Abstract
The system of oceanic flows constituting the Atlantic Meridional Overturning Circulation (AMOC) moves heat and other properties to the subpolar North Atlantic, controlling regional climate, ...weather, sea levels, and ecosystems. Climate models suggest a potential AMOC slowdown towards the end of this century due to anthropogenic forcing, accelerating coastal sea level rise along the western boundary and dramatically increasing flood risk. While direct observations of the AMOC are still too short to infer long-term trends, we show here that the AMOC-induced changes in gyre-scale heat content, superimposed on the global mean sea level rise, are already influencing the frequency of floods along the United States southeastern seaboard. We find that ocean heat convergence, being the primary driver for interannual sea level changes in the subtropical North Atlantic, has led to an exceptional gyre-scale warming and associated dynamic sea level rise since 2010, accounting for 30-50% of flood days in 2015-2020.
Of 35 patients with transfusion-dependent β-thalassemia treated with gene-edited autologous hematopoietic stem and progenitor cells, 32 had hemoglobin levels maintained without red-cell transfusions ...for at least 12 consecutive months.
Of 30 patients with severe sickle cell disease who were treated with gene-edited autologous hematopoietic stem and progenitor cells, 29 were free from vaso-occlusive crises for at least 12 ...consecutive months.
Summary
Very Late Antigen‐4 (VLA‐4, α4β1‐integrin, ITGA4) orchestrates cell‐cell and cell‐endothelium adhesion. Given the proposed role of VLA‐4 in sickle cell disease (SCD) pathophysiology, we ...evaluated the ability of the VLA‐4 blocking antibody natalizumab to inhibit SCD blood cell adhesion. Natalizumab recognized surface VLA‐4 on leucocytes and reticulocytes in whole blood from SCD subjects. SCD reticulocytes were positive for VLA‐4, while VLA‐4 staining of non‐SCD reticulocytes was undetectable. Titrations with natalizumab revealed the presence of saturable levels of VLA‐4 on both SCD reticulocytes and leucocytes similar to healthy subject leucocytes. Under physiological flow conditions, the adhesion of SCD whole blood cells and isolated SCD leucocytes to immobilized vascular cell adhesion molecule 1 (VCAM‐1) was blocked by natalizumab in a dose‐dependent manner, which correlated with cell surface receptor binding. Natalizumab also inhibited >50% of whole blood cell binding to TNF‐α activated human umbilical vein endothelial cell monolayers under physiological flow at clinically relevant concentrations (10 to 100 μg/ml). This indicates that VLA‐4 is the dominant receptor that drives SCD reticulocyte and mononuclear cell adhesion to VCAM‐1 and that the VLA‐4 adhesion to VCAM‐1 is a significant contributor to SCD blood cell adhesion to endothelium. Thus, VLA‐4 blockade may be beneficial in sickle cell disease.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Observations show that the upper 2 km of the subtropical North Atlantic Ocean cooled throughout 2010 and remained cold until at least December 2011. We show that these cold anomalies are partly ...driven by anomalous air‐sea exchange during the cold winters of 2009/2010 and 2010/2011 and, more surprisingly, by extreme interannual variability in the ocean's northward heat transport at 26.5°N. This cooling driven by the ocean's meridional heat transport affects deeper layers isolated from the atmosphere on annual timescales and water that is entrained into the winter mixed layer thus lowering winter sea surface temperatures. Here we connect, for the first time, variability in the northward heat transport carried by the Atlantic Meridional Overturning Circulation to widespread sustained cooling of the subtropical North Atlantic, challenging the prevailing view that the ocean plays a passive role in the coupled ocean‐atmosphere system on monthly‐to‐seasonal timescales.
Key Points
The upper 2 km of the subtropical North Atlantic Ocean cooled throughout 2010
Cooling driven by a 30% reduction in meridional heat transport
AMOC contributes to heat content anomalies in the seasonal mixed layer
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Purpose
Pittsburgh Compound-B (
11
C-PiB) and
18
F-florbetapir are amyloid-β (Aβ) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer’s disease (AD) clinical ...trials to evaluate the efficacy of anti-Aβ monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if different Aβ radiotracers were used. To study the consequences of using different Aβ radiotracers to measure Aβ clearance, we performed a head-to-head comparison of
11
C-PiB and
18
F-florbetapir in a Phase 2/3 clinical trial of anti-Aβ monoclonal antibodies.
Methods
Sixty-six mutation-positive participants enrolled in the gantenerumab and placebo arms of the first Dominantly Inherited Alzheimer Network Trials Unit clinical trial (DIAN-TU-001) underwent both
11
C-PiB and
18
F-florbetapir PET imaging at baseline and during at least one follow-up visit. For each PET scan, regional standardized uptake value ratios (SUVRs), regional Centiloids, a global cortical SUVR, and a global cortical Centiloid value were calculated. Longitudinal changes in SUVRs and Centiloids were estimated using linear mixed models. Differences in longitudinal change between PET radiotracers and between drug arms were estimated using paired and Welch two sample
t
-tests, respectively. Simulated clinical trials were conducted to evaluate the consequences of some research sites using
11
C-PiB while other sites use
18
F-florbetapir for Aβ PET imaging.
Results
In the placebo arm, the absolute rate of longitudinal change measured by global cortical
11
C-PiB SUVRs did not differ from that of global cortical
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F-florbetapir SUVRs. In the gantenerumab arm, global cortical
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C-PiB SUVRs decreased more rapidly than global cortical
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F-florbetapir SUVRs. Drug effects were statistically significant across both Aβ radiotracers. In contrast, the rates of longitudinal change measured in global cortical Centiloids did not differ between Aβ radiotracers in either the placebo or gantenerumab arms, and drug effects remained statistically significant. Regional analyses largely recapitulated these global cortical analyses. Across simulated clinical trials, type I error was higher in trials where both Aβ radiotracers were used versus trials where only one Aβ radiotracer was used. Power was lower in trials where
18
F-florbetapir was primarily used versus trials where
11
C-PiB was primarily used.
Conclusion
Gantenerumab treatment induces longitudinal changes in Aβ PET, and the absolute rates of these longitudinal changes differ significantly between Aβ radiotracers. These differences were not seen in the placebo arm, suggesting that Aβ-clearing treatments may pose unique challenges when attempting to compare longitudinal results across different Aβ radiotracers. Our results suggest converting Aβ PET SUVR measurements to Centiloids (both globally and regionally) can harmonize these differences without losing sensitivity to drug effects. Nonetheless, until consensus is achieved on how to harmonize drug effects across radiotracers, and since using multiple radiotracers in the same trial may increase type I error, multisite studies should consider potential variability due to different radiotracers when interpreting Aβ PET biomarker data and, if feasible, use a single radiotracer for the best results.
Trial registration
ClinicalTrials.gov NCT01760005. Registered 31 December 2012. Retrospectively registered.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Toxic industrial chemicals induce liver injury, which is difficult to diagnose without invasive procedures. Identifying indicators of end organ injury can complement exposure-based assays and improve ...predictive power. A multiplexed approach was used to experimentally evaluate a panel of 67 genes predicted to be associated with the fibrosis pathology by computationally mining DrugMatrix, a publicly available repository of gene microarray data. Five-day oral gavage studies in male Sprague Dawley rats dosed with varying concentrations of 3 fibrogenic compounds (allyl alcohol, carbon tetrachloride, and 4,4'-methylenedianiline) and 2 nonfibrogenic compounds (bromobenzene and dexamethasone) were conducted. Fibrosis was definitively diagnosed by histopathology. The 67-plex gene panel accurately diagnosed fibrosis in both microarray and multiplexed-gene expression assays. Necrosis and inflammatory infiltration were comorbid with fibrosis. ANOVA with contrasts identified that 51 of the 67 predicted genes were significantly associated with the fibrosis phenotype, with 24 of these specific to fibrosis alone. The protein product of the gene most strongly correlated with the fibrosis phenotype PCOLCE (Procollagen C-Endopeptidase Enhancer) was dose-dependently elevated in plasma from animals administered fibrogenic chemicals (P < .05). Semiquantitative global mass spectrometry analysis of the plasma identified an additional 5 protein products of the gene panel which increased after fibrogenic toxicant administration: fibronectin, ceruloplasmin, vitronectin, insulin-like growth factor binding protein, and α2-macroglobulin. These results support the data mining approach for identifying gene and/or protein panels for assessing liver injury and may suggest bridging biomarkers for molecular mediators linked to histopathology.
Vaso-occlusion, hemolysis, and oxidative stress are hallmarks of sickle cell disease (SCD). This pathology is accompanied by systemic endothelial activation, rendering the endothelium more adhesive ...for blood cells, including sickle erythrocytes. Activated endothelial cells display or secrete several adhesive molecules, including von Willebrand factor (VWF). We assessed several VWF parameters in SCD patients at baseline: multimer pattern, antigen concentration (VWF:Ag), activation factor (VWF:AF), and total active VWF (VWF:TA). VWF:AF was determined using a llama nanobody (AU/VWFa-11) that detects a platelet-binding conformation of the A1 domain; VWF:TA was calculated by multiplying VWF:Ag by VWF:AF. SCD plasma contained elevated VWF:Ag and ultralarge VWF multimers. VWF:TA, a measure of total VWF reactivity, correlated closely with hemolysis, as determined by serum lactate dehydrogenase. ADAMTS13 activity and antigen were normal in all patients. These findings suggest an important role for hyperreactive VWF in SCD pathology and connect SCD to other microangiopathies, particularly thrombotic thrombocytopenic purpura.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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