Persistence of full glacial conditions in the central Pacific until 15,000 years ago

The magnitude of atmospheric cooling during the Last Glacial Maximum and the timing of the transition into the current interglacial period remain poorly constrained in tropical regions, partly because of a lack of suitable climate records. Glacial moraines provide a method of reconstructing past temperatures, but they are relatively rare in the tropics. Here we present a reconstruction of atmospheric temperatures in the central Pacific during the last deglaciation on the basis of cosmogenic ^3He ages of moraines and numerical modelling of the ice cap on Mauna Kea volcano, Hawaii—the only highland in the central Pacific on which moraines that formed during the last glacial period are preserved. Our reconstruction indicates that the Last Glacial Maximum occurred between 19,000 and 16,000 years ago in this region and that temperatures at high elevations were about 7 °C lower than today during this interval. Glacial retreat began about 16,000 years ago, but temperatures were still about 6.5 °C lower than today until 15,000 years ago. When combined with estimates of sea surface temperatures in the central Pacific Ocean, our reconstruction indicates that the lapse rate during the Last Glacial Maximum was higher than at present, which is consistent with the proposal that the atmosphere was drier at that time. Furthermore, the persistence of full glacial conditions until 15,000 years ago is consistent with the relatively late and abrupt transition to warmer temperatures in Greenland5, indicating that there may have been an atmospheric teleconnection between the central Pacific and North Atlantic regions during the last deglaciation

Holocene evolution of summer winds and marine productivity in the tropical Indian Ocean in response to insolation forcing: data-model comparison

The relative abundance of <i>Globigerinoides bulloides</i> was used to infer Holocene paleo-productivity changes on the Oman margin and at the southern tip of India. Today, the primary productivity at both sites reaches its maximum during the summer season, when monsoon winds result in local Eckman pumping, which brings more nutrients to the surface. On a millennium time-scale, however, the % <i>G. bulloides</i> records indicate an opposite evolution of paleo-productivity at these sites through the Holocene. The Oman Margin productivity was maximal at ~9 ka (boreal summer insolation maximum) and has decreased since then, suggesting a direct response to insolation forcing. On the contrary, the productivity at the southern tip of India was minimum at ~9 ka, and strengthened towards the present. <br><br> Paleo-reconstructions of wind patterns, marine productivity and foraminifera assemblages were obtained using the IPSL-CM4 climate model coupled to the PISCES marine biogeochemical model and the FORAMCLIM ecophysiological model. These reconstructions are fully coherent with the marine core data. They confirm that the evolution of particulate export production and foraminifera assemblages at our two sites were directly linked with the strength of the upwelling. Model simulations at 9 ka and 6 ka BP show that the relative evolution between the two sites since the early Holocene can be explained by the weakening but also the southward shift of monsoon winds over the Arabian Sea during boreal summer

H008 Le blocage des récepteurs AT1 de L′angiotensine II inhibe L′hypertrophie ventriculaire gauche et L′activation de FHL1 chez la souris hétérozygote déficiente en cMyBP-C

Les mutations de la protéine C cardiaque (cMyBP-C) sont une cause de cardiomyopathies hypertrophiques (CMH). Les souris transgéniques hétérozygotes défi cientes en cMyBP-C (HET) présentent une CMH d′apparition tardive à fonction systolique conservée. Le système rénine angiotensine (SRA) cardiaque joue un rôle important dans l′hypertrophie, mais son rôle dans le développement d′une CMH génétiquement déterminée a été peu étudié.Cette étude évaluait le rôle du SRA dans l′induction de la CMH chez la souris HET. Des souris HET et sauvages (WT), âgées de 5 mois, ont été traitées par irbésartan (50mg/kg/jour) ou placebo pendant 8 semaines. L′expression dans le ventricule gauche (VG) des gènes de l′enzyme de conversion de l′angiotensine I (ACE), du récepteur AT1 de l′angiotensine II (AGTR1), de la calcineurine A (PPP3CB) de la calcipressin 1 (RCAN1), et de FHL1 (four and a half LIM domains 1, une protéine associée à cMyBP-C au sein du sarcomère) a été analysée par RT-qPCR.Après 8 semaines de traitement, la pression artérielle est normale dans tous les groupes. Le poids du VG/poids du corps des souris HET est augmenté par rapport aux WT (3,9±0,3 vs. 3,3±0,4mg/g; p<0.01) dans le groupe placebo. Dans les groupes traités par irbésartan, ce rapport est comparable pour les souris HET (3,4±0,5mg/g) et WT (3,2±0,4mg/g; p=ns). L′expression des gènes de l′ACE, PPP3CB et RCAN1 est comparable entre les souris HET et WT et n′est pas affectée par le traitement par irbésartan. L′expression d′AGTR1 est similaire chez les souris HET et WT traitées par placebo mais augmente après traitement par irbésartan uniquement chez les souris HET. A l′inverse, l′expression de FHL1 est activée chez les souris HET par rapport aux souris WT mais cette augmentation est prévenue par le traitement par irbésartan.En conclusion, chez la souris cMyBP-C, le développement de l′hypertrophie est accompagné par une augmentation de l′expression du gène FHL1 dans le VG. Le traitement par irbésartan inhibe l′hypertrophie et l′activation de l′expression de FHL1 don′t le mécanisme reste à déterminer

Lag and mixing during sediment transfer across the Tian Shan piedmont caused by climate-driven aggradation-incision cycles

Transient sediment storage and mixing of deposits of various ages during transport across alluvial piedmonts alter the clastic sedimentary record. We quantify buffering and mixing during cycles of aggradation–incision in the north piedmont of the Eastern Tian Shan. We complement existing chronologic data with 20 new luminescence ages and one cosmogenic radionuclide age of terrace abandonment and alluvial aggradation. Over the last 0.5 Myr, the piedmont deeply incised and aggraded many times per 100 kyr. Aggradation is driven by an increased flux of glacial sediment accumulated in the high range and flushed onto the piedmont by greater water discharge at stadial–interstadial transitions. After this sediment is evacuated from the high range, the reduced input sediment flux results in fluvial incision of the piedmont as fast as 9 cm year−1 and to depths up to 330 m. The timing of incision onset is different in each river and does not directly reflect climate forcing but the necessary time for the evacuation of glacial sediment from the high range. A significant fraction of sediments evacuated from the high range is temporarily stored on the piedmont before a later incision phase delivers it to the basin. Coarse sediments arrive in the basin with a lag of at least 7–14 kyrs between the first evacuation from the mountain and later basinward transport. The modern output flux of coarse sediments from the piedmont contains a significant amount of recycled material that was deposited on the piedmont as early as the Middle Pleistocene. Variations in temperature and moisture delivered by the Westerlies are the likely cause of repeated aggradation–incision cycles in the north piedmont instead of monsoonal precipitation. The arrival of the gravel front into the proximal basin is delayed relative to the fine-grained load and both are separated by a hiatus. This work shows, based on field observations and data, how sedimentary systems respond to climatic perturbations, and how sediment recycling and mixing can ensue

Byrd ice core debris constrains the sediment provenance signature of central West Antarctica

Provenance records from sediments deposited offshore of the West Antarctic Ice Sheet (WAIS) can help identify past major ice retreat, thus constraining ice-sheet models projecting future sea-level rise. Interpretations from such records are, however, hampered by the ice obscuring Antarctica's geology. Here, we explore central West Antarctica's subglacial geology using basal debris from within the Byrd ice core, drilled to the bed in 1968. Sand grain microtextures and a high kaolinite content (∼38–42%) reveal the debris consists predominantly of eroded sedimentary detritus, likely deposited initially in a warm, pre-Oligocene, subaerial environment. Detrital hornblende 40Ar/39Ar ages suggest proximal late Cenozoic subglacial volcanism. The debris has a distinct provenance signature, with: common Permian-Early Jurassic mineral grains; absent early Ross Orogeny grains; a high kaolinite content; and high 143Nd/144Nd and low 87Sr/86Sr ratios. Detecting this “fingerprint” in Antarctic sedimentary records could imply major WAIS retreat, revealing the WAIS's sensitivity to future warming

Implicating Calpain in Tau-Mediated Toxicity In Vivo

Alzheimer's disease and other related neurodegenerative disorders known as tauopathies are characterized by the accumulation of abnormally phosphorylated and aggregated forms of the microtubule-associated protein tau. Several laboratories have identified a 17 kD proteolytic fragment of tau in degenerating neurons and in numerous cell culture models that is generated by calpain cleavage and speculated to contribute to tau toxicity. In the current study, we employed a Drosophila tauopathy model to investigate the importance of calpain-mediated tau proteolysis in contributing to tau neurotoxicity in an animal model of human neurodegenerative disease. We found that mutations that disrupted endogenous calpainA or calpainB activity in transgenic flies suppressed tau toxicity. Expression of a calpain-resistant form of tau in Drosophila revealed that mutating the putative calpain cleavage sites that produce the 17 kD fragment was sufficient to abrogate tau toxicity in vivo. Furthermore, we found significant toxicity in the fly retina associated with expression of only the 17 kD tau fragment. Collectively, our data implicate calpain-mediated proteolysis of tau as an important pathway mediating tau neurotoxicity in vivo

Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease

Common neurodegenerative proteinopathies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by the misfolding and aggregation of toxic protein species, including the amyloid beta (Aß) peptide, microtubule-associated protein Tau (Tau), and alpha-synuclein (αSyn) protein. These factors also show toxicity in Drosophila; however, potential limitations of prior studies include poor discrimination between effects on the adult versus developing nervous system and neuronal versus glial cell types. In addition, variable expression paradigms and outcomes hinder systematic comparison of toxicity profiles. Using standardized conditions and medium-throughput assays, we express human Tau, Aß or αSyn selectively in neurons of the adult Drosophila retina and monitor age-dependent changes in both structure and function, based on tissue histology and recordings of the electroretinogram (ERG), respectively. We find that each protein causes a unique profile of neurodegenerative pathology, demonstrating distinct and separable impacts on neuronal death and dysfunction. Strikingly, expression of Tau leads to progressive loss of ERG responses whereas retinal architecture and neuronal numbers are largely preserved. By contrast, Aß induces modest, age-dependent neuronal loss without degrading the retinal ERG. αSyn expression, using a codon-optimized transgene, is characterized by marked retinal vacuolar change, progressive photoreceptor cell death, and delayed-onset but modest ERG changes. Lastly, to address potential mechanisms, we perform transmission electron microscopy (TEM) to reveal potential degenerative changes at the ultrastructural level. Surprisingly, Tau and αSyn each cause prominent but distinct synaptotoxic profiles, including disorganization or enlargement of photoreceptor terminals, respectively. Our findings highlight variable and dynamic properties of neurodegeneration triggered by these disease-relevant proteins in vivo, and suggest that Drosophila may be useful for revealing determinants of neuronal dysfunction that precede cell loss, including synaptic changes, in the adult nervous system

Predicting major bleeding in patients with noncardioembolic stroke on antiplatelets

Objective: To develop and externally validate a prediction model for major bleeding in patients with a TIA or ischemic stroke on antiplatelet agents. Methods: We combined individual patient data from 6 randomized clinical trials (CAPRIE, ESPS-2, MATCH, CHARISMA, ESPRIT, and PRoFESS) investigating antiplatelet therapy after TIA or ischemic stroke. Cox regression analyses stratified by trial were performed to study the association between predictors and major bleeding. A risk prediction model was derived and validated in the PERFORM trial. Performance was assessed with the c statistic and calibration plots. Results: Major bleeding occurred in 1,530 of the 43,112 patients during 94,833 person-years of follow-up. The observed 3-year risk of major bleeding was 4.6% (95% confidence interval [CI] 4.4%–4.9%). Predictors were male sex, smoking, type of antiplatelet agents (aspirin-clopidogrel), outcome on modified Rankin Scale ≥3, prior stroke, high blood pressure, lower body mass index, elderly, Asian ethnicity, and diabetes (S2TOP-BLEED). The S2TOP-BLEED score had a c statistic of 0.63 (95% CI 0.60–0.64) and showed good calibration in the development data. Major bleeding risk ranged from 2% in patients aged 45–54 years without additional risk factors to more than 10% in patients aged 75–84 years with multiple risk factors. In external validation, the model had a c statistic of 0.61 (95% CI 0.59–0.63) and slightly underestimated major bleeding risk. Conclusions: The S2TOP-BLEED score can be used to estimate 3-year major bleeding risk in patients with a TIA or ischemic stroke who use antiplatelet agents, based on readily available characteristics. The discriminatory performance may be improved by identifying stronger predictors of major bleeding