A dual-time-window protocol to reduce acquisition time of dynamic tau PET imaging using [F-18]MK-6240

Background [F-18]MK-6240 is a PET tracer with sub-nanomolar affinity for neurofibrillary tangles. Therefore, tau quantification is possible with [F-18]MK-6240 PET/CT scans, and it can be used for assessment of Alzheimer's disease. However, long acquisition scans are required to provide fully quantitative estimates of pharmacokinetic parameters. Therefore, on the present study, dual-time-window (DTW) acquisitions was simulated to reduce PET/CT acquisition time, while taking into consideration perfusion changes and possible scanning protocol non-compliance. To that end, time activity curves (TACs) representing a 120-min acquisition (TAC(120)) were simulated using a two-tissue compartment model with metabolite corrected arterial input function from 90-min dynamic [F-18]MK-6240 PET scans of three healthy control subjects and five subjects with mild cognitive impairment or Alzheimer's disease. Therefore, TACs corresponding to different levels of specific binding were generated and then various perfusion changes were simulated. Next, DTW acquisitions were simulated consisting of an acquisition starting at tracer injection, a break and a second acquisition starting at 90 min post-injection. Finally, non-compliance with the PET/CT scanning protocol were simulated to assess its impact on quantification. All TACs were quantified using reference Logan's distribution volume ratio (DVR) and standardized uptake value ratio (SUVR90) using the cerebellar cortex as reference region. Results It was found that DVR from a DTW protocol with a 60-min break between two 30-min dynamic scans closely approximates the DVR from the uninterrupted TAC(120), with a regional bias smaller than 2.5%. Moreover, SUVR90 estimates were more susceptible (regional bias</p

Large fluctuations of dissolved oxygen in the Indian and Pacific oceans during Dansgaard-Oeschger oscillations caused by variations of North Atlantic Deep Water Subduction: Paleoceanography

Paleoclimate records from glacial Indian and Pacific oceans sediments document millennial-scale fluctuations of subsurface dissolved oxygen levels and denitrification coherent with North Atlantic temperature oscillations. Yet the mechanism of this teleconnection between the remote ocean basins remains elusive. Here we present model simulations of the oxygen and nitrogen cycles that explain how changes in deepwater subduction in the North Atlantic can cause large and synchronous variations of oxygen minimum zones throughout the Northern Hemisphere of the Indian and Pacific oceans, consistent with the paleoclimate records. Cold periods in the North Atlantic are associated with reduced nutrient delivery to the upper Indo-Pacific oceans, thereby decreasing productivity. Reduced export production diminishes subsurface respiration of organic matter leading to higher oxygen concentrations and less denitrification. This effect of reduced oxygen consumption dominates at low latitudes. At high latitudes in the Southern Ocean and North Pacific, increased mixed layer depths and steepening of isopycnals improve ocean ventilation and oxygen supply to the subsurface. Atmospheric teleconnections through changes in wind-driven ocean circulation modify this basin-scale pattern regionally. These results suggest that changes in the Atlantic Ocean circulation, similar to those projected by climate models to possibly occur in the centuries to come because of anthropogenic climate warming, can have large effects on marine ecosystems and biogeochemical cycles even in remote areas.Keywords: ocean circulation, oxygen, Dansgaard-Oeschger oscillation

Large fluctuations of dissolved oxygen in the Indian and Pacific oceans during Dansgaard-Oeschger oscillations caused by variations of North Atlantic Deep Water subduction

Paleoclimate records from glacial Indian and Pacific oceans sediments document millennial-scale fluctuations of subsurface dissolved oxygen levels and denitrification coherent with North Atlantic temperature oscillations. Yet the mechanism of this teleconnection between the remote ocean basins remains elusive. Here we present model simulations of the oxygen and nitrogen cycles that explain how changes in deepwater subduction in the North Atlantic can cause large and synchronous variations of oxygen minimum zones throughout the Northern Hemisphere of the Indian and Pacific oceans, consistent with the paleoclimate records. Cold periods in the North Atlantic are associated with reduced nutrient delivery to the upper Indo-Pacific oceans, thereby decreasing productivity. Reduced export production diminishes subsurface respiration of organic matter leading to higher oxygen concentrations and less denitrification. This effect of reduced oxygen consumption dominates at low latitudes. At high latitudes in the Southern Ocean and North Pacific, increased mixed layer depths and steepening of isopycnals improve ocean ventilation and oxygen supply to the subsurface. Atmospheric teleconnections through changes in wind-driven ocean circulation modify this basin-scale pattern regionally. These results suggest that changes in the Atlantic Ocean circulation, similar to those projected by climate models to possibly occur in the centuries to come because of anthropogenic climate warming, can have large effects on marine ecosystems and biogeochemical cycles even in remote areas

PET/CT Imaging of Zr-89-N-sucDf-Pembrolizumab in Healthy Cynomolgus Monkeys

PURPOSE: Programmed cell death-1 receptor (PD-1) and its ligand (PD-L1) are the targets for immunotherapy in many cancer types. Although PD-1 blockade has therapeutic effects, the efficacy differs between patients. Factors contributing to this variability are PD-L1 expression levels and immune cells present in tumors. However, it is not well understood how PD-1 expression in the tumor microenvironment impacts immunotherapy response. Thus, imaging of PD-1-expressing immune cells is of interest. This study aims to evaluate the biodistribution of Zirconium-89 (89Zr)-labeled pembrolizumab, a humanized IgG4 kappa monoclonal antibody targeting PD-1, in healthy cynomolgus monkeys as a translational model of tracking PD-1-positive immune cells. PROCEDURES: Pembrolizumab was conjugated with the tetrafluorophenol-N-succinyl desferal-Fe(III) ester (TFP-N-sucDf) and subsequently radiolabeled with 89Zr. Four cynomolgus monkeys with no previous exposure to humanized monoclonal antibodies received tracer only or tracer co-injected with pembrolizumab intravenously over 5 min. Thereafter, a static whole-body positron emission tomography (PET) scan was acquired with 10 min per bed position on days 0, 2, 5, and 7. Image-derived standardized uptake values (SUVmean) were quantified by region of interest (ROI) analysis. RESULTS: 89Zr-N-sucDf-pembrolizumab was synthesized with high radiochemical purity (> 99 %) and acceptable molar activity (> 7 MBq/nmol). In animals dosed with tracer only, 89Zr-N-sucDf-pembrolizumab distribution in lymphoid tissues such as mesenteric lymph nodes, spleen, and tonsils increased over time. Except for the liver, low radiotracer distribution was observed in all non-lymphoid tissue including the lung, muscle, brain, heart, and kidney. When a large excess of pembrolizumab was co-administered with a radiotracer, accumulation in the lymph nodes, spleen, and tonsils was reduced, suggestive of target-mediated accumulation. CONCLUSIONS: 89Zr-N-sucDf-pembrolizumab shows preferential uptake in the lymphoid tissues including the lymph nodes, spleen, and tonsils. 89Zr-N-sucDf-pembrolizumab may be useful in tracking the distribution of a subset of immune cells in non-human primates and humans. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02760225

A Domain-Agnostic Approach for Characterization of Lifelong Learning Systems

Despite the advancement of machine learning techniques in recent years, state-of-the-art systems lack robustness to "real world" events, where the input distributions and tasks encountered by the deployed systems will not be limited to the original training context, and systems will instead need to adapt to novel distributions and tasks while deployed. This critical gap may be addressed through the development of "Lifelong Learning" systems that are capable of 1) Continuous Learning, 2) Transfer and Adaptation, and 3) Scalability. Unfortunately, efforts to improve these capabilities are typically treated as distinct areas of research that are assessed independently, without regard to the impact of each separate capability on other aspects of the system. We instead propose a holistic approach, using a suite of metrics and an evaluation framework to assess Lifelong Learning in a principled way that is agnostic to specific domains or system techniques. Through five case studies, we show that this suite of metrics can inform the development of varied and complex Lifelong Learning systems. We highlight how the proposed suite of metrics quantifies performance trade-offs present during Lifelong Learning system development - both the widely discussed Stability-Plasticity dilemma and the newly proposed relationship between Sample Efficient and Robust Learning. Further, we make recommendations for the formulation and use of metrics to guide the continuing development of Lifelong Learning systems and assess their progress in the future.Comment: To appear in Neural Network

The Complete Genome of Teredinibacter turnerae T7901: An Intracellular Endosymbiont of Marine Wood-Boring Bivalves (Shipworms)

Here we report the complete genome sequence of Teredinibacter turnerae T7901. T. turnerae is a marine gamma proteobacterium that occurs as an intracellular endosymbiont in the gills of wood-boring marine bivalves of the family Teredinidae (shipworms). This species is the sole cultivated member of an endosymbiotic consortium thought to provide the host with enzymes, including cellulases and nitrogenase, critical for digestion of wood and supplementation of the host's nitrogen-deficient diet. T. turnerae is closely related to the free-living marine polysaccharide degrading bacterium Saccharophagus degradans str. 2–40 and to as yet uncultivated endosymbionts with which it coexists in shipworm cells. Like S. degradans, the T. turnerae genome encodes a large number of enzymes predicted to be involved in complex polysaccharide degradation (>100). However, unlike S. degradans, which degrades a broad spectrum (>10 classes) of complex plant, fungal and algal polysaccharides, T. turnerae primarily encodes enzymes associated with deconstruction of terrestrial woody plant material. Also unlike S. degradans and many other eubacteria, T. turnerae dedicates a large proportion of its genome to genes predicted to function in secondary metabolism. Despite its intracellular niche, the T. turnerae genome lacks many features associated with obligate intracellular existence (e.g. reduced genome size, reduced %G+C, loss of genes of core metabolism) and displays evidence of adaptations common to free-living bacteria (e.g. defense against bacteriophage infection). These results suggest that T. turnerae is likely a facultative intracellular ensosymbiont whose niche presently includes, or recently included, free-living existence. As such, the T. turnerae genome provides insights into the range of genomic adaptations associated with intracellular endosymbiosis as well as enzymatic mechanisms relevant to the recycling of plant materials in marine environments and the production of cellulose-derived biofuels

The Complete Genome of \u3cem\u3eTeredinibacter turnerae\u3c/em\u3e T7901: An Intracellular Endosymbiont of Marine Wood-Boring Bivalves (Shipworms)

Here we report the complete genome sequence of Teredinibacter turnerae T7901. T. turnerae is a marine gamma proteobacterium that occurs as an intracellular endosymbiont in the gills of wood-boring marine bivalves of the family Teredinidae (shipworms). This species is the sole cultivated member of an endosymbiotic consortium thought to provide the host with enzymes, including cellulases and nitrogenase, critical for digestion of wood and supplementation of the host\u27s nitrogen-deficient diet. T. turnerae is closely related to the free-living marine polysaccharide degrading bacterium Saccharophagus degradans str. 2–40 and to as yet uncultivated endosymbionts with which it coexists in shipworm cells. Like S. degradans, the T. turnerae genome encodes a large number of enzymes predicted to be involved in complex polysaccharide degradation (\u3e100). However, unlike S. degradans, which degrades a broad spectrum (\u3e10 classes) of complex plant, fungal and algal polysaccharides, T. turnerae primarily encodes enzymes associated with deconstruction of terrestrial woody plant material. Also unlike S. degradans and many other eubacteria, T. turnerae dedicates a large proportion of its genome to genes predicted to function in secondary metabolism. Despite its intracellular niche, the T. turnerae genome lacks many features associated with obligate intracellular existence (e.g. reduced genome size, reduced %G+C, loss of genes of core metabolism) and displays evidence of adaptations common to free-living bacteria (e.g. defense against bacteriophage infection). These results suggest that T. turnerae is likely a facultative intracellular ensosymbiont whose niche presently includes, or recently included, free-living existence. As such, the T. turnerae genome provides insights into the range of genomic adaptations associated with intracellular endosymbiosis as well as enzymatic mechanisms relevant to the recycling of plant materials in marine environments and the production of cellulose-derived biofuels

Novel Anti-Metastatic Action of Cidofovir Mediated by Inhibition of E6/E7, CXCR4 and Rho/ROCK Signaling in HPV+ Tumor Cells

Cervical cancer is frequently associated with HPV infection. The expression of E6 and E7 HPV oncoproteins is a key factor in its carcinogenicity and might also influence its virulence, including metastatic conversion. The cellular mechanisms involved in metastatic spread remain elusive, but pro-adhesive receptors and their ligands, such as SDF-1α and CXCR4 are implicated. In the present study, we assessed the possible relationship between SDF-1α/CXCR4 signaling, E6/E7 status and the metastatic process. We found that SDF-1α stimulated the invasion of E6/E7-positive cancer cell lines (HeLa and TC-1) in Matrigel though CXCR4 and subsequent Rho/ROCK activation. In pulmonary metastatic foci generated by TC-1 cells IV injection a high proportion of cells expressed membrane-associated CXCR4. In both cases models (in vitro and in vivo) cell adhesion and invasion was abrogated by CXCR4 immunological blockade supporting a contribution of SDF-1α/CXCR4 to the metastatic process. E6 and E7 silencing using stable knock-down and the approved anti-viral agent, Cidofovir decreased CXCR4 gene expression as well as both, constitutive and SDF-1α-induced cell invasion. In addition, Cidofovir inhibited lung metastasis (both adhesion and invasion) supporting contribution of E6 and E7 oncoproteins to the metastatic process. Finally, potential signals activated downstream SDF-1α/CXCR4 and involved in lung homing of E6/E7-expressing tumor cells were investigated. The contribution of the Rho/ROCK pathway was suggested by the inhibitory effect triggered by Cidofovir and further confirmed using Y-27632 (a small molecule ROCK inhibitor). These data suggest a novel and highly translatable therapeutic approach to cervix cancer, by inhibition of adhesion and invasion of circulating HPV-positive tumor cells, using Cidofovir and/or ROCK inhibition

Discovery of [11C]MK-6884: a positron emission tomography (PET) imaging agent for the study of M4 muscarinic receptor positive allosteric modulators (PAMs) in neurodegenerative diseases

The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884