential means of distinguishing among these alternative scenarios; however, oxygen isotopic records generated to date have failed to settle the debate. This lack of resolution is because δ18O records are open to multiple interpretations and potentially confounding factors related to local environmental conditions have not been tested by examining the critical interval in multiple areas and different depositional settings. To begin to address this shortcoming, we present new species-specific and mixed assemblage conodont δ18O values in samples spanning the M4/M5 boundary from the Upper Mississippi Valley, Alabama, and Virginia. The new results are combined with previous studies, providing a record of δ18O variability across SE Laurentia. The combined dataset allows us to test for regional trends at a resolution not previously available. Our results document a ~1.5‰ decrease in values across Laurentia instead of increasing δ18O values across the M4/M5 as predicted in various \u27cool-water\u27 scenarios. In short, these results do not support a shift to \u27cool-water\u27 conditions as an explanation for changes in early Katian carbonates across the M4/M5

Identification of novel pathways of osimertinib disposition and potential implications for the outcome of lung cancer therapy

Abstract Purpose: Osimertinib is a third-generation inhibitor of the epidermal growth factor receptor used in treatment of non–small cell lung cancer. A full understanding of its disposition and capacity for interaction with other medications will facilitate its effective use as a single agent and in combination therapy. Experimental Design: Recombinant cytochrome P450s and liver microsomal preparations were used to identify novel pathways of osimertinib metabolism in vitro. A panel of knockout and mouse lines humanized for pathways of drug metabolism were used to establish the relevance of these pathways in vivo. Results: Although some osimertinib metabolites were similar in mouse and human liver samples there were several significant differences, in particular a marked species difference in the P450s involved. The murine Cyp2d gene cluster played a predominant role in mouse, whereas CYP3A4 was the major human enzyme responsible for osimertinib metabolism. Induction of this enzyme in CYP3A4 humanized mice substantially decreased circulating osimertinib exposure. Importantly, we discovered a further novel pathway of osimertinib disposition involving CPY1A1. Modulation of CYP1A1/CYP1A2 levels markedly reduced parent drug concentrations, significantly altering metabolite pharmacokinetics (PK) in humanized mice in vivo. Conclusions: We demonstrate that a P450 enzyme expressed in smokers' lungs and lung tumors has the capacity to metabolise osimertinib. This could be a significant factor in defining the outcome of osimertinib treatment. This work also illustrates how P450-humanized mice can be used to identify and mitigate species differences in drug metabolism and thereby model the in vivo effect of critical metabolic pathways on anti-tumor response. Clin Cancer Res; 24(9); 2138–47. ©2018 AACR.</jats:p

Biotic and Paleoceanographic Changes Across the Late Cretaceous Oceanic Anoxic Event 2 in the Southern High Latitudes (IODP Sites U1513 and U1516, SE Indian Ocean)

Oceanic Anoxic Event 2, spanning the Cenomanian/Turonian boundary (93.9 Ma), was an episode of major perturbations in the global carbon cycle. To investigate the response of biota and the paleoceanographic conditions across this event, we present data from International Ocean Discovery Program sites U1513 and U1516 in the Mentelle Basin (offshore SW Australia; paleolatitude 59°–60°S in the mid-Cretaceous) that register the first complete records of OAE 2 at southern high latitudes. Calcareous nannofossils provide a reliable bio-chronostratigraphic framework. The distribution and abundance patterns of planktonic and benthic foraminifera, radiolaria, and calcispheres permit interpretation of the dynamics of the water mass stratification and provide support for the paleobathymetric reconstruction of the two sites, with Site U1513 located northwest of the Mentelle Basin depocenter and at a deeper depth than Site U1516. The lower OAE 2 interval is characterized by reduced water mass stratification with alternating episodes of enhanced surface water productivity and variations of the thickness of the mixed layer as indicated by the fluctuations in abundance of the intermediate dwelling planktonic foraminifera. The middle OAE 2 interval contains lithologies composed almost entirely of radiolaria reflecting extremely high marine productivity; the low CaCO3 content is consistent with marked shoaling of the Carbonate Compensation Depth and ocean acidification because of CaCO3 undersaturation. Conditions moderated after deposition of the silica-rich, CaCO3-poor rocks as reflected by the microfossil changes indicating a relatively stable water column although episodes of enhanced eutrophy did continue into the lower Turonian at Site U1516

Effect of flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor

Background and Purpose Flecainide is a use-dependent blocker of cardiac Na+ channels. Mechanistic analysis of this block showed that the cationic form of flecainide enters the cytosolic vestibule of the open Na+ channel. Flecainide is also effective in the treatment of catecholaminergic polymorphic ventricular tachycardia but, in this condition, its mechanism of action is contentious. We investigated how flecainide derivatives influence Ca2+-release from the sarcoplasmic reticulum through the ryanodine receptor channel (RyR2) and whether this correlates with their effectiveness as blockers of Na+ and/or RyR2 channels. Experimental Approach We compared the ability of fully charged (QX-FL) and neutral (NU-FL) derivatives of flecainide to block individual recombinant human RyR2 channels incorporated into planar phospholipid bilayers, and their effects on the properties of Ca2+ sparks in intact adult rat cardiac myocytes. Key Results Both QX-FL and NU-FL were partial blockers of the non-physiological cytosolic to luminal flux of cations through RyR2 channels but were significantly less effective than flecainide. None of the compounds influenced the physiologically relevant luminal to cytosol cation flux through RyR2 channels. Intracellular flecainide or QX-FL, but not NU-FL, reduced Ca2+ spark frequency. Conclusions and Implications Given its inability to block physiologically relevant cation flux through RyR2 channels, and its lack of efficacy in blocking the cytosolic-to-luminal current, the effect of QX-FL on Ca2+ sparks is likely, by analogy with flecainide, to result from Na+ channel block. Our data reveal important differences in the interaction of flecainide with sites in the cytosolic vestibules of Na+ and RyR2 channels

ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling

ISG15 is an ubiquitin-like modifier that is associated with reduced survival rates in breast cancer patients. The mechanism by which ISG15 achieves this however remains elusive. We demonstrate that modification of Rab GDP-Dissociation Inhibitor Beta (GDI2) by ISG15 (ISGylation) alters endocytic recycling of the EGF receptor (EGFR) in non-interferon stimulated cells using CRISPR-knock out models for ISGylation. By regulating EGFR trafficking, ISGylation enhances EGFR recycling and sustains Akt-signalling. We further show that Akt signalling positively correlates with levels of ISG15 and its E2-ligase in basal breast cancer cohorts, confirming the link between ISGylation and Akt signalling in human tumours. Persistent and enhanced Akt activation explains the more aggressive tumour behaviour observed in human breast cancers. We show that ISGylation can act as a driver of tumour progression rather than merely being a bystander.</p

A lower to middle Eocene astrochronology for the Mentelle Basin (Australia) and its implications for the geologic time scale

The geologic time scale for the Cenozoic Era has been notably improved over the last decades by virtue of integrated stratigraphy, combining high-resolution astrochronologies, biostratigraphy and magnetostratigraphy with high-precision radioisotopic dates. However, the middle Eocene remains a weak link. The so-called “Eocene time scale gap” reflects the scarcity of suitable study sections with clear astronomically-forced variations in carbonate content, primarily because large parts of the oceans were starved of carbonate during the Eocene greenhouse. International Ocean Discovery Program (IODP) Expedition 369 cored a carbonate-rich sedimentary sequence of Eocene age in the Mentelle Basin (Site U1514, offshore southwest Australia). The sequence consists of nannofossil chalk and exhibits rhythmic clay content variability. Here, we show that IODP Site U1514 allows for the extraction of an astronomical signal and the construction of an Eocene astrochronology, using 3-cm resolution X-Ray fluorescence (XRF) core scans. The XRF-derived ratio between calcium and iron content (Ca/Fe) tracks the lithologic variability and serves as the basis for our U1514 astrochronology. We present a 16 million-year-long (40-56 Ma) nearly continuous history of Eocene sedimentation with variations paced by eccentricity and obliquity. We supplement the high-resolution XRF data with low-resolution bulk carbon and oxygen isotopes, recording the long-term cooling trend from the Paleocene-Eocene Thermal Maximum (PETM – ca. 56 Ma) into the middle Eocene (ca. 40 Ma). Our early Eocene astrochronology corroborates existing chronologies based on deep-sea sites and Italian land sections. For the middle Eocene, the sedimentological record at U1514 provides a single-site geochemical backbone and thus offers a further step towards a fully integrated Cenozoic geologic time scale at orbital resolution