The Alps Paleoelevation and Paleoclimate Experiment: Reconstructing Eastward Propagation of Surface Uplift in the ALps (REAL)

Geological observations, geodynamic models, and seismic studies suggest Neogene eastward propagating surface uplift of the European Alps. Whereas 4DMB Phase I project APE focused on reconstructing surface uplift of the Central Alps, 4DMB Phase II project REAL aims at testing the predicted west-to-east surface uplift of the Alps by combining stable isotope paleoaltimetry and paleoclimate modeling. Stable isotope paleoaltimetry is based on the inverse relationship between elevation and the stable isotopic composition of meteoric water and provides a tool to reconstruct the elevation of mountain belts in the geological past. First, REAL explores applications of the δ-δ method (see Poster Phase I APE), which requires that various recorders of past rainfall are available in the rock record: soil carbonates from low-elevation (foreland) basins and hydrous minerals from high-elevation fault gouges/shear zones. Paleoelevation estimates are obtained by contrasting time-equivalent low- and high-elevation proxy data sets, provided that the isotopic composition of the fluids during mineral formation is estimated accurately. Whereas formation temperatures of fault gouge minerals (such as illite and syntectonic micas) can be readily estimated, we apply clumped isotope paleothermometry to provide robust estimates of meteoric water δ18O from the low-elevation foreland basin carbonate record. Second, meteoric water δ18O values are not only sensitive to local elevation, but also to the complex climatic changes resulting from different paleoenvironmental boundary conditions and regional topographic configuration. To isolate the contribution of each of these components δ-δ stable isotope paleoaltimetry is applied in combination with ECHAM5-wiso paleoclimate simulations for a number of topographic scenarios of diachronous surface uplift. This unique combination allows for the removal of climate change effects on the stable isotope data, and therefore improves the accuracy of paleoelevation reconstructions. Results from our ongoing Phase II project (spring 2021 - spring 2024): 1. Reveal that diachronous surface uplift would produce patterns of climate, δ18O in precipitation values, and isotopic lapse rates that are distinctly different from those of today and those produced by bulk surface uplift scenarios. Importantly, this signal would be detectable in stable isotope paleoaltimetry results (Boateng et al., in revision). 2. Present a Miocene (23–13 Ma) continental paleotemperature record from the northern Mediterranean region (Digne-Valensole basin, SE France), which indicates near-constant temperatures from 23.0-18.8 Ma, followed by a highly variable and warm climate during the Middle Miocene and rapid cooling after 14 Ma (Ballian et al., 2023). 3. Together with new and existing paleotemperature records, preliminary results of the δ-δ method show for the first time that (a) the Central Alps were already high during the Early Miocene and (b) the Eastern Alps were appreciably lower than the Central Alps during the Middle Miocene (Ballian et al., 2022)

Expression of Rb2/p130 in breast and endometrial cancer: correlations with hormone receptor status

Rb2/p130 is a member of the retinoblastoma family of proteins, consisting of Rb, Rb2 and p107, which are important negative regulators of cell cycle progression and differentiation. While Rb2 downregulation was observed in several malignant tumours including endometrial cancer, the role of p130 in breast carcinomas is still unknown. We investigated Rb2 protein expression in tumour tissue from 68 mammary and 41 endometrial carcinomas, 4 mammary cell lines, and normal tissue samples. Therefore, we performed Western blot experiments for Rb2, Rb, and the oestrogen and progesterone receptors (ER, PR-A, PR-B). Weak or absent Rb2 expression was more often found in endometrial (59%) than in mammary carcinomas (24%). We found significant positive correlations of Rb2 expression with Rb, ER, and PR-B in breast cancer samples, and of Rb2 with Rb, PR-A, PR-B, and younger age in endometrial carcinomas. No significant associations with histological grading, stage, nodal involvement, or Ki67 staining were detected. Rb2 mRNA expression was studied by semi-quantitative RT-PCR in 56 endometrial or mammary tissue samples and correlated significantly with Western blot results. Our results indicate that loss of Rb2 expression, mostly by transcriptional down-regulation, may be associated with the development and dedifferentiation of most endometrial and a subset of mammary carcinomas. © 2001 Cancer Research Campaign http://bjcancer.co

Synergistic effects of diachronous surface uplift and global climate change on the isotopic composition of meteoric waters: implications on paleoelevation estimates across the European Alps

Stable isotope paleoaltimetry is widely used to infer past elevations of orogens due to the robust systematic inverse relationships between elevation and oxygen (δ18O) and hydrogen (δD) isotopic composition of meteoric waters recorded in geologic archives, such as paleosol carbonates or hydrous silicates. This δ18O-elevation relationship (or isotopic lapse rate) is commonly attributed to the preferential rainout of heavy water isotopologues from air masses ascending over topography. However, numerous non-linear climatic processes, such as surface recycling, vapor mixing, variability in moisture source, and precipitation dynamics, can also influence the isotopic lapse rate and thus complicate stable isotope paleoaltimetry estimates. This highlights the need for a better quantitative understanding of topographic and regional climatic effects on the isotopic composition of ancient waters. Through topographic sensitivity experiments, Boateng et al. (2023) suggested plausible changes in isotopic lapse rates across the Alps in response to different diachronous surface uplift scenarios and validated that the expected isotopic signal difference due to elevation changes is significant enough to be reflected in geologic archives. Recent paleoelevation reconstructions across the Alps estimate the mean elevation of >4000 m in the Central Alps during the Middle Miocene (Krsnik et al., 2021). These high elevation estimates have been attributed to the complicated transition from pre- to mid-Miocene Central Alps with a diverse landscape and a complex topography, mainly driven by the rapid exhumation of deep-seated core complexes, followed by a rearrangement of the drainage system. However, the paleoelevation estimate is based on the assumptions that the isotopic lapse rate (1) is similar to the modern lapse rate (~2.0 ‰/km), which is lower than the global average, (2) did not change during the deposition of the paleoaltimetry proxies compared to the present day, and (3) remained constant across the entire Alps. Here, we use a high-resolution isotope-tracking ECHAM5-wiso General Circulation Model to simulate the Middle Miocene climate and δ18Op responses to different surface uplift scenarios of the Alps. More specifically, we performed topographic sensitivity experiments by varying the height of the Western/Central Alps and Eastern Alps under two atmospheric CO2 concentration scenarios for Middle Miocene paleoenvironmental conditions. The simulated δ18Op values are consistent with the proxy reconstructions across the low- and high-elevation sites in the Alps. The topographic scenarios indicated δ18Op values differences of up to -10 ‰ between the low- and high-elevation sites, primarily due to changes in orographic precipitation and local near-surface temperature. Even though the differences across the low-elevation sites showed minor changes compared to the present-day climate, the high-elevation sites indicated significant changes mainly due to differences in moisture transport and moisture redistribution. These changes resulted in different isotopic lapse rates across the different transects around the Alps, contradicting the assumption of a regionally similar isotopic lapse rate. Using the simulated Middle Miocene isotopic lapse rates with the reconstructed Δδ18Op signal between the low-elevation Northern Alpine Foreland Basin and high-elevation Simplon fault gouge reveals an overestimation of paleoelevation estimates by 2 km when compared to the constant isotopic lapse rate of -2.0 ‰/km across the Alps. These uncertainty estimates are an improvement of the previous paleoelevation reconstruction across the Alps and support the integration of paleoaltimetry and paleoclimate modelling to reconstruct past surface elevations accurately

The effects of diachronous surface uplift of the European Alps on regional climate and the oxygen isotopic composition of precipitation

The European Alps are hypothesized to have experienced diachronous surface uplift in response to post-collisional processes such as, e.g., slab break-off. Therefore, understanding the geodynamic and geomorphic evolution of the Alps requires knowledge of its surface uplift history. This study presents the simulated response of regional climate and oxygen isotopic composition of precipitation (&delta;18Op) to different along-strike topographic evolution scenarios. These responses are modeled to determine if diachronous surface uplift in the Western and Eastern Alps would produce &delta;18Op signals in the geologic record that are sufficiently large and distinct for stable isotope paleoaltimetry. This is tested with a series of sensitivity experiments conducted with the water isotope tracking atmospheric General Circulation Model (GCM) ECHAM5-wiso. The topographic scenarios are created from the variation of two free parameters, (1) the elevation of the West-Central Alps and (2) the elevation of the Eastern Alps. Results suggest significant changes in the spatial patterns of &delta;18Op, the elevation-dependent rate of change in &delta;18Op (&ldquo;isotopic lapse rate&rdquo;), near-surface temperatures, precipitation amounts, and atmospheric circulation patterns in response to the different scenarios. The predictions for the diachronous surface uplift experiments are distinctly different from simulations forced with present-day topography and for simulations where the entire Alps experience synchronous surface uplift. Topographic scenarios with higher elevations in the West-Central Alps produce higher magnitude changes and an expansion of the affected geographical domain surrounding the Alps when compared to present-day topography. Furthermore, differences in &delta;18Op values of up to &minus;2 to &minus;8 &permil; are predicted along the strike of the Alps for the diachronous uplift scenarios, suggesting that the signal can be preserved and measured in geologic archives. Lastly, the results highlight the importance of sampling far-field and low-elevation sites using the &delta;-&delta; paleoaltimetry approach to discern between different surface uplift histories.</p

The transmembrane Bax inhibitor motif (TMBIM) containing protein family: Tissue expression, intracellular localization and effects on the ER CA2+-filling state

AbstractBax inhibitor-1 (BI-1) is an evolutionarily conserved pH-dependent Ca2+ leak channel in the endoplasmic reticulum and the founding member of a family of six highly hydrophobic mammalian proteins named transmembrane BAX inhibitor motif containing (TMBIM) 1-6 with BI-1 being TMBIM6. Here we compared the structure, subcellular localization, tissue expression and the effect on the cellular Ca2+ homeostasis of all family members side by side. We found that all TMBIM proteins possess the di-aspartyl pH sensor responsible for pH sensing identified in TMBIM6 and its bacterial homologue BsYetJ. TMBIM1-3 and TMBIM4-6 represent two phylogenetically distinct groups that are localized in the Golgi apparatus (TMBIM1-3), endoplasmic reticulum (TMBIM4-6) or mitochondria (TMBIM5) but share a common structure of at least seven transmembrane domains with the last domain being semi-hydrophobic. TMBIM1 is mainly expressed in muscle, TMBIM2 and 3 in the nervous system, TMBIM4 and 5 are ubiquitously expressed and TMBIM6 in skeletal muscle, kidney, liver and spleen. All TMBIM proteins reduce the Ca2+ content of the endoplasmic reticulum, and all but TMBIM5 also reduce the cytosolic resting Ca2+ concentration. These results suggest that the TMBIM family has comparable functions in the maintenance of intracellular Ca2+ homeostasis in a wide variety of tissues. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. Guest Editors: Jacques Haiech, Claus Heizmann and Joachim Krebs

The effects of diachronous surface uplift of the European Alps on regional climate and the oxygen isotopic composition of precipitation

This study presents the simulated response of regional climate and the oxygen isotopic composition of precipitation (δ18Op) to different along-strike topographic evolution scenarios. These simulations are conducted to determine if the previously hypothesized diachronous surface uplift in the Western and Eastern Alps would produce δ18Op signals in the geologic record that are sufficiently large and distinct to be detected using stable isotope paleoaltimetry. We present a series of topographic sensitivity experiments conducted with the water-isotope-tracking atmospheric general circulation model (GCM) ECHAM5-wiso. The topographic scenarios are created from the variation of two free parameters, (1) the elevation of the Western–Central Alps and (2) the elevation of the Eastern Alps. The results indicate Δδ18Op values (i.e., the difference between δ18Op values at the low- and high-elevation sites) of up to −8 ‰ along the strike of the Alps for the diachronous uplift scenarios, primarily due to changes in orographic precipitation and adiabatic lapse rate driven localized changes in near-surface variables. These simulated magnitudes of Δδ18Op values suggest that the expected isotopic signal would be significant enough to be preserved and measured in geologic archives. Moreover, the simulated slight δ18Op differences of 1 ‰–2 ‰ across the low-elevation sites support the use of the δ–δ paleoaltimetry approach and highlight the importance of sampling far-field low-elevation sites to differentiate between the different surface uplift scenarios. The elevation-dependent rate of change in δ18Op (“isotopic lapse rate”) varies depending on the topographic configuration and the extent of the surface uplift. Most of the changes are significant (e.g., −1.04 ‰ km−1 change with slope error of ±0.09 ‰ km−1), while others were within the range of the statistical uncertainties (e.g., −0.15 ‰ km−1 change with slope error of ±0.13 ‰ km−1). The results also highlight the plausible changes in atmospheric circulation patterns and associated changes in moisture transport pathways in response to changes in the topography of the Alps. These large-scale atmospheric dynamics changes can complicate the underlying assumption of stable isotope paleoaltimetry and therefore require integration with paleoclimate modeling to ensure accurate reconstruction of the paleoelevation of the Alps

Middle Miocene Climate and Stable Oxygen Isotopes in Europe Based on Numerical Modeling

The Middle Miocene (15.99–11.65 Ma) of Europe witnessed major climatic, environmental, and vegetational change, yet we are lacking detailed reconstructions of Middle Miocene temperature and precipitation patterns over Europe. Here, we use a high-resolution (∼0.75°) isotope-enabled general circulation model (ECHAM5-wiso) with time-specific boundary conditions to investigate changes in temperature, precipitation, and δ18O in precipitation (δ18Op). Experiments were designed with variable elevation configurations of the European Alps and different atmospheric CO2 levels to examine the influence of Alpine elevation and global climate forcing on regional climate and δ18Op patterns. Modeling results are in agreement with available paleobotanical temperature data and with low-resolution Middle Miocene experiments of the Miocene Model Intercomparison Project (MioMIP1). However, simulated precipitation rates are 300–500 mm/yr lower in the Middle Miocene than for pre-industrial times for central Europe. This result is consistent with precipitation estimates from herpetological fossil assemblages, but contradicts precipitation estimates from paleobotanical data. We attribute the Middle Miocene precipitation change in Europe to shifts in large-scale pressure patterns in the North Atlantic and over Europe and associated changes in wind direction and humidity. We suggest that global climate forcing contributed to a maximum δ18Op change of ∼2‰ over high elevation (Alps) and ∼1‰ over low elevation regions. In contrast, we observe a maximum modeled δ18Op decrease of 8‰ across the Alpine orogen due to Alpine topography. However, the elevation-δ18Op lapse rate shallows in the Middle Miocene, leading to a possible underestimation of paleotopography when using present-day δ18Op—elevation relationships data for stable isotope paleoaltimetry studies

A Case of Relapsing-Remitting Neuroborreliosis? Challenges in the Differential Diagnosis of Recurrent Myelitis

We report the case of a 31-year-old woman with 4 episodes of myelitis with pleocytosis, a positive Borrelia burgdorferi serology with positive antibody indices, and full recovery each time after antibiotic and steroid treatment, suggesting neuroborreliosis. We nevertheless believe that recurrent neuroborreliosis is improbable based on the levels of the chemokine CXCL13 in cerebrospinal fluid and favor the diagnosis of post-infectious autoimmune-mediated transverse myelitis possibly triggered by an initial neuroborreliosis as the cause of the relapses observed in our patient. We demonstrate the diagnostic steps and procedures which were important in the differential diagnosis of this unusual and challenging case

Using exomarkers to assess mitochondrial reactive species in vivo

Background: The ability to measure the concentrations of small damaging and signalling molecules such as reactive oxygen species (ROS) in vivo is essential to understanding their biological roles. While a range of methods can be applied to in vitro systems, measuring the levels and relative changes in reactive species in vivo is challenging. Scope of review: One approach towards achieving this goal is the use of exomarkers. In this, exogenous probe compounds are administered to the intact organism and are then transformed by the reactive molecules in vivo to produce a diagnostic exomarker. The exomarker and the precursor probe can be analysed ex vivo to infer the identity and amounts of the reactive species present in vivo. This is akin to the measurement of biomarkers produced by the interaction of reactive species with endogenous biomolecules. Major conclusions and general significance: Our laboratories have developed mitochondria-targeted probes that generate exomarkers that can be analysed ex vivo by mass spectrometry to assess levels of reactive species within mitochondria in vivo. We have used one of these compounds, MitoB, to infer the levels of mitochondrial hydrogen peroxide within flies and mice. Here we describe the development of MitoB and expand on this example to discuss how better probes and exomarkers can be developed. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. Abbreviations: EPR, electron paramagnetic resonance; GFP, green fluorescent protein; 4-HNE, 4-hydroxynonenal; MitoB, 3-(dihydroxyboronyl)benzyltriphenylphosphonium bromide; MitoP, (3-hydroxybenzyl)triphenylphosphonium bromide; ROS, reactive oxygen species; SOD, superoxide dismutase; TPMP, methyltriphenylphosphonium; TPP, triphenylphosphonium catio

Identification and quantification of protein S-nitrosation by nitrite in the mouse heart during ischemia.

Nitrate (NO3-) and nitrite (NO2-) are known to be cardioprotective and to alter energy metabolism in vivo NO3- action results from its conversion to NO2- by salivary bacteria, but the mechanism(s) by which NO2- affects metabolism remains obscure. NO2- may act by S-nitrosating protein thiols, thereby altering protein activity. But how this occurs, and the functional importance of S-nitrosation sites across the mammalian proteome, remain largely uncharacterized. Here we analyzed protein thiols within mouse hearts in vivo using quantitative proteomics to determine S-nitrosation site occupancy. We extended the thiol-redox proteomic technique, isotope-coded affinity tag labeling, to quantify the extent of NO2--dependent S-nitrosation of proteins thiols in vivo Using this approach, called SNOxICAT (S-nitrosothiol redox isotope-coded affinity tag), we found that exposure to NO2- under normoxic conditions or exposure to ischemia alone results in minimal S-nitrosation of protein thiols. However, exposure to NO2- in conjunction with ischemia led to extensive S-nitrosation of protein thiols across all cellular compartments. Several mitochondrial protein thiols exposed to the mitochondrial matrix were selectively S-nitrosated under these conditions, potentially contributing to the beneficial effects of NO2- on mitochondrial metabolism. The permeability of the mitochondrial inner membrane to HNO2, but not to NO2-, combined with the lack of S-nitrosation during anoxia alone or by NO2- during normoxia places constraints on how S-nitrosation occurs in vivo and on its mechanisms of cardioprotection and modulation of energy metabolism. Quantifying S-nitrosated protein thiols now allows determination of modified cysteines across the proteome and identification of those most likely responsible for the functional consequences of NO2- exposure