Modelling global-scale climate impacts of the late Miocene Messinian Salinity Crisis

Late Miocene tectonic changes in Mediterranean–Atlantic connectivity and climatic changes caused Mediterranean salinity to fluctuate dramatically, including a ten-fold increase and near-freshening. Recent proxy- and model-based evidence suggests that at times during this Messinian Salinity Crisis (MSC, 5.96–5.33 Ma), highly saline and highly fresh Mediterranean water flowed into the North Atlantic Ocean, whilst at others, no Mediterranean Outflow Water (MOW) reached the Atlantic. By running extreme, sensitivity-type experiments with a fully coupled ocean–atmosphere general circulation model, we investigate the potential of these various MSC MOW scenarios to impact global-scale climate. The simulations suggest that although the effect remains relatively small, MOW had a greater influence on North Atlantic Ocean circulation and climate than it does today. We also find that depending on the presence, strength and salinity of MOW, the MSC could have been capable of cooling mid–high northern latitudes by a few degrees, with the greatest cooling taking place in the Labrador, Greenland–Iceland–Norwegian and Barents seas. With hypersaline MOW, a component of North Atlantic Deep Water formation shifts to the Mediterranean, strengthening the Atlantic Meridional Overturning Circulation (AMOC) south of 35° N by 1.5–6 Sv. With hyposaline MOW, AMOC completely shuts down, inducing a bipolar climate anomaly with strong cooling in the north (mainly −1 to −3 °C, but up to −8 °C) and weaker warming in the south (up to +0.5 to +2.7 °C). These simulations identify key target regions and climate variables for future proxy reconstructions to provide the best and most robust test cases for (a) assessing Messinian model performance, (b) evaluating Mediterranean–Atlantic connectivity during the MSC and (c) establishing whether or not the MSC could ever have affected global-scale climate

Differential inhibition of human cytomegalovirus (HCMV) by toll-like receptor ligands mediated by interferon-beta in human foreskin fibroblasts and cervical tissue

Human cytomegalovirus (HCMV) can be acquired sexually and is shed from the genital tract. Cross-sectional studies in women show that changes in genital tract microbial flora affect HCMV infection and/or shedding. Since genital microbial flora may affect HCMV infection or replication by stimulating cells through Toll-like receptors (TLR), we assessed the effects of defined TLR-ligands on HCMV replication in foreskin fibroblasts and ectocervical tissue. Poly I:C (a TLR3-ligand) and lipopolysaccharide (LPS, a TLR4-ligand) inhibited HCMV and induced secretion of IL-8 and Interferon-beta (IFNβ) in both foreskin fibroblasts and ectocervical tissue. The anti-HCMV effect was reversed by antibody to IFNβ. CpG (TLR9 ligand) and lipoteichoic acid (LTA, TLR2 ligand) also inhibited HCMV infection in ectocervical tissue and this anti-HCMV effect was also reversed by anti-IFNβ antibody. In contrast, LTA and CpG did not inhibit HCMV infection in foreskin fibroblasts. This study shows that TLR ligands induce an HCMV-antiviral effect that is mediated by IFNβ suggesting that changes in genital tract flora may affect HCMV infection or shedding by stimulating TLR. This study also contrasts the utility of two models that can be used for assessing the interaction of microbial flora with HCMV in the genital tract. Clear differences in the response to different TLR ligands suggests the explant model more closely reflects in vivo responses to genital infections

Ocean circulation drifts in multi-millennial climate simulations: the role of salinity corrections and climate feedbacks

Low-resolution, complex general circulation models (GCMs) are valuable tools for studying the Earth system on multi-millennial timescales. However, slowly evolving salinity drifts can cause large shifts in climatic and oceanic regimes over thousands of years. We test two different schemes for neutralising unforced salinity drifts in the FAMOUS GCM: surface flux correction and volumetric flux correction. Although both methods successfully maintain a steady global mean salinity, local drifts and subsequent feedbacks promote cooling (≈ 4 °C over 6000 years) and freshening (≈ 2 psu over 6000 years) in the North Atlantic Ocean, and gradual warming (≈ 0.2 °C per millennium) and salinification (≈ 0.15 psu per millennium) in the North Pacific Ocean. Changes in the surface density in these regions affect the meridional overturning circulation (MOC), such that, after several millennia, the Atlantic MOC (AMOC) is in a collapsed state, and there is a strong, deep Pacific MOC (PMOC). Furthermore, the AMOC exhibits a period of metastability, which is only identifiable with run lengths in excess of 1500 years. We also compare simulations with two different land surface schemes, demonstrating that small biases in the surface climate may cause regional salinity drifts and significant shifts in the MOC (weakening of the AMOC and the initiation then invigoration of PMOC), even when the global hydrological cycle has been forcibly closed. Although there is no specific precursor to the simulated AMOC collapse, the northwest North Pacific and northeast North Atlantic are important areas that should be closely monitored for trends arising from such biases

Coherent deglacial changes in western Atlantic Ocean circulation

Abrupt climate changes in the past have been attributed to variations in Atlantic Meridional Overturning Circulation (AMOC) strength. However, the exact timing and magnitude of past AMOC shifts remain elusive, which continues to limit our understanding of the driving mechanisms of such climate variability. Here we show a consistent signal of the 231Pa/230Th proxy that reveals a spatially coherent picture of western Atlantic circulation changes over the last deglaciation, during abrupt millennial-scale climate transitions. At the onset of deglaciation, we observe an early slowdown of circulation in the western Atlantic from around 19 to 16.5 thousand years ago (ka), consistent with the timing of accelerated Eurasian ice melting. The subsequent weakened AMOC state persists for over a millennium (~16.5–15 ka), during which time there is substantial ice rafting from the Laurentide ice sheet. This timing indicates a role for melting ice in driving a two-step AMOC slowdown, with a positive feedback sustaining continued iceberg calving and climate change during Heinrich Stadial 1NERC | Ref. NE/K008536/

RELACIÓN ENTRE FACTORES DE RIESGO DEL CONSUMO DE DROGAS Y PRONÓSTICO ACADÉMICO EN ESTUDIANTES DE NUEVO INGRESO EN LA CARRERA DE ENFERMERÍA EN DOS UNIVERSIDADES LATINOAMERICANAS

 The objective of this study was to compare risk factors associated with licit and illicit drugs use and academic prognosis of first year nursing students from two Latin American universities.  The research design was non-experimental, transectional, and correlational-descriptive. Two questionnaires were used: Academic Prognosis Test (APT) by Bennett and Drug Use Screening Inventory (DUSI) test by OEA/CICAD.  The outcome indicates that the academic prognosis was different in both countries, and the most relevant risk factors associated with licit and illicit drugs abuse were recreation and free time use in students from both universities. It was found that abstract reasoning ability is a drug consumption protective factor. It is concluded that it is relevant to create preventive programs, based on psychosocial skills that make students develop thinking abilities and decision making as a life skill that helps them to withstand pressures from peer groups.El objetivo del estudio fue comparar los factores de riesgo del consumo de drogas y  el  pronóstico académico en estudiantes de nuevo ingreso de la carrera de enfermería en dos universidades latinoamericanas.  El diseño fue no experimental, de tipo transeccional, descriptivo-correlacional, se aplicaron dos instrumentos: el Test de Pronóstico académico (APT) de Bennett y la prueba DUSI (Drug Use Screening Inventory) de la OEA/CICAD.  Los hallazgos evidenciaron que el pronóstico académico fue diferente en ambos países, y los factores de riesgo mas relevantes para el consumo de drogas fueron la recreación y el uso del tiempo libre para estudiantes de ambas universidades. Se encontró que la presencia de un razonamiento abstracto es un factor protector del consumo de drogas, se concluye en la necesidad de crear programas preventivos, basados en el enfoque de habilidades psicosociales, que desarrollen en los estudiantes la capacidad de pensar y tomar decisiones como una habilidad para la vida que les permitiría resistir las presiones de grupos propias de la edad

5-Phenyl-1,3,4-oxadiazol-2(3H)-ones Are Potent Inhibitors of Notum Carboxylesterase Activity Identified by the Optimization of a Crystallographic Fragment Screening Hit

Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-triazole 7 as an attractive starting point for a structure-based drug design hit-to-lead program. Optimization of 7 identified oxadiazol-2-one 23dd as a preferred example with properties consistent with drug-like chemical space. Screening 23dd in a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of 23dd demonstrated good plasma exposure and partial blood–brain barrier penetration. Significant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling

Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity

The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles

Klima. 30 pitanja za razumijevanje Konferencije u Parizu (Pascal Canfin i Peter Staime)

The last deglaciation, which marked the transition between the last glacial and present interglacial periods, was punctuated by a series of rapid (centennial and decadal) climate changes. Numerical climate models are useful for investigating mechanisms that underpin the climate change events, especially now that some of the complex models can be run for multiple millennia. We have set up a Paleoclimate Modelling Intercomparison Project (PMIP) working group to coordinate efforts to run transient simulations of the last deglaciation, and to facilitate the dissemination of expertise between modellers and those engaged with reconstructing the climate of the last 21 000 years. Here, we present the design of a coordinated Core experiment over the period 21–9 thousand years before present (ka) with time-varying orbital forcing, greenhouse gases, ice sheets and other geographical changes. A choice of two ice sheet reconstructions is given, and we make recommendations for prescribing ice meltwater (or not) in the Core experiment. Additional focussed simulations will also be coordinated on an ad hoc basis by the working group, for example to investigate more thoroughly the effect of ice meltwater on climate system evolution, and to examine the uncertainty in other forcings. Some of these focussed simulations will target shorter durations around specific events in order to understand them in more detail and allow for the more computationally expensive models to take part

Wind-driven evolution of the North Pacific subpolar gyre over the last deglaciation

North Pacific atmospheric and oceanic circulations are key missing pieces in our understanding of the reorganisation of the global climate system since the Last Glacial Maximum (LGM). Here, using a basin-wide compilation of planktic foraminiferal δ18O, we show that the North Pacific subpolar gyre extended ~3 degrees further south during the LGM, consistent with sea surface temperature and productivity proxy data. Analysis of an ensemble of climate models indicates that the expansion of the subpolar gyre was associated with a substantial gyre strengthening. These gyre circulation changes were driven by a southward shift in the mid-latitude westerlies and increased wind-stress from the polar easterlies. Using single-forcing model runs, we show these atmospheric circulation changes are a non-linear response to the combined topographic and albedo effects of the Laurentide Ice Sheet. Our reconstruction suggests the gyre boundary (and thus westerly winds) began to migrate northward at ~17-16 ka, during Heinrich Stadial 1