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Reliable estimates of bottom-water oxygen contents are crucial to understanding the formation of past oxygen-depleted environments. Here, we investigate the relationship between pore density in calcareous benthic foraminiferal tests and environmental factors like bottom-water oxygen and nitrate concentration, water depth, and temperature in living (Rose Bengal stained) specimens of the shallow-infaunal species Bolivina pacifica, and the two deep-infaunal species Fursenkoina mexicana, and Chilostomella oolina. Used samples span an oxygen-gradient (0.10 to 4.62mlL.sup.-1) across oxygen minimum zones (OMZ) off Namibia and Pakistan.

Oceanic Anoxic Event-2 (OAE-2, ∼94 Ma ago) is marked by a significant perturbation to the carbon and nutrient cycles. Despite the general idea of widespread expansion of the oceanic anoxia during OAE-2, various localities likely experienced heterogeneous redox fluctuations throughout the roughly 500-thousand-year-long event. In certain localities, redox-sensitive elements imply persistent anoxic-to-euxinic conditions, notwithstanding paleontological data that indicate short-term hypoxic-to-anoxic oscillations in bottom waters. Such discrepancies likely result from sampling resolution, local proxy sensitivity, and/or time-integration of signals, particularly for severe hypoxic conditions. We applied vanadium (V) isotopes to three well-studied OAE-2 localities in the proto-North Atlantic Basin. Under the relatively stable anoxic-to-euxinic conditions throughout OAE-2 at Well S75 and Site 367, the sedimentary δ 51 V values present consistent variations analogous to modern anoxic-to-euxinic environments. However, at Site 1258, the sedimentary δ 51 V values present greater perturbations toward more negative values that are indicative of short-term oxygenation in bottom waters. These negative perturbations of δ 51 V values covary with the abundances of the low-oxygen-tolerant benthic foraminifers. Together, these data refine the heterogeneous redox fluctuations in individual localities, revealing occasional short-term weak oxygenation under the generally anoxic conditions throughout OAE-2. This study documents the unique utility of V isotopes to track bottom water redox fluctuations, particularly short-term variations from anoxic to mildly oxic conditions that are hard to track with other methods. • A framework for utilizing V isotopes using 3 well-constrained sites during OAE-2. • Limited global perturbation to the seawater δ 51 V values during OAE-2. • The sedimentary δ 51 V can track local benthic hypoxic-to-euxinic redox fluctuations. • One site shows covariation of local sedimentary δ 51 V and benthic foraminiferal data. [ABSTRACT FROM AUTHOR]

It is not clear how regulation of T-cell function is altered during development of inflammatory bowel diseases (IBD). We studied the mechanisms by which geranylgeranyltransferase-mediated prenylation controls T-cell localization to the intestine and chronic inflammation. We generated mice with T-cell–specific disruption of the geranylgeranyltransferase type I, beta subunit gene (Pggt1b), called Pggt1b ΔCD4 mice, or the ras homolog family member A gene (Rhoa), called Rhoa ΔCD4 mice. We also studied mice with knockout of CDC42 or RAC1 and wild-type mice (controls). Intestinal tissues were analyzed by histology, multiphoton and confocal microscopy, and real-time polymerase chain reaction. Activation of CDC42, RAC1, and RHOA were measured with G-LISA, cell fractionation, and immunoblots. T cells and lamina propria mononuclear cells from mice were analyzed by flow cytometry or transferred to Rag1 –/– mice. Mice were given injections of antibodies against integrin alpha4beta7 or gavaged with the RORC antagonist GSK805. We obtained peripheral blood and intestinal tissue samples from patients with and without IBD and analyzed them by flow cytometry. Pggt1b ΔCD4 mice developed spontaneous colitis, characterized by thickening of the intestinal wall, edema, fibrosis, accumulation of T cells in the colon, and increased expression of inflammatory cytokines. Compared with control CD4+ T cells, PGGT1B-deficient CD4+ T cells expressed significantly higher levels of integrin alpha4beta7, which regulates their localization to the intestine. Inflammation induced by transfer of PGGT1B-deficient CD4+ T cells to Rag1–/– mice was blocked by injection of an antibody against integrin alpha4beta7. Lamina propria of Pggt1b ΔCD4 mice had increased numbers of CD4+ T cells that expressed RORC and higher levels of cytokines produced by T-helper 17 cells (granulocyte-macrophage colony-stimulating factor, interleukin [IL]17A, IL17F, IL22, and tumor necrosis factor [TNF]). The RORC inverse agonist GSK805, but not antibodies against IL17A or IL17F, prevented colitis in Pggt1b ΔCD4 mice. PGGT1B-deficient CD4+ T cells had decreased activation of RHOA. RhoA ΔCD4 mice had a similar phenotype to Pggt1b ΔCD4 mice, including development of colitis, increased numbers of CD4+ T cells in colon, increased expression of integrin alpha4beta7 by CD4+ T cells, and increased levels of IL17A and other inflammatory cytokines in lamina propria. T cells isolated from intestinal tissues from patients with IBD had significantly lower levels of PGGT1B than tissues from individuals without IBD. Loss of PGGT1B from T cells in mice impairs RHOA function, increasing CD4+ T-cell expression of integrin alpha4beta7 and localization to colon, resulting in increased expression of inflammatory cytokines and colitis. T cells isolated from gut tissues from patients with IBD have lower levels of PGGT1B than tissues from patients without IBD. [ABSTRACT FROM AUTHOR]

Abstract Electroporation has been a widely established method for delivering DNA and other material into cells in vitro. Conventional electroporation infrastructure is typically immobile, non-customizable, non-transparent regarding the characteristics of output pulses, and expensive. Here, we describe a portable electroporator for DNA delivery into bacterial cells that can quickly be reconstructed using 3D desktop printing and off-the-shelf components. The device is light weight (700 g), small (70 × 180 × 210 mm) and extremely low-cost (

We evaluate the potential of calcareous dinoflagellates as archives for Sr/Ca-based paleo-temperature reconstructions and δ 44/40 Ca seawater fluctuations on sediments from Ocean Drilling Program Expedition 113 (Hole 690C, Weddell Sea, Southern Ocean). Between 73 and 68 Ma, Sr/Ca ratios of two Cretaceous dinoflagellate species, Pirumella krasheninnikovii and Orthopithonella globosa show a pronounced decrease, consistent with a significant drop in sea-surface temperature as reflected by the δ 18 O of planktic foraminifers. The apparent temperature sensitivity of the dinoflagellate cysts' Sr/Ca is ~0.06 and ~0.08 mmol/mol °C −1 , using δ 18 O-derived paleo sea-surface temperatures, which is significant and large enough to resolve paleoenvironmental temperature changes at current analytical precision. As the chemical composition of the cyst calcite appears to have a good preservation, the Sr/Ca of calcareous dinoflagellates has a potential to serve as paleo-temperature proxy, although the chemical composition of the Cretaceous seawater and potential impacts on the cyst geochemistry is pending further inspection. The Ca isotope composition of the two dinoflagellate species shows identical trends of increasing δ 44/40 Ca between 73 and 67 Ma. The planktic foraminifer Archaeoglobigerina australis and the benthic foraminifer Nuttallides truempyi reveal the same increase of about 0.4‰ but are offset relative to the dinoflagellates by about +0.5‰, presumably due to species-specific Ca isotope fractionation. Bulk carbonate sediment shows significant scatter, likely caused by changes in faunal composition and does not reproduce the trend revealed by the dinoflagellate and foraminifer records. These observations demonstrate the importance of taxon-specific records and careful determination of fractionation factors of selected archives and highlight complications arising from utilizing less suitable archives, such as bulk sediments, for δ 44/40 Ca seawater reconstructions. Our records indicate strong changes in the marine Ca cycle associated with the global temperature decrease towards the end of the Cretaceous. [ABSTRACT FROM AUTHOR]

Ketamine and its stereoisomer S(+)-ketamine are widely used for sedation in pediatric anesthesia and intensive care medicine. Numerous experimental studies indicate that ketamine is potentially toxic to the developing brain. Here, we examined the long-term effects of NMDA receptor blockade on NMDA receptor subunit expression, alterations in neuronal Ca 2+ -oscillations and apoptosis. Hippocampal neurons, 15 days in culture, were exposed to either S(+)-ketamine or the NMDA receptor blocker MK801 for 24 h. Cytosolic Ca 2+ -concentration was determined by fluorescence microscopy and the expression of the NMDA subunits NR1, NR2A and 2B was assessed by qRT-PCR, whereas Western blots and activated Caspase-3 served to measure the extent of apoptosis. Long-term incubation with MK801 or higher doses of S(+)-ketamine resulted in a dose-dependent decreased ability of MK801 to reduce amplitude and frequency of the Ca 2+ -oscillations 15 min following washout of the drug. This was accompanied by an increase in NR1 mRNA but not the NR2A and B subunit expression at the same time point. 24 h following washout of the specific drug, a significant elevation of the pro-apoptotic marker BAX, as well as activated Caspase-3 positive neurons, could be detected in cultures exposed to 100 μM MK801 and 25 μM S(+)-ketamine. Here, we show that long-term blockade of the NMDA receptor in developing rat hippocampal neurons significantly increased NR1 subunit expression, and that this was associated with an alteration in neuronal activity. Apoptosis was only induced 24 h after withdrawal of long-term blockade for high doses of S(+)-ketamine. [ABSTRACT FROM AUTHOR]

The human complement system is the most effective defense mechanism of the human innate immune system. One major negative regulator of the alternative pathway in human blood is complement factor H (FH). It binds to autologous cells and thus, prevents complement attack against body-cells or tissues. Various pathogens are known to escape complement recognition by recruiting FH to provide protection against the host’s immune system. This immune evasion mechanism was recently qualitatively reported for asexual malaria blood stages. To indirectly evaluate the stage-specific potential of FH-receptor proteins as vaccine candidates, we quantified the FH molecules bound to the surface of different malaria blood stage parasites by Western blot and a commercially available FH-ELISA, which was originally designed to measure the FH concentration in human serum. Host-cell-free merozoites and intracellular mature schizont (here called segmenter) stages bind significantly more FH molecules than earlier parasite stages. [ABSTRACT FROM AUTHOR]

Abstract: The Middle Eocene Climatic Optimum (MECO) was a ~650kyr long interval of pronounced warmth superimposed on the long-term Eocene cooling trend. We investigate benthic foraminiferal assemblage and fossil fish tooth cerium anomaly variability from Ocean Drilling Program (ODP) Site 738 in the Indian sector of the Southern Ocean (Southern Kerguelen Plateau) to assess changes in bottom water chemistry and effects on benthic foraminiferal ecosystems. The studied section spans 41.9 to 38.4Ma, encompassing the MECO as well as extensive Pre-MECO and Post-MECO intervals. We report a marked faunal turnover at 40.4Ma, 200kyrs after the onset of the MECO at ~40.6Ma, from an assemblage dominated by epifaunal benthic foraminifera to an infaunal-dominated assemblage. The infaunal domination persisted until the termination of the MECO at 39.95Ma. Thereafter, the Pre-MECO assemblage returned. This change is attributed to an increase in export productivity associated with the warming, possibly caused by an increase in continental runoff or the influence of a more eutrophic surface water mass. Superimposed on the change in tropic state the Ce/Ce* record shows a positive excursion during the 100kyrs long MECO peak warming at around 40.05Ma, indicative of a decrease in bottom-water oxygen content. Synchronously, infaunal benthic foraminifera drop briefly in abundance. Hence, we suggest that the peak warming is associated with bottom water oxygen depletion potentially caused by elevated productivity and/or a transient influence of an older, oxygen-depleted water mass. [Copyright &y& Elsevier]

Abstract: The Campanian–Maastrichtian transition is characterized by a negative carbon-isotope excursion, the so-called Campanian–Maastrichtian Boundary Event (CMBE), thought to have been triggered by climatic cooling and sea-level fall. This event is known from stable isotope datasets around the world, but little is known about the causal mechanisms of the proposed cooling or the exact timing of this event. A tool both to enhance our knowledge about this event and to highlight the relative timing between the cooling and the proposed sea-level fall, is high-resolution carbon-isotope stratigraphy. In this study, an upper Campanian–Maastrichtian high-resolution carbon-isotope record from bulk carbonates of Ocean Drilling Program Hole 1210B at Shatsky Rise is presented. The new carbon-isotope record shows a number of distinct variations on short and longer time scales, which can be calibrated with age-diagnostic planktonic foraminifera and calcareous nannoplankton datum levels. This detailed biostratigraphically calibrated carbon-isotope stratigraphy can be correlated with the carbon-isotope record of Deep Sea Drilling Project Site 305 (∼500m deeper in palaeodepth than Hole 1210B). One result of this correlation is the detection of two major hiatuses at Site 305 associated with the lower and upper part of the CMBE. As possible mechanisms for these hiatuses, we discuss the effects of erosion as a result of mass wasting and/or of changes in the strength of bottom currents. By reducing stratigraphic uncertainties our new correlation proves the usefulness of biostratigraphically calibrated carbon-isotope stratigraphy, even for time intervals of small changes in the global carbon cycle as in the late Campanian–Maastrichtian. The new carbon-isotope record of Hole 1210B may serve in future as a reference for detailed calibration and correlation with other well-established δ13C records from shelf seas and open-ocean settings. This will help to enhance our understanding of ocean-climate processes associated with the CMBE. [Copyright &y& Elsevier]

Copyright of Revue de Micropaleontologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: Skeletal muscle is highly specialized for the rapid delivery of Ca2+ to the contractile apparatus during excitation–contraction coupling (EC coupling). Previous studies have shown the presence of a relatively fast-activated store-operated Ca2+ entry (SOCE) mechanism (<1s) to be present in skeletal muscle, unlike the situation occurring in non-excitable cells. We simultaneously imaged [Ca2+] in the t-system and cytoplasm in mechanically skinned fibers during SR Ca2+ release and observed both cell-wide Ca2+ release and Ca2+ waves. SOCE activation followed cell-wide Ca2+ release from high sarcoplasmic reticulum (SR) [Ca2+] ([Ca2+]SR) by seconds, consistent with depletion of [Ca2+]SR to an absolute threshold for SOCE and an unformed SOCE complex at high [Ca2+]SR. Ca2+ waves occurred at low [Ca2+]SR, close to the threshold for SOCE, minimizing the time between Ca2+ release and Ca2+ influx. Local activation of SOCE during Ca2+ waves occurred in ∼27ms following local initiation of SR depletion indicating a steep relationship between [Ca2+]SR and SOCE activation. Most of this delay was due to slow release of Ca2+ from SR, leaving only milliseconds at most for the activation of Ca2+ entry following store depletion. SOCE was also observed to deactivate effectively instantly during store refilling at low [Ca2+]SR. These rapid kinetics of SOCE persisted as subsequent Ca2+ waves propagated along the fiber. Thus we show for the first time millisecond activation and deactivation of SOCE during low amplitude [Ca2+]SR oscillations at low [Ca2+]SR. To account for the observed Ca2+ movements we propose the SOCE complex forms during the progressive depletion of [Ca2+]SR prior to reaching the activation threshold of SOCE and this complex remains stable at low [Ca2+]SR. [Copyright &y& Elsevier]

During the cardiac cycle, electrical excitation is coupled with mechanical response of the myocardium. Besides the active contraction, passive mechanics plays an important role, and its behaviour differs in healthy and diseased hearts as well as among different animal species. The aim of this study is the characterisation of passive mechanical properties in healthy and infarcted rat myocardium by means of mechanical testing and subsequent parameter fitting. Elasticity assessments via uniaxial extension tests are performed on healthy and infarcted tissue samples from left ventricular rat myocardium. In order to fully characterise the orthotropic cardiac tissue, our experimental data are combined with other previously published tests in rats – shear tests on healthy myocardium and equibiaxial tests on infarcted tissue. In a first step, we calibrate the Holzapfel-Ogden strain energy function in the healthy case. Sa far, this orthotropic constitutive law for the passive myocardium has been fitted to experimental data in several species, however there is a lack of an appropriate parameter set for the rat. With our determined parameters, a finite element simulation of the end-diastolic filling is performed. In a second step, we propose a model for the infarcted tissue. It is represented as a mixture of intact myocardium and a transversely isotropic scar structure. In our mechanical experiments, the tissue after myocardial infarction shows significantly stiffer behaviour than in the healthy case, and the stiffness correlates with the amount of fibrosis. A similar relationship is observed in the computational simulation of the end-diastolic filling. We conclude that our new proposed material model can capture the behaviour of two kinds of tissues – healthy and infarcted rat myocardium, and its calibration with the fitted parameters represents the experimental data well. [Display omitted] • Stiffness of the myocardium positively correlates with the amount of fibrosis. • Scar tissue expresses anisotropy in rat left ventricle after myocardial infarction. • Mixture model of healthy and infarcted myocardium. • Calibration of modified Holzapfel-Ogden strain energy function. • Finite element simulation of end-diastolic filling with varying infarction size. [ABSTRACT FROM AUTHOR]

Abstract: The ammonite fauna from the Hannover-Lahe borehole, northern Germany, is described. The core comprises a monotonous claystone succession that is late Middle Albian Euhoplites nitidus ammonite Subzone at the base and early Late Albian C. auritus Subzone at the top. Furthermore, inoceramid taxa are discussed in relation to the ammonite biostratigraphy, establishing this core as a reference profile for the Middle/Upper Albian boundary interval of the Lower Saxony Basin. A continuous record of nektonic and benthic organisms, as well as strong bioturbation throughout the section, indicates well-oxygenated conditions during deposition. The uppermost Middle Albian sedimentary succession of the Hannover-Lahe core is expanded compared to sections in the Anglo-Paris Basin. The Middle Albian part of the Hannover-Lahe core yielded almost exclusively ammonites of the genus Euhoplites, typical for the Hoplitinid Faunal Province. There is a break in faunal assemblages at the Middle/Upper Albian boundary. Half of the Late Albian fauna of the core is characterised by Callihoplites spp., as members of the Hoplitinid Faunal Province, and half by mortoniceratids of the Brancoceratinid Faunal Province. This Middle/Late Albian faunal change to more cosmopolitan faunas coincides with a rapidly rising sea level. This is also indicated by a condensed interval in the lower Upper Albian enriched in debris of inoceramids, phosphoritic concretions, ammonites, and complete inoceramid specimens. This level contains ammonites of the Hysteroceras orbignyi and H. varicosum Subzones. There is no ammonite evidence for the earliest Late Albian Dipoloceras cristatum Subzone. [Copyright &y& Elsevier]

Abstract: S100A1, a Ca2+-sensor protein of the EF-hand type, exerts positive inotropic effects in the heart via enhanced cardiac ryanodine receptor (RyR2) activity. Here we report that S100A1 protein (0.1μM) interacts with the RyR2 in resting permeabilized cardiomyocytes at free Ca2+-levels comparable to diastolic Ca2+-concentrations (∼150nM). Alterations of RyR2 function due to S100A1 binding was assessed via analysis of Ca2+-spark characteristics. Ca2+-spark frequency, amplitude and duration were all reduced upon perfusion with 0.1μM S100A1 protein by 38%, 14% and 18%, respectively. Most likely, these effects were conveyed through the S100A1 C-terminus (S100A1-ct; amino acids 75–94) as the corresponding S100A1-ct peptide (0.1μM) inhibited S100A1 protein binding to the RyR2 and similarly attenuated frequency, amplitude and duration of Ca2+-sparks by 52%, 8% and 26%, respectively. Accordingly, the sarcoplasmic reticulum (SR) Ca2+-content was slightly increased but the stoichiometry of other accessory RyR2 modulators (sorcin/FKBP12.6) remained unaltered by S100A1. Hence, we propose S100A1 as a novel inhibitory modulator of RyR2 function at diastolic Ca2+-concentrations in rabbit ventricular cardiomyocytes. [Copyright &y& Elsevier]

Copyright of Revue de Micropaleontologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: This paper is based on Santonian–Campanian sediments of Ocean Drilling Program Sites 1257 (2951mbsl) and 1259 (2353mbsl) from Demerara Rise (Leg 207, western tropical Atlantic, off Surinam). According to its position, Demerara Rise should have been influenced by the early opening of the Equatorial Atlantic Gateway and the establishment of a bottom-water connection between the central and South Atlantic Oceans during the Late Cretaceous. The investigated benthic foraminiferal faunas demonstrate strong fluctuations in bottom-water oxygenation and organic-matter flux to the sea-floor. The Santonian–earliest Campanian interval is characterised by laminated black shales without benthic foraminifera in the lowermost part, followed by an increasing number of benthic foraminifera. These are indicative of anoxic to dysoxic bottom waters, high organic-matter fluxes and a position within the oxygen minimum zone. At the shallower Site 1259, benthic foraminifera occurred earlier (Santonian) than at the deeper Site 1257 (Early Campanian). This suggests that the shallower site was characterised by fluctuations in the oxygen minimum zone and that a re-oxygenation of the sea-floor started considerably earlier at shallower water-depths. We speculate that this re-oxygenation was related to the ongoing opening of the Equatorial Atlantic Gateway. A condensed glauconitic chalk interval of Early Campanian age (Nannofossil Zone CC18 of Sissingh) overlies the laminated shales at both sites. This interval contains benthic foraminiferal faunas reflecting increasing bottom-water oxygenation and reduced organic-matter flux. This glauconitic chalk is strongly condensed and contains most of the Lower and mid-Campanian. Benthic foraminiferal species indicative of well-oxygenated and more oligotrophic environments characterise the overlying mid- to Upper Campanian nannofossil chalk. During deposition of the nannofossil chalk, a permanent deep-water connection between the central and South Atlantic Oceans is proposed, leading to ventilated and well-oxygenated bottom waters. If this speculation is true, the establishment of a permanent deep-water connection between the central and South Atlantic Oceans terminated Oceanic Anoxic Event 3 “black shale” formation in the central and South Atlantic marginal basins during the Early Campanian (Nannofossil Zone CC18) and led to well-oxygenated bottom waters in the entire Atlantic Ocean during the Late Campanian (at least from Nannofossil Zone CC22 onwards). [Copyright &y& Elsevier]

Myopathies Occurring in critically ill patients have gained increasing interest during the past years. For the patient, they represent a crucial factor for prolonged intensive care unit treatment and secondary complications Critical illness myopathies (CIMs) seem to be related to various pathogenic factors. Among those, the septic inflammatory response syndrome seems to play a major role. It has been suggested that, similar to sepsis-related multiorgan failure, CIM might be considered a failure of the organ muscle. Muscle function might be impaired by proposed "myotoxic" humoral factors. These could be endogenously produced during the innate immune response to sepsis. This article follows up recent evidence for such active fractions in the blood serum of CIM patients. To explain muscle weakness in CIM, serum fractions acutely modified membrane excitability and subcellular Ca2+ regulation in an animal model. From the differential serum effects, early-phase CIM seems to involve a reduction in the overall force generation in muscle but also a compensation by the membrane, increasing the excitability. Different animal models will help to elucidate the underlying mechanisms accounting for the specific proteolytic activities found in different forms of CIM. CIM represents a systemic rather than a local disorder. Humoral factors might initiate the local reaction of skeletal muscle clinically seen as muscle weakness, altered excitability, and proteolysis of contractile proteins. Establishing the interactions in the excitation-contraction cascade in CIM is a challenging task, not only to clarify its pathomechanism but also to deduce clinical interventions. [ABSTRACT FROM AUTHOR]

Abstract: The heart as a contractile hollow organ finely tunes mechanical parameters such as stroke volume, stroke pressure and cardiac output according to filling volumes, filling pressures via intrinsic and neuronal routes. At the cellular level, cardiomyocytes in beating hearts are exposed to large mechanical stress during successive heart beats. Although the mechanisms of excitation–contraction coupling are well established in mammalian heart cells, the putative contribution of mechanosensitive channels to Ca2+ homeostasis, Ca2+ signaling and force generation has been primarily investigated in relation to heart disease states. For instance, transient receptor potential channels (TRPs) are up-regulated in animal models of congestive heart failure or hypertension models and seem to play a vital role in pathological Ca2+ overload to cardiomyocytes, thus aggravating the pathology of disease at the cellular level. Apart from that, the contribution of mechanosensitive channels (MsC) in the normal beating heart to the downstream force activation cascade has not been addressed. We present an overview of the current literature and concepts of mechanosensitive channel involvement in failing hearts and cardiomyopathies and novel data showing a likely contribution of Ca2+ influx via mechanosensitive channels in beating normal cardiomyocytes during systolic shortening. [Copyright &y& Elsevier]

Abstract: Mg/Ca palaeothermometry in foraminiferal calcite is a widely applied tool in palaeoceanography. However, our understanding of the effects of planktic foraminiferal ecology and early diagenesis on test calcite Mg/Ca is limited. Here we report results of a study designed to shed new light on ecological, size-related and very early (water column) diagenetic controls on Mg/Ca in planktic foraminiferal calcite. We analysed Mg/Ca and stable isotopes of nine modern planktic foraminiferal species across fourteen mostly 50μm-window sieve fractions in a core-top sample from the North Atlantic Ocean. We also analysed Mg/Ca in four of these nine species from plankton-tow samples collected from 0 to 2500m water depth in the North Atlantic Ocean and Arabian Sea. Our core-top study confirms that sensitivity of Mg/Ca to change in test size is species-specific but reveals an overall decrease in Mg/Ca with increasing test size in all but one species, Orbulina universa, for which Mg/Ca increases with size. These findings are broadly consistent with known ecological behaviour suggesting that the size-related signal is largely environmentally rather than calcification-rate controlled. Our results underscore the need to undertake Mg/Ca palaeothermometry on narrow size fractions of planktic foraminifers, particularly for shallow-dwelling species such as G. bulloides and G. ruber where Mg/Ca is most sensitive to test size across the size range of 200–350μm. Our plankton-tow data from the Arabian Sea are in agreement with in-situ temperatures. In contrast, our data from the North Atlantic Ocean reveal large variability and marked offsets (to warmer values) from in-situ temperatures that are interpreted to reflect lateral advection from the south, storm-induced vertical mixing of the water column and/or the influence of surface-water salinity on the Mg/Ca signal. None of our plankton-tow Mg/Ca data shows any evidence of test dissolution in the water column. Our study provides important verification that the Mg/Ca signal recorded during calcification does not undergo diagenetic degradation during test transport to the sea floor, thereby satisfying an important precondition of its palaeo-proxy utility. [Copyright &y& Elsevier]

Abstract: Background: In immature neurons anesthetics induce apoptosis and influence neuronal differentiation. Neuronal Ca2+-oscillations regulate differentiation and synaptogenesis. We examined the effects of the long-term blockade of hippocampal Ca2+-oscillations with midazolam on neuronal synapsin expression. Material and methods: Hippocampal neurons were incubated at day 15 in culture with the specific GABAA receptor agonist muscimol (50μM) or with midazolam (100 and 300nM), respectively, for 24h. TUNEL and activated-Caspase-3 staining were used to detect apoptotic neurons. Ca2+-oscillations were detected using the Ca2+-sensitive dye FURA-2 and dual wavelength excitation fluorescence microscopy. Synapsin was identified with confocal anti-synapsin immunofluorescence microscopy. Results: Muscimol, when applied for 24h, decreased the amplitude and frequency Ca2+-oscillations significantly. Midazolam concentration-dependently suppressed the amplitude and frequency of the Ca2+-oscillations. This was associated by a downregulation of the synapsin expression 24h after washout. Conclusion: Neuronal Ca2+-oscillations mediate neuronal differentiation and are involved in synaptogenesis. By acting via the GABAA receptor, midazolam exerts its toxic effect through the suppression of neuronal Ca2+-oscillations, a reduction in synapsin expression and consecutively reduced synaptic integrity. [Copyright &y& Elsevier]

Abstract: The late Cenomanian–early Turonian Oceanic Anoxic Event (OAE-2) represents major paleoceanographic and faunal perturbations. Samples from the northern Tethyan margin (Rehkogelgraben, Eastern Alps) were investigated in order to trace the paleoceanographic processes. Paleoecologic conditions were reconstructed by combining the results of assemblage counts of indicative microfossil groups (foraminifera, and radiolaria). Assemblages, size distributions and abundances show a tripartite subdivision for surface and bottom waters: 1) Oligotrophic surface conditions and oxic bottom waters with a reasonably high food supply for the late Cenomanian interval. 2) An OAE period with black shales characterized by very low numbers but high diversities and a lack of high-productivity indicators among planktic foraminifera. Low abundances of small sized benthic foraminifera indicate low oxic–dysoxic conditions at the seafloor. 3) Post-OAE assemblages are characterized by mesotrophic planktic species and benthic foraminifera suggest oxic bottom waters. It took about 300ky to re-establish a pelagic carbonate-producing regime. The semi-enclosed basin situation of the Penninic Ocean is thought to be responsible for differences between the high productivity in the world ocean during the OAE-2 and the overall absence of high-productivity indicators and high foraminiferal diversities at Rehkogelgraben. The Penninic Ocean may have even served as a refuge during the environmental crisis. [ABSTRACT FROM AUTHOR]

Abstract: This study is based on Cenomanian sediments of Ocean Drilling Program (ODP) Sites 1258 and 1260 from Demerara Rise (Leg 207, western tropical Atlantic, off Suriname, ~1000 and ~500 m paleo-water depth, respectively). Studied sediments consist of laminated black shales with TOC values between 3 and 18% and include the Mid Cenomanian Event (MCE), a positive carbon isotope excursion predating the well-known Oceanic Anoxic Event 2 (OAE 2). Benthic foraminiferal assemblages of the continuously eutrophic environment at Demerara Rise are characterized by low diversities (≤9 species per sample) and large fluctuations in abundances, indicating oxygen depletion and varying organic matter fluxes. Dominant species at both sites are Bolivina anambra, Gabonita levis, Gavelinella dakotensis, Neobulimina albertensis, Praebulimina prolixa, and Tappanina cf. laciniosa. Benthic foraminiferal assemblages across the MCE show a threefold pattern: (1) stable ecological conditions below the MCE interval indicated by relatively high oxygenation and fluctuating organic matter flux, (2) decreasing oxygenation and/or higher organic matter flux during the MCE with decreasing benthic foraminiferal numbers and diversities (Site 1258) and a dominance of opportunistic species (Site 1260), and (3) anoxic to slightly dysoxic bottom-water conditions above the MCE as indicated by very low diversities and abundances or even the absence of benthic foraminifera. Slightly dysoxic conditions prevailed until OAE 2 at Demerara Rise. A comparison with other Atlantic Ocean and Tethyan sections indicates that the MCE reflects a paleoceanographic turning point towards lower bottom-water oxygenation, at least in the proto-North Atlantic Ocean and in the Tethyan and Boreal Realms. This general trend towards lower oxygenation of bottom waters across the MCE is accompanied by ongoing climate warming in combination with rising sea-level and the development of vast shallow epicontinental seas during the Middle and Late Cenomanian. These changes are proposed to have favoured the formation of warm and saline waters that may have contributed to intermediate- and deep-water masses at least in the restricted proto-North Atlantic and Tethyan Ocean basins, poor oxygenation of the Late Cenomanian sediments, and the changes in benthic foraminiferal assemblages across the MCE. [Copyright &y& Elsevier]

Abstract: Abundance patterns of planktic and benthic foraminifera from a tropical Atlantic drill site (Ocean Drilling Program Site 1259, Demerara Rise, Suriname margin) display a pronounced 400 kyr cyclicity, uninterrupted throughout our ∼87.8–92 Ma record, between two clearly distinguishable assemblages: (1) a pelagic foraminifer fauna, which represents a deep oxygen minimum zone, and (2) another assemblage representing a shallow oxygen minimum zone where the foraminifer fauna is dominated by a higher diversity population of mostly small clavate and biserial species common in epicontinental seas. The cyclic changes in the long eccentricity band (400 kyr) between these two assemblages are proposed to reflect changes in the mean latitudinal position of the Intertropical Convergence Zone (ITCZ). Associated fluctuations in precipitation and trade wind strength may have influenced the upwelling regime at Demerara Rise leading to the observed cyclicity of planktic foraminiferal assemblages. The severe Turonian to Coniacian paleoclimatic and paleoceanographic changes in the Atlantic Ocean (e.g., gateway opening, cooling, and glaciation), however, seem to have no influence on the composition of tropical planktic foraminiferal faunas. There is no apparent relationship between foraminifer abundances and a major deflection in the stable isotope record interpreted elsewhere as a sign of the growth and decay of a large polar ice sheet. [Copyright &y& Elsevier]

Abstract: Benthic foraminiferal faunas from the Lower Maastrichtian (Globotruncana falsostuarti–Gansserina gansseri Planktic Foraminiferal Zone) of DSDP Site 390 (Blake Nose, western North Atlantic) were investigated in order to characterize changes in organic matter flux and bottom-water oxygenation and their relation to paleoceanographic changes. Benthic foraminiferal faunas in the lower part of the studied succession show high abundances of Praebulimina reussi and Nuttallides truempyi and are proposed to reflect fluctuations in organic matter flux to the seafloor (meso- to eutrophic) under oxygenated bottom-water conditions. The middle interval is characterized by very low numbers of benthic foraminiferal specimens but a dominance of thick-walled species (e.g., lenticulinids, laevidentalinids), may reflect carbonate dissolution. In contrast to the lower part, benthic foraminifera from the upper part of the succession show well-oxygenated bottom waters. The most dominant species during this interval are Gavelinella beccariiformis, Reussella szajnochae, and N. truempyi. Parallel to this change in the benthic foraminiferal assemblages the number of inoceramid shells decreases, reflecting a significant increase in bottom-water oxygenation. Based on these data we speculate, that the observed changes in benthic foraminiferal assemblages towards a well-oxygenated environment within the Early Maastrichtian of DSDP Site 390 could reflect the onset of a shift from low-latitude to high-latitude deep-water sources. This speculation will predate the major reorganization of the oceanic circulation resulting in a circulation mode similar to today at the Early/Late Maastrichtian boundary by ∼1 Ma. [Copyright &y& Elsevier]

Abstract: In order to determine the possible usefulness of stable isotope measurements on calcareous dinoflagellate cysts for paleoceanographic and paleoclimatic studies, we have produced oxygen and carbon isotope records of the species Pirumella krasheninnikovii (Bolli, H.M., 1974. Jurassic and Cretaceous Calcisphaerulidae from DSDP Leg 27, eastern Indian Ocean. Initial Reports of the Deep Sea Drilling Project 27, 843–907.) for the latest Campanian to earliest Maastrichtian (∼ 73–68 Ma) of high-latitude Ocean Drilling Program Hole 690C in the southern South Atlantic (eastern Weddell Sea). Foraminiferal stable isotope values characterize this time interval as a phase of continuous cooling, superimposed by a short-term, strong cooling event between 71 and 70 Ma that was detected at various sites in the mid to high latitudes. This event is interpreted to reflect short-term surface-water cooling, leading to changes in the mode and direction of deep-water formation and possibly the growth of continental ice sheets. Our δ 18O values of calcareous cysts verify this event as well as the general cooling of surface waters during the latest Campanian and early Maastrichtian. Prior to this cooling event, between ∼ 72 and 71 Ma, a negative excursion in accompanying δ 13C records of planktic and benthic foraminifera was observed. This negative excursion and the subsequent positive one were proposed to reflect sea-level fluctuations, changes in productivity, and/or changes in the ratio of organic to inorganic carbon input to the ocean. The δ 13C values of calcareous cysts show the positive excursion between 71 and 70 Ma, but don''t show the expected negative excursion before. In addition, they yield extremely light carbon isotope values that probably resulted from photosynthetic processes. As the stable oxygen isotope data of the calcareous dinoflagellate species P. krasheninnikovii show isotopic shifts comparable to planktic foraminifera from the same locality and from various other sites in the Pacific and South Atlantic oceans, we suggest that calcareous cyst oxygen isotopes can provide information for paleoceanographic reconstructions of sea-surface water temperatures and paleoceanographic changes. However, the application of carbon isotope data from cysts of P. krasheninnikovii appears to be questionable, and investigations of different species are needed to further evaluate the reconstruction potential based on stable isotopes and to assess species-specific vital effects. [Copyright &y& Elsevier]

Abstract: The stable carbon and oxygen isotope composition of different benthic foraminiferal species of the latest Campanian and earliest Maastrichtian from Ocean Drilling Project Hole 690C (Weddell Sea, southern South Atlantic, ∼1800 m paleowater depth) have been investigated. The total range of measured isotope values of all samples exceeds ∼4‰ for δ 13C and 1.1‰ for δ 18O. Carbon isotope values of proposed deep infaunal species are generally similar or only slightly lower when compared to proposed epifaunal to shallow infaunal species. Interspecific differences vary between samples probably reflecting temporal changes in organic carbon fluxes to the sea floor. Constantly lower δ 13C values for Pullenia marssoni and Pullenia reussi suggest the deepest habitat for these species. The strong depletion of δ 13C values by up to 3‰ within lenticulinids may be attributed to a deep infaunal microhabitat, strong vital effects, or different feeding strategy when compared to other species or modern lenticulinids. The mean δ 18O values reveal a strong separation of epifaunal to shallow infaunal and deep infaunal species. Epifaunal to shallow infaunal species are characterized by low δ 18O values, deep infaunal species by higher values. This result possibly reflects lower metabolic rates and longer life cycles of deep infaunal species or the operating of a pore water [CO3 2−] effect on the benthic foraminiferal stable isotopes. Pyramidina szajnochae shows an enrichment of oxygen isotopes with test size comprising a total of 0.6‰ between 250 and 1250 μm shell size. Although δ 13C lacks a corresponding trend these data likely represent the presence of changes in metabolic rates during ontogenesis. These results demonstrate the general applicability of multi-species stable isotope measurements of pristine Cretaceous benthic foraminifera to reconstruct past microhabitats and to evaluate biological and environmental effects on the stable isotope composition. [Copyright &y& Elsevier]

The acidic food vacuole exerts several important functions during intraerythrocytic development of the human malarial parasite Plasmodium falciparum. Hemoglobin taken up from the host erythrocyte is degraded in the food vacuole, and the heme liberated during this process is crystallized to inert hemozoin. Several anti-malarial drugs target food vacuolar pathways, such as hemoglobin degradation and heme crystallization. Resistance and sensitization to some antimalarials is associated with mutations in food vacuolar membrane proteins. Other studies suggest a role of the food vacuole in ion homeostasis, and release of Ca2+ from the food vacuole may mediate adopted physiological responses. To investigate whether the food vacuole is an intracellular Ca2+ store, which in turn may affect other physiological functions in which this organelle partakes, we have investigated total and exchangeable Ca2+ within the parasite's food vacuole using x-ray microanalysis and quantitative confocal live cell Ca2+ imaging. Apparent free Ca2+ concentrations of ∼90, ∼350, and ∼400 nM were found in the host erythrocyte cytosol, the parasite cytoplasm, and the food vacuole, respectively. In our efforts to determine free intracellular Ca2+ concentrations, we evaluated several Ca2+-sensitive fluorochromes in a live cell confocal setting. We found that the ratiometric Ca2+ indicator Fura-Red provides reliable determinations, whereas measurements using the frequently used Fluo-4 are compromised due to problems arising from phototoxicity, photobleaching, and the strong pH dependence of the dye. Our data suggest that the food vacuole contains only moderate amounts of Ca2+, disfavoring a role as a major intracellular Ca2+ store. [ABSTRACT FROM AUTHOR]

A large body of genetic, reverse genetic, and epidemiological data has linked chloroquine-resistant malaria to polymorphisms within a gene termed pfcrt in the human malarial parasite Plasmodium falciparum. To investigate the biological function of the chloroquine resistance transporter, PfCRT, as well as its role in chloroquine resistance, we functionally expressed this protein in Xenopus laevis oocytes. Our data show that PfCRT-expressing oocytes exhibit a depolarized resting membrane potential and a higher intracellular pH compared with control oocytes. Pharmacological and electrophysiological studies link the higher intracellular pH to an enhanced amiloride-sensitive H+ extrusion and the low membrane potential to an activated nonselective cation conductance. The finding that both properties are independent of each other, together with the fact that they are endogenously present in X. laevis oocytes, supports a model in which PfCRT activates transport systems. Our data suggest that PfCRT plays a role as a direct or indirect activator or modulator of other transporters. [ABSTRACT FROM AUTHOR]

We propose that the observed short-term stable isotope fluctuations reflect changes in high- and low-latitude intermediate to deep water sources, based on a high-resolution stable isotope record of planktic and benthic foraminifera from the Early Maastrichtian (∼71.3 to ∼69.6 Ma) of Blake Nose (DSDP Site 390A, North Atlantic). Sources of these waters may have been the low-latitude eastern Tethys and high-latitude North Atlantic. Changes in intermediate to deep water sources were probably steered by eccentricity-controlled insolation fluctuations. Lower insolation favored the formation of high-latitude deep waters due to positive feedback mechanisms resulting in high-latitude cooling. This led to a displacement of low-latitude deep waters at Blake Nose. Higher insolation reduced intermediate to deep-water formation in high latitudes, yielding a more northern flow of low-latitude deep waters. [Copyright &y& Elsevier]

We present paleoceanographic models for the formation of the marlstone facies and the most prominent black shale intervals of the Late Aptian Niveau Fallot black shale succession from the Vocontian Basin (SE France). In the lower part of the succession, the composition of benthic foraminiferal assemblages of the Niveau Fallot 2′ and 2″ black shales suggests an enhanced burial of organic matter due to more eutrophic conditions and resulting low oxygen conditions at the seafloor. In the upper part of the succession (including Niveau Fallot 3 and 4), a third-order sea-level fall, indicated by a decrease in the stable carbon isotope values, may have resulted in a reduced water mass exchange between the Vocontian Basin and the western Tethyan Ocean. This may have led to dysoxic conditions at the seafloor of the Vocontian Basin and may have favored the formation of organic-rich sediments as shown by benthic foraminiferal assemblages. Decreased evaporation, however, is proposed as the most important mechanism causing a restriction of deep water formation within the basin which finally led to the formation of the Niveau Fallot 3 and 4 black shales. Based on our investigations, the formation of the Niveau Fallot black shales was caused by different factors, the most prominent ones include sea-level fluctuations, increasing productivity, and changes in precipitation and evaporation rates. Furthermore, Niveau Fallot 3 can probably be correlated with the Thalmann black shale event in California and a dark horizon at the Mazagan Plateau (DSDP Site 545). [Copyright &y& Elsevier]

Interest in muscle biomechanics is growing with availabilities of patient biopsies and animal models related to muscle diseases, muscle wasting (sarcopenia, cachexia), exercise and drug effects. However, development of technologies or facilitated systems required to measure biomechanical and contractile properties of single fibres has not kept pace with this demand. Most studies use manual mechatronics systems that have not changed in decades and are confined to a few labs worldwide. Available commercial systems are expensive and limited in versatility, throughput and user-friendliness. We review major standard systems available from research labs and commercial sources, and benchmark those to our recently developed automated MyoRobot biomechatronics platform that provides versatility to cover multiple organ scales, is flexible in programming for active/passive muscle biomechanics using custom-made graphics user interfaces, employs on-the-fly data analyses and does not rely on external research microscopes. With higher throughput, this system blends Industry 4.0 automation principles into myology. [ABSTRACT FROM AUTHOR]

Background & Aims Intestinal fibrosis is a long-term complication in inflammatory bowel diseases (IBD) that frequently results in functional damage, bowel obstruction, and surgery. Interleukin (IL) 36 is a group of cytokines in the IL1 family with inflammatory effects. We studied the expression of IL36 and its receptor, interleukin 1 receptor like 2 (IL1RL2 or IL36R) in the development of intestinal fibrosis in human tissues and mice. Methods We obtained intestinal tissues from 92 patients with Crohn's disease (CD), 48 patients with ulcerative colitis, and 26 patients without inflammatory bowel diseases (control individuals). Tissues were analyzed by histology to detect fibrosis and by immunohistochemistry to determine the distribution of fibroblasts and levels of IL36R ligands. Human and mouse fibroblasts were incubated with IL36 or control medium, and transcriptome-wide RNA sequences were analyzed. Mice were given neutralizing antibodies against IL36R, and we studied intestinal tissues from Il1rl2 –/– mice; colitis and fibrosis were induced in mice by repetitive administration of DSS or TNBS. Bone marrow cells were transplanted from Il1rl2 –/– to irradiated wild-type mice and intestinal tissues were analyzed. Antibodies against IL36R were applied to mice with established chronic colitis and fibrosis and intestinal tissues were studied. Results Mucosal and submucosal tissue from patients with CD or ulcerative colitis had higher levels of collagens, including type VI collagen, compared with tissue from control individuals. In tissues from patients with fibrostenotic CD, significantly higher levels of IL36A were noted, which correlated with high numbers of activated fibroblasts that expressed α-smooth muscle actin. IL36R activation of mouse and human fibroblasts resulted in expression of genes that regulate fibrosis and tissue remodeling, as well as expression of collagen type VI. Il1rl2 –/– mice and mice given injections of an antibody against IL36R developed less severe colitis and fibrosis after administration of DSS or TNBS, but bone marrow cells from Il1rl2 –/– mice did not prevent induction of colitis and fibrosis. Injection of antibodies against IL36R significantly reduced established fibrosis in mice with chronic intestinal inflammation. Conclusion We found higher levels of IL36A in fibrotic intestinal tissues from patients with IBD compared with control individuals. IL36 induced expression of genes that regulate fibrogenesis in fibroblasts. Inhibition or knockout of the IL36R gene in mice reduces chronic colitis and intestinal fibrosis. Agents designed to block IL36R signaling could be developed for prevention and treatment of intestinal fibrosis in patients with IBD. [ABSTRACT FROM AUTHOR]

Lacustrine sediments are important archives for paleoclimate reconstructions. The application of grain-size analysis as palaeoclimatic proxy in lacustrine clastics is valuable but also difficult because the typical polymodal grain-size distribution in these clastics. To better understand the grain-size distribution of lacustrine clastics and to promote the application of grain size in paleoenvironmental interpretation, this study investigates lacustrine clastics from northern and southern China. The grain-size distribution of these sediments was decomposed by log-normal distribution function fitting method. Based on the results, and drawing upon the concept of paleomagnetic demagnetization and “Characteristic Remnant Magnetization” from paleomagnetism, a conceptual system has been established and defined for grain-size distribution analysis. The system is composed of four components: (I) Characteristic Grain Size Component (ChGSC), (II) Affiliated Grain Size Component, (III) Meaningful Grain Size Component, and (IV) Combination Feature of Grain Size Components (CFGSCs). Based on the proposed system, ChGSC and CFGSCs were used to detect the grain-size distribution of clastics from the different lake zones investigated. Our results show the number, modal size, and percentage of ChGSC(s) in grain-size distributions are sensitive to changes in the lacustrine environment. The ChGSC(s) mirrors the dominant depositional process and hydrodynamic conditions. The modal size of ChGSC(s) is more sensitive to hydrological conditions than the widely used mean grain-size approach. Thus, the ChGSC(s) provide a useful process-related parameter for paleoenvironmental reconstructions. To test this promising application, we applied this approach to a deep drill core from the Qaidam Basin in the northeastern Tibetan Plateau. [ABSTRACT FROM AUTHOR]

The Oligocene–Miocene transition (OMT; ~ 23.1 Ma) terminates the late Oligocene warming trend and is marked by a transient, large-amplitude expansion of Antarctic ice sheets. The associated glacial maximum, which is expressed by a ~ 1‰ positive shift in benthic foraminiferal oxygen-isotope values, is commonly referred to as the ‘Mi-1 isotope event’. Whereas the causes for the glacial maximum at the OMT are intrinsically connected to Southern Hemisphere ice-sheet dynamics, the behavior of the surface ocean in the Northern Hemisphere during this time is poorly known. To contribute to a better understanding of the paleoceanographic evolution during the OMT in the higher-latitude North Atlantic, we have analysed both marine and terrestrial palynomorphs from Integrated Ocean Drilling Program (IODP) Site U1406 offshore Newfoundland; this site has yielded a complete OMT section and exhibits a high-quality magnetostratigraphy that provides precise age control and allows reliable correlation to other records beyond Newfoundland. Our palynological data, which span the interval from 23.3 to 22.5 Ma and have a mean temporal resolution of 11.9 kyrs, show strong ~ 110-kyr eccentricity-paced oscillations during the earliest Miocene; these oscillations are in phase with similar cyclicity identified in previously published benthic foraminiferal oxygen-isotope records. More specifically, a pronounced sea-level variability is documented by the abundances of neritic dinoflagellate cysts (dinocysts) and terrigenous palynomorphs, which both reach maxima during peak glacial intervals as inferred from previously published South Atlantic benthic oxygen-isotope data. A decline in the abundance of warmer-water dinocysts suggests a surface-water cooling offshore Newfoundland from the latest Oligocene onwards. Surface-water productivity (as derived from the ratio between heterotrophic and autotrophic dinocysts) remained generally low throughout the studied interval. Notably, this ratio does not exhibit any correlation with changes in surface-water temperature, which is estimated from the ratio of warm-water over cold-water dinocysts. Together with the consistently low surface-water productivity, the lack of a correlation between surface-water productivity and temperature makes it highly unlikely that the observed paleoceanographic change was caused by a southward migration of the Arctic Front. Instead, we argue that our data may document an enhanced influence of the (Proto-) Labrador Current on surface waters offshore Newfoundland during the earliest Miocene that suppressed the influence of the Gulf Stream in this region of the Northwest Atlantic. We speculate that the enhanced influence of the (Proto-) Labrador Current was triggered by cooling of the northern hemisphere and possibly modulated by high-latitude sea-ice expansion. [ABSTRACT FROM AUTHOR]

The Mid-Pleistocene Transition (MPT) is arguably the most prominent shift in the Earth's climate system during the entire Pleistocene. It is characterized by a shift from a ∼ 40 kyr to a ∼ 100 kyr glacial cyclicity, going in hand with considerable growth of glacial continental ice-sheets. In search for potential drivers of these changes in the cryosphere, a slow-down of deep ocean circulation has been proposed as an important factor that might have reduced the atmospheric pCO 2 level and thus created boundary conditions favourable for pertaining large ice-sheets. Additionally, as argued for the Last Glacial Maximum, enhanced production of intermediate waters might enhance intermediate to deep oceanic stratification and thus suppress CO 2 release from the deep ocean and thereby reduce atmospheric greenhouse gas concentrations. To investigate potential changes in the North Atlantic intermediate water-mass configuration across the MPT we utilize δ18O and δ13C records obtained on the deep thermocline-dwelling foraminifera Globorotalia crassaformis from mid-latitude International Ocean Discovery Program (IODP) Site U1313. In conjunction with benthic and planktic δ18O and δ13C data from reference sites for Labrador Sea Water (IODP Site U1305) and intermediate water formation in the north-eastern North Atlantic (Ocean Drilling Program Site 982) our data show that major changes in the production and dispersal of intermediate water masses took place across the MPT. In particular, we note a shoaling of glacial intermediate waters commencing with Marine Isotope Stage (MIS) 22, which we interpret as the first occurrence of Glacial North Atlantic Intermediate Water, a prominent constituent of Late Pleistocene glacial water masses in the Atlantic Ocean. We further infer that the amount and vertical position of the warm and saline Mediterranean Outflow Water (MOW) had a major impact on the spatial configuration of North Atlantic intermediate water masses during the MPT, due to its capacity to modulate subsurface heat transport and isopycnal configuration. Our new findings thus provide evidence for a so far underestimated role of intermediate water circulation in shaping oceanic and potentially atmospheric changes during the MPT. • Benthic and planktic δ18O and δ13C as tracers for water-mass geometry. • Shoaling of glacial intermediate overturning cell during the mid-Pleistocene Transition. • Potential impact of intermediate circulation on atmospheric p CO 2 budget. [ABSTRACT FROM AUTHOR]

Human pluripotent embryonal carcinoma (NT2) cells are increasingly considered as a suitable model for in vitro toxicity testing, e.g. developmental toxicity and neurotoxicity (DT/DNT) studies, as they undergo neuronal differentiation upon stimulation with retinoic acid (RA) and permit toxicity testing at different stages of maturation. NT2 cells have recently been reported to show specific changes in dielectric resistance profiles during differentiation which can be observed as early as 24 h upon RA-stimulation. These observations suggest altered susceptibility to chemicals at an early stage of differentiation. However, chemical susceptibility of early differentiating NT cells has not yet been studied. To address this question, we have established a cell fitness screening assay based on the analysis of intracellular ATP levels and we applied the assay in a large-scale drug screening experiment in NT2 stem cells and early differentiating NT2 cells. Subsequent analysis of ranked fitness phenotypes revealed 19 chemicals with differential toxicity profile in early differentiating NT2 cells. To evaluate whether any of the identified drugs have previously been associated with DT/DNT, we conducted a literature search on the identified molecules and quantified the fraction of chemicals assigned to the FDA (Food and Drug Administration) pregnancy risk categories (PRC) N, A, B, C, D, and X in the hit list and the small molecule library. While the fractions of the categories N and B were decreased (0.81 and 0.35-fold), the classes C, D and X were increased (1.35, 1.47 and 3.27-fold) in the hit list compared to the chemical library. From these data as well as from the literature review, identifying large fractions of chemicals being directly (∼42%) and indirectly associated with DT/DNT (∼32%), we conclude that our method may be beneficial to systematic in vitro-based primary screening for developmental toxicants and neurotoxicants and we propose cell fitness screening in early differentiating NT2 cells as a strategy for evaluating chemical susceptibility at different stages of differentiation to reduce animal testing in the context of the 3Rs. [ABSTRACT FROM AUTHOR]

Abstract: Duchenne muscular dystrophy is an inherited degenerative muscle disease with progressive weakness of skeletal and cardiac muscle. Disturbed calcium homeostasis and signalling pathways result in degeneration/regeneration cycles with fibrotic remodelling of muscle tissue, sustained by chronic inflammation. In addition to altered microarchitecture, regeneration in dystrophic muscle fibres is often only classified by centrally located nuclei but correlation of the regeneration process to nuclear volumes, myosin amounts, architecture and functional quality are missing, in particular in old muscles where the regenerative capacity is exhausted. Such information could yield novel regeneration-to-function biomarkers. Here we used second harmonic generation and multi photon fluorescence microscopy in intact single muscle fibres from wild-type, dystrophic mdx and transgenic mdx mice expressing an Δex 17–48 mini-dystrophin to determine the percentage of centronucleated fibres and nucleus-to-myosin volume ratio as a function of age. Based on this ratio we define a ‘biomotoric efficiency’ as an optical measure for fibre maturation, which is close to unity in adult wild-type and mini-dystrophin fibres, but smaller in very young and old mdx mice as a result of ongoing cell maturation (young) and regeneration (aged). With these parameters it is possible to provide a quantitative measure about muscle fibre regeneration. [Copyright &y& Elsevier]

Abstract: The evolution of global ocean circulation toward deep-water production in the high southern latitudes is thought to have been closely linked to the transition from extreme mid-Cretaceous warmth to the cooler Cenozoic climate. The relative influences of climate cooling and the opening and closure of oceanic gateways on the mode of deep-ocean circulation are, however, still unresolved. Here we reconstruct intermediate- to deep-water circulation for the latest Cretaceous based on new high-resolution radiogenic neodymium (Nd) isotope data from several sites and for different water depths in the South Atlantic, Southern Ocean, and proto-Indian Ocean. Our data document the presence of markedly different intermediate water Nd-isotopic compositions in the South Atlantic and Southern Ocean. In particular, a water mass with a highly radiogenic Nd isotope signature most likely originating from intense hotspot-related volcanic activity bathed the crest of Walvis Ridge between 71 and 69Ma, which formed a barrier that prevented deep-water exchange between the Southern Ocean and the North Atlantic basins. We suggest that the Cenozoic mode of global deep-ocean circulation was still suppressed by tectonic barriers in the latest Cretaceous, and that numerous, mostly regionally-formed and sourced intermediate to deep waters supplied the deep ocean prior to 68millionyr ago. [Copyright &y& Elsevier]

Abstract: In addition to Oceanic Anoxic Event 2 (OAE2), other perturbations of the carbon cycle occurred during the Cenomanian and Turonian, of which the Middle Cenomanian Event (MCE) is the most prominent one. In palaeoecological publications, however, this event is strongly underrepresented in contrast to the well-studied OAE2. In order to fill this gap, we have studied Early Cenomanian to Late Turonian calcareous nannofossil and benthic foraminiferal assemblages of Ocean Drilling Program Site 1260 at Demerara Rise (western equatorial North Atlantic), in order to decipher biotic changes throughout this interval and especially across the MCE. Our data show distinctive changes in the relative abundance of certain calcareous nannofossil taxa and a drastic decrease in benthic foraminiferal diversities and abundances associated with the MCE. In the lower part of the studied section and prior to the MCE, a mixed water-column with high nutrient availability in the upper photic zone is suggested based on very high relative abundances of the mesotrophic/eutrophic nannofossil species Biscutum constans. Around the MCE interval, certain nannofossil taxa (e.g., Rhagodiscus asper) show a distinctive decrease in relative abundance while others become more dominant. Taxa which increase in relative abundance after the MCE (e.g., Eprolithus floralis) are interpreted as either having favoured less eutrophic surface-waters or having inhabited deeper parts of the photic zone in a well stratified water-column. This interpretation is supported by published oxygen isotope and TEX86 data, which suggest increased water-column stratification starting with the MCE and lasting to the end of the Cenomanian stage, as a result of the implementation of a saline intermediate- to deep-water mass during this interval. Our study shows that the MCE was a significant biotic event in the Cenomanian/Turonian equatorial Atlantic, characterised by a lasting change of surface- and bottom-water ecosystems. [Copyright &y& Elsevier]

High-resolution carbon isotope stratigraphy is established for the Aptian to Lower Albian of the Vocontian Basin (SE France), and correlated to the carbon isotope record of the Mazagan Plateau (DSDP Site 545). The carbon isotope stratigraphy of the Vocontian Basin is proposed as a standard reference curve for the Aptian to Lower Albian, due to the completeness and high temporal resolution of the stratigraphic succession, the good biostratigraphical time control, and the frequent occurrence of regional to global black shale horizons including Oceanic Anoxic Events 1a (OAE 1a) of the Lower Aptian and OAE 1b of the Lower Albian. The carbon isotope record appears better suited for long-distance short-term correlation of different marine and terrestrial environments than biostratigraphy because of the synchroneity of carbon isotope signals in a range of sediment types. However, the combination of both biostratigraphy and carbon isotope stratigraphy provides an effective tool to reconstruct biotic change and paleoceanography, and to correlate regional to global black shale horizons in different marine environments. This combined approach allows us to ascertain the synchroneities or diachroneities of first and last appearances of biostratigraphic marker species. Based on the demonstrated diachroneity of important biostratigraphic markers of the Aptian/Albian boundary, the globally observed break point between the end of the uppermost Aptian positive carbon isotope excursion and the onset of the pronounced negative shift of δ13C values, is an alternative criterion. The distinctive structure and amplitudes of the carbon isotope record are observed in both the inorganic and organic carbon and can therefore be recognized in all marine and terrestrial environments of the Aptian to Lower Albian. [Copyright &y& Elsevier]

Calcareous nannoplankton, palynomorph, benthic foraminifera, and oxygen isotope records from the supraregionally distributed Niveau Paquier (Early Albian age, Oceanic Anoxic Event 1b) and regionally distributed Niveau Kilian (Late Aptian age) black shales in the Vocontian Basin (SE France) exhibit variations that reflect paleoclimatic and paleoceanographic changes in the mid-Cretaceous low latitudes. To quantify surface water productivity and temperature changes, nutrient and temperature indices based on calcareous nannofossils were developed. The nutrient index strongly varies in the precessional band, whereas variations of the temperature index reflect eccentricity. Since polar ice caps were not present during the mid-Cretaceous, these variations probably result from feedback mechanisms within a monsoonal climate system of the mid-Cretaceous low latitudes involving warm/humid and cool/dry cycles. A model is proposed that explains the formation of mid-Cretaceous black shales through monsoonally driven changes in temperature and evaporation/precipitation patterns. The Lower Albian Niveau Paquier, which has a supraregional distribution, formed under extremely warm and humid conditions when monsoonal intensity was strongest. Bottom water ventilation in the Vocontian Basin was diminished, probably due to increased precipitation and reduced evaporation in regions of deep water formation at low latitudes. Surface water productivity in the Vocontian Basin was controlled by the strength of monsoonal winds. The Upper Aptian Niveau Kilian, which has a regional distribution only, formed under a less warm and humid climate than the Niveau Paquier. Low-latitude deep water formation was reduced to a lesser extent and/or on regional scale only. The threshold for the formation of a supraregional black shale was not reached. The intensity of increases in temperature and humidity controlled whether black shales developed on a regional or supraregional scale. At least in the Vocontian Basin, the increased preservation of organic matter at the sea floor was more significant in black shale formation than the role of enhanced productivity. [Copyright &y& Elsevier]

The transformation of electrical signals into mechanical action of the heart underlying blood circulation results in mechanical stimuli during active contraction or passive filling distention, which conversely modulate electrical signals. This feedback mechanism is known as cardiac mechano-electric coupling (MEC). The cardiac MEC involves complex activation of mechanical biosensors initiating short-term and long-term effects through Ca2+ signals in cardiomyocytes in acute and chronic pressure overload scenarios (e.g. cardiac hypertrophy). Although it is largely still unknown how mechanical forces alter cardiac function at the molecular level, mechanosensitive channels, including the recently discovered family of Piezo channels, have been thought to play a major role in the cardiac MEC and are also suspected to contribute to development of cardiac hypertrophy and heart failure. The earliest reports of mechanosensitive channel activity recognized that their gating could be controlled by membrane stretch. In this article, we provide an overview of the stretch devices, which have been employed for studies of the effects of mechanical stimuli on muscle and heart cells. We also describe novel experiments examining the activity of Piezo1 channels under multiaxial stretch applied using polydimethylsiloxane (PDMS) stretch chambers and IsoStretcher technology to achieve isotropic stretching stimulation to cultured HL-1 cardiac muscle cells which express an appreciable amount of Piezo1. [ABSTRACT FROM AUTHOR]

To reconstruct the timing and underlying forcing of major shifts in the composition of terrestrial ecosystems in arid Central Asia during the late Cenozoic (past ~7 Ma), we carry out palynological analysis of lake sediments from the Qaidam Basin (NE Tibetan Plateau, China). Our results show that the steppe/semi-desert biomes dominating the Qaidam Basin experienced marked turnovers at ~3.6 and 3.3 Ma. Most notably, the younger of these turnover events is characterized by a two- to three-fold expansion of Artemisia at the expense of other steppe/semi-desert taxa. This turnover event led to the replacement of the Ephedraceae/Chenopodiaceae-dominated and Nitraria -rich steppe/semi-deserts that were dominant in the Qaidam Basin during the Paleogene and abundant during the Miocene by Artemisia /Chenopodiaceae-dominated steppe/semi-deserts as they exist until today. The vegetation turnover events are synchronous with shifts towards drier conditions in Central Asia as documented in climate records from the Chinese Loess Plateau and the Central North Pacific Ocean. On a global scale, they can be correlated to early glaciation events in the Northern Hemisphere during the Pliocene. Integration of our palynological data from the Qaidam Basin with Northern Hemisphere climate-proxy and regional-scale tectonic information suggests that the uplift of the Tibetan Plateau posed ecological pressure on Central Asian plant communities, which made them susceptible to the effects of early Northern Hemisphere glaciations during the late Pliocene. Although these glaciations were relatively small in comparison to their Pleistocene counterparts, the transition towards drier/colder conditions pushed previously existing plant communities beyond their tolerance limits, thereby causing a fundamental reorganization of arid ecosystems. The Artemisia dominance since ~3.3 Ma resulting from this reorganization marks a point in time after which the Artemisia /Chenopodiaceae pollen ratio can serve as a reliable indicator for moisture availability in Central Asia. • Major shifts in vegetation composition in the Qaidam Basin at ~3.6 and ~3.3 Ma. • Expansion of Artemisia /Chenopodiaceae-dominated semi-deserts in the late Pliocene. • Late Pliocene glaciations caused reorganization of arid ecosystems in Central Asia. • The A/C ratio can be applied as an indicator for moisture change from 3.3 Ma onwards. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Severe malaria and viral infections cause life-threatening diseases in millions of people worldwide every year. In search for effective bioactive hybrid molecules, which may possess improved properties compared to their parent compounds, a series of betulinic acid/betulin based dimer and hybrid compounds carrying ferrocene and/or artesunic acid moieties, was designed and, synthesized de novo. Furthermore, they were analyzed in vitro against malaria parasites (growth inhibition of 3D7-strain P. falciparum-infected erythrocytes) and human cytomegalovirus (HCMV). From this series of hybrids/dimers, the betulinic acid/betulin and artesunic acid hybrids 11 and 12 showed the most potent activities against P. falciparum and HCMV. On the strength of results, additive and/or synergistic effects between the natural or semisynthetic products, such as betulinic acid-/betulin- and artesunic acid-derived compounds, are suggested on the basis of putatively complex modes of antimicrobial action. This advantage may be taken into account in future drug development. [ABSTRACT FROM AUTHOR]

Hybridization of natural products has high potential to further improve their activities and may produce synergistic effects between linked pharmacophores. Here we report synthesis of nine new hybrids of natural products egonol, homoegonol, thymoquinone and artemisinin and evaluation of their activities against P. falciparum 3D7 parasites, human cytomegalovirus, sensitive and multidrug-resistant human leukemia cells. Most of the new hybrids exceed their parent compounds in antimalarial, antiviral and antileukemia activities and in some cases show higher in vitro efficacy than clinically used reference drugs chloroquine, ganciclovir and doxorubicin. Combined, our findings stress the high potency of these hybrids and encourages further use of the hybridization concept in applied pharmacological research. [ABSTRACT FROM AUTHOR]

Time-of-flight (TOF) magnetic sensing of rolling immunomagnetically-labeled cells offers great potential for single cell function analysis at the bedside in even optically opaque media, such as whole blood. However, due to the spatial resolution of the sensor and the low flow rate regime required to observe the behavior of rolling cells, the concentration range of such a workflow is limited. Potential clinical applications, such as testing of leukocyte function, require a cytometer which can cover a cell concentration range of several orders of magnitude. This is a challenging task for an integrated dilution-free workflow, as for high cell concentrations coincidences need to be avoided, while for low cell concentrations sufficient statistics should be provided in a reasonable time-to-result. Here, we extend the spatial bandwidth of a magnetoresistive sensor with an adaptive and integratable workflow concept combining mechanical and magnetophoretic guiding of magnetically labeled targets for in-situ enrichment over a dynamic concentration range of 3 orders of magnitude. We achieve hybrid integration of the enrichment strategy in a cartridge mold and a giant-magnetoresistance (GMR) sensor in a functionalized Quad Flat No-Lead (QFN) package, which allows for miniaturization of the Si footprint for potential low-cost bedside testing. The enrichment results demonstrate that TOF magnetic flow cytometry with adaptive particle focusing can match the clinical requirements for a point-of-care (POC) cytometer and can potentially be of interest for other sheath-less methodologies requiring workflow integration. [ABSTRACT FROM AUTHOR]