Mid-Miocene cooling and the extinction of tundra in continental Antarctica

A major obstacle in understanding the evolution of Cenozoic climate has been the lack of well dated terrestrial evidence from high-latitude, glaciated regions. Here, we report the discovery of exceptionally well preserved fossils of lacustrine and terrestrial organisms from the McMurdo Dry Valleys sector of the Transantarctic Mountains for which we have established a precise radiometric chronology. The fossils, which include diatoms, palynomorphs, mosses, ostracodes, and insects, represent the last vestige of a tundra community that inhabited the mountains before stepped cooling that first brought a full polar climate to Antarctica. Paleoecological analyses, 40Ar/39Ar analyses of associated ash fall, and climate inferences from glaciological modeling together suggest that mean summer temperatures in the region cooled by at least 8°C between 14.07 ± 0.05 Ma and 13.85 ± 0.03 Ma. These results provide novel constraints for the timing and amplitude of middle-Miocene cooling in Antarctica and reveal the ecological legacy of this global climate transition

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk. Current long-term therapies to prevent arterial occlusion in diabetes are focussed on anti-platelet agents, a strategy that fails to address the contribution of coagulation proteins to the enhanced thrombotic milieu. Moreover, antiplatelet treatment is associated with bleeding complications, particularly with newer agents and more aggressive combination therapies, questioning the safety of this approach. Therefore, to safely control thrombosis risk in diabetes, an alternative approach is required with the fibrin network representing a credible therapeutic target. In the current review, we address diabetes-specific mechanistic pathways responsible for hypofibrinolysis including the role of clot structure, defects in the fibrinolytic system and increased incorporation of anti-fibrinolytic proteins into the clot. Future anti-thrombotic therapeutic options are discussed with special emphasis on the potential advantages of modulating incorporation of the anti-fibrinolytic proteins into fibrin networks. This latter approach carries theoretical advantages, including specificity for diabetes, ability to target a particular protein with a possible favourable risk of bleeding. The development of alternative treatment strategies to better control residual thrombosis risk in diabetes will help to reduce vascular events, which remain the main cause of mortality in this condition

Procoagulant Activity in Hemostasis and Thrombosis: Virchowʼs Triad Revisited

Virchow’s triad is traditionally invoked to explain pathophysiologic mechanisms leading to thrombosis, alleging concerted roles for abnormalities in blood composition, vessel wall components, and blood flow in the development of arterial and venous thrombosis. Given the tissue-specific bleeding observed in hemophilia patients, it may be instructive to consider the principles of Virchow’s triad when investigating mechanisms operant in hemostatic disorders as well. Blood composition (the function of circulating blood cells and plasma proteins) is the most well-studied component of the triad. For example, increased levels of plasma procoagulant proteins such as prothrombin and fibrinogen are established risk factors for thrombosis, whereas deficiencies in plasma factors VIII and IX result in bleeding (hemophilia A and B, respectively). Vessel wall (cellular) components contribute adhesion molecules that recruit circulating leukocytes and platelets to sites of vascular damage, tissue factor, which provides a procoagulant signal of vascular breach, and a surface upon which coagulation complexes are assembled. Blood flow is often characterized by two key variables: shear rate and shear stress. Shear rate affects several aspects of coagulation, including transport rates of platelets and plasma proteins to and from the injury site, platelet activation, and the kinetics of fibrin monomer formation and polymerization. Shear stress modulates adhesion rates of platelets and expression of adhesion molecules and procoagulant activity on endothelial cells lining the blood vessels. That no one abnormality in any component of Virchow’s triad fully predicts coagulopathy a priori suggests coagulopathies are complex, multifactorial and interactive. In this review, we focus on contributions of blood composition, vascular cells, and blood flow to hemostasis and thrombosis, and suggests cross-talk among the three components of Virchow’s triad is necessary for hemostasis and determines propensity for thrombosis or bleeding. Investigative models that permit interplay among these components are necessary to understand the operant pathophysiology, and effectively treat and prevent thrombotic and bleeding disorders

Elevated Prothrombin Promotes Venous, but Not Arterial, Thrombosis in Mice

Individuals with elevated prothrombin, including those with the prothrombin G20210A mutation, have increased risk of venous thrombosis. Although these individuals do not have increased circulating prothrombotic biomarkers, their plasma demonstrates increased tissue factor-dependent thrombin generation in vitro. The objectives of this study were to determine the pathologic role of elevated prothrombin in venous and arterial thrombosis in vivo, and distinguish thrombogenic mechanisms in these vessels

Data report: age-depth model of the Corinth synrift sequence, Site M0079, IODP Expedition 381

We present a high-resolution age-depth model for Site M0079, drilled in the Corinth rift, central Greece, during International Ocean Discovery Program Expedition 381. To establish the model, we use available age constrains derived from postcruise research, including ages from 14C analysis and visible tephra layers, together with published ages from U/Th analysis, magnetostratigraphy, and relative paleointensity data. The age-depth model is built for the entire length of the Site M0079 drill hole using a probabilistic modeling approach in OxCal software. The resulting age-depth model provides a robust chronological framework for sediment accumulation within the Gulf of Corinth, constraining the most recent phase of synrift deposition over the past 800,000 y

Procoagulant Activity in Hemostasis and Thrombosis

Virchow’s triad is traditionally invoked to explain pathophysiologic mechanisms leading to thrombosis, alleging concerted roles for abnormalities in blood composition, vessel wall components, and blood flow in the development of arterial and venous thrombosis. Given the tissue-specific bleeding observed in hemophilia patients, it may be instructive to consider the principles of Virchow’s triad when investigating mechanisms operant in hemostatic disorders as well. Blood composition (the function of circulating blood cells and plasma proteins) is the most well-studied component of the triad. For example, increased levels of plasma procoagulant proteins such as prothrombin and fibrinogen are established risk factors for thrombosis, whereas deficiencies in plasma factors VIII and IX result in bleeding (hemophilia A and B, respectively). Vessel wall (cellular) components contribute adhesion molecules that recruit circulating leukocytes and platelets to sites of vascular damage, tissue factor, which provides a procoagulant signal of vascular breach, and a surface upon which coagulation complexes are assembled. Blood flow is often characterized by two key variables: shear rate and shear stress. Shear rate affects several aspects of coagulation, including transport rates of platelets and plasma proteins to and from the injury site, platelet activation, and the kinetics of fibrin monomer formation and polymerization. Shear stress modulates adhesion rates of platelets and expression of adhesion molecules and procoagulant activity on endothelial cells lining the blood vessels. That no one abnormality in any component of Virchow’s triad fully predicts coagulopathy a priori suggests coagulopathies are complex, multifactorial and interactive. In this review, we focus on contributions of blood composition, vascular cells, and blood flow to hemostasis and thrombosis, and suggests cross-talk among the three components of Virchow’s triad is necessary for hemostasis and determines propensity for thrombosis or bleeding. Investigative models that permit interplay among these components are necessary to understand the operant pathophysiology, and effectively treat and prevent thrombotic and bleeding disorders

Strontium isotopic, chemical, and sedimentological evidence for the evolution of Lake Lisan and the Dead Sea

Precise strontium isotope ratios, combined with chemical analyses and sedimentological information, are used to monitor the water sources and the evolution of the Dead Sea and its late Pleistocene precursor, Lake Lisan (70-18 kyr B.P.). The materials analyzed include bulk aragonite, water-leached soluble salts, and residual aragonite and gypsum from the Lisan Formation in the Perazim Valley (near the SW shore of the Dead Sea). The residual aragonite and the associated soluble salts display systematic fluctuations in 17Sr86Sr ratios between 0.70803 and 0.70806 and from 0.70805 to 0.70807, respectively. In individual soluble salt-residual aragonite pairs, the soluble salt displays a higher 87Sr86Sr ratio. Gypsum samples yield 17Sr86Sr ratios similar to the soluble salts from adjacent layers in the section. This shows that, in individual samples, the source of Sr in aragonite was distinct from that in soluble salts and the gypsum. The sterility of the Lisan sediments, their strictly nonbioturbated fine lamination, and their high content of chloride salts indicate that Lake Lisan was a saline, or even hypersaline water body. In the absence of alternative sources of HCO3− and S042− the abundance of primary aragonite and gypsum in the Lisan column reflects an import of very large volumes of freshwater into the otherwise saline lake, resulting in a density stratification of this water body. The history of the upper water layer and that of the lower brine is reflected in the chemical and strontium isotope composition of the aragonite and in that of the associated soluble salts and in the gypsum samples, respectively. Whereas the bicarbonate and much of the Ca2+ required for aragonite crystallization were supplied by the freshwater, the complementary Ca2+ (and Sr 2+) were added by the lower brine. The upper water layer of Lake Lisan acted as a SO42− capacitor during the lake's rise periods. It was removed therefrom, as prominent gypsum beds, upon climatic-induced (drier period) mixing or even complete overturn of the lake. The evolution of Lake Lisan took place between two distinct modes. The first was characterized by an extensive supply of freshwater and resulted in a rise of the lake's level, a (density) layered structure, and precipitation of aragonite. The second mode was marked by a diminishing freshwater input, resulting in mixing or complete overturn of its water, and precipitation of gypsum. These two modes reflect the climatic evolution of the region in the late Pleistocene which fluctuated between drier and wetter periods. The transition to the Holocene is accompanied by the dry up of Lake Lisan and its contraction to the present Dead Sea

Anticoagulation Inhibits Tumor Cell-Mediated Release Of Platelet Angiogenic Proteins and Disrupts The Platelet Angiogenic Potential

Abstract Platelets are a reservoir for angiogenic proteins that are secreted in a differentially regulated process. While the involvement of platelets in hematogenous tumor metastasis has long been recognized, the cause and effect relationship linking the two remains unclear. Due to the propensity for clotting, patients with malignancy are often anti-coagulated with heparin products, which paradoxically offer a survival benefit by an unknown mechanism. We hypothesized that anti-thrombotic agents alter the release of angiogenesis regulatory proteins from platelets. We have previously shown that we can manipulate the angiogenic potential of the platelet releasate through physiological (platelet agonists) and pathological activation (MCF-7 tumor cells) (Battinelli et al., 2011). Our data reveals that platelets exposed to heparin (UFH) or its derivative low molecular weight heparin (LMWH) release statistically significant decreased amounts of VEGF in response to activation by either the platelet agonist ADP or interaction with tumor cells (MCF-7 cells). The angiogenic potential from ADP or tumor cell generated platelet releasate is also significantly decreased as evidenced by dramatically diminished capillary tube branch point formation and endothelial cell migration. To explore the impact of these anticoagulants on the angiogenic protein contents of the releasate, we analyzed the releasate from platelets exposed to LMWH alone or activated with ADP or MCF-7 cells in conjunction with LMWH. Using a angiogenesis protein array to simultaneously sample the angiogenic content of the platelet releasate, we found that exposure to LMWH resulted in a decrease in pro-angiogenic protein content. Fondaparinux (Xa inhibitor) demonstrated similar impact on the platelet angiogenic potential. Since MCF-7 cells are known to secrete thrombin; the main target of anticoagulants, we hypothesized that these drugs disrupt thrombin signaling through the platelet PAR1 receptor. Addition of PAR1 antagonists to platelets decreased VEGF release and angiogenic potential. Exposure to a PAR1 agonist in the presence of anticoagulants rescued the angiogenic potential. Direct evidence of disrupted PAR1 signaling was demonstrated by decreased cleavage (activation) of the PAR1 receptor on anticoagulated platelets in the presence of MCF-7 cells (as measured by SPAN12 using Flow Cytometry). This data establishes a mechanism by which anticoagulants can decrease the angiogenic potential of platelets through impaired PAR1 activation. The impact of anticoagulants was also observed in platelet releasate of patients. We measured the VEGF concentration in the platelet releasate of patients currently medicated with LMWH or Fondaparinux and observed a statistically significant decrease in VEGF release after exposure to MCF-7 cells. Taken together, these data underscore the pivotal role of platelets in regulating tumor angiogenesis and point to a potential source for development of therapeutic intervention targeting the PAR1 receptor. Disclosures: No relevant conflicts of interest to declare. </jats:sec