In vivo imaging of protease activity by Probody therapeutic activation.

Probody™ therapeutics are recombinant, proteolytically-activated antibody prodrugs, engineered to remain inert until activated locally by tumor-associated proteases. Probody therapeutics exploit the fundamental dysregulation of extracellular protease activity that exists in tumors relative to healthy tissue. Leveraging the ability of a Probody therapeutic to bind its target at the site of disease after proteolytic cleavage, we developed a novel method for profiling protease activity in living animals. Using NIR optical imaging, we demonstrated that a non-labeled anti-EGFR Probody therapeutic can become activated and compete for binding to tumor cells in vivo with a labeled anti-EGFR monoclonal antibody. Furthermore, by inhibiting matriptase activity in vivo with a blocking-matriptase antibody, we show that the ability of the Probody therapeutic to bind EGFR in vivo was dependent on protease activity. These results demonstrate that in vivo imaging of Probody therapeutic activation can be used for screening and characterization of protease activity in living animals, and provide a method that avoids some of the limitations of prior methods. This approach can improve our understanding of the activity of proteases in disease models and help to develop efficient strategies for cancer diagnosis and treatment

Problems for the Purported Cognitive Penetration of Perceptual Color Experience and Macpherson’s Proposed Mechanism

Fiona Macpherson (2012) argues that various experimental results provide strong evidence in favor of the cognitive penetration of perceptual color experience. Moreover, she proposes a mechanism for how such cognitive penetration occurs. We argue, first, that the results on which Macpherson relies do not provide strong grounds for her claim of cognitive penetrability; and, second, that, if the results do reflect cognitive penetrability, then time-course considerations raise worries for her proposed mechanism. We base our arguments in part on several of our own experiments, reported herein

PHFinder: Assisted detection of point heteroplasmy in Sanger sequencing chromatograms

Heteroplasmy is the presence of two or more organellar genomes (mitochondrial or plastid DNA) in an organism, tissue, cell or organelle. Heteroplasmy can be detected by visual inspection of Sanger sequencing chromatograms, where it appears as multiple peaks of fluorescence at a single nucleotide position. Visual inspection of chromatograms is both consuming and highly subjective, as heteroplasmy is difficult to differentiate from background noise. Few software solutions are available to automate the detection of point heteroplasmies, and those that are available are typically proprietary, lack customization or are unsuitable for automated heteroplasmy assessment in large datasets. Here, we present PHFinder, a Python-based, open source tool to assist in the detection of point heteroplasmies in large numbers of Sanger chromatograms. PHFinder automatically identifies point heteroplasmies directly from the chromatogram trace data. The program was tested with Sanger sequencing data from 100 humpback whale (Megaptera novaeangliae) tissue samples with known heteroplasmies. PHFinder detected most (90%) of the known heteroplasmies thereby greatly reducing the amount of visual inspection required. PHFinder is flexible, enabling explicit specification of key parameters to infer double peaks (i.e., heteroplasmies)

Evaluating remote facilitation intensity for multi-national translation of nurse-initiated stroke protocols (QASC Australasia): a protocol for a cluster randomised controlled trial

Economic evaluation; Process evaluation; StrokeAvaluació econòmica; Avaluació de processos; IctusEvaluación económica; Evaluación de procesos; IctusBackground Facilitated implementation of nurse-initiated protocols to manage fever, hyperglycaemia (sugar) and swallowing difficulties (FeSS Protocols) in 19 Australian stroke units resulted in reduced death and dependency for stroke patients. However, a significant gap remains in translating this evidence-based care bundle protocol into standard practice in Australia and New Zealand. Facilitation is a key component for increasing implementation. However, its contribution to evidence translation initiatives requires further investigation. We aim to evaluate two levels of intensity of external remote facilitation as part of a multifaceted intervention to improve FeSS Protocol uptake and quality of care for patients with stroke in Australian and New Zealand acute care hospitals. Methods A three-arm cluster randomised controlled trial with a process evaluation and economic evaluation. Australian and New Zealand hospitals with a stroke unit or service will be recruited and randomised in blocks of five to one of the three study arms—high- or low-intensity external remote facilitation or a no facilitation control group—in a 2:2:1 ratio. The multicomponent implementation strategy will incorporate implementation science frameworks (Theoretical Domains Framework, Capability, Opportunity, Motivation – Behaviour Model and the Consolidated Framework for Implementation Research) and include an online education package, audit and feedback reports, local clinical champions, barrier and enabler assessments, action plans, reminders and external remote facilitation. The primary outcome is implementation effectiveness using a composite measure comprising six monitoring and treatment elements of the FeSS Protocols. Secondary outcome measures are as follows: composite outcome of adherence to each of the combined monitoring and treatment elements for (i) fever (n=5); (ii) hyperglycaemia (n=6); and (iii) swallowing protocols (n=7); adherence to the individual elements that make up each of these protocols; comparison for composite outcomes between (i) metropolitan and rural/remote hospitals; and (ii) stroke units and stroke services. A process evaluation will examine contextual factors influencing intervention uptake. An economic evaluation will describe cost differences relative to each intervention and study outcomes. Discussion We will generate new evidence on the most effective facilitation intensity to support implementation of nurse-initiated stroke protocols nationwide, reducing geographical barriers for those in rural and remote areas.This study is funded by a National Health and Medical Research Council Investigator Grant (Grant ID: APP1196352) awarded to SM. The funding body has no role in the design of the study and collection, analysis and interpretation of data and in writing the manuscript

Challenges in Quantifying Air‐Water Carbon Dioxide Flux Using Estuarine Water Quality Data: Case Study for Chesapeake Bay

Estuaries play an uncertain but potentially important role in the global carbon cycle via CO2 outgassing. The uncertainty mainly stems from the paucity of studies that document the full spatial and temporal variability of estuarine surface water partial pressure of carbon dioxide ( p CO2). Here, we explore the potential of utilizing the abundance of pH data from historical water quality monitoring programs to fill the data void via a case study of the mainstem Chesapeake Bay (eastern United States). We calculate p CO2 and the air‐water CO2 flux at monthly resolution from 1998 to 2018 from tidal fresh to polyhaline waters, paying special attention to the error estimation. The biggest error is due to the pH measurement error, and errors due to the gas transfer velocity, temporal sampling, the alkalinity mixing model, and the organic alkalinity estimation are 72%, 27%, 15%, and 5%, respectively, of the error due to pH. Seasonal, interannual, and spatial variability in the air‐water flux and surface p CO2 is high, and a correlation analysis with oxygen reveals that this variability is driven largely by biological processes. Averaged over 1998–2018, the mainstem bay is a weak net source of CO2 to the atmosphere of 1.2 (1.1, 1.4) mol m−2 yr−1 (best estimate and 95% confidence interval). Our findings suggest that the abundance of historical pH measurements in estuaries around the globe should be mined in order to constrain the large spatial and temporal variability of the CO2 exchange between estuaries and the atmosphere

Influence of nanostructured ceria support on platinum nanoparticles for methanol electrooxidation in alkaline media

The catalytic activity of platinum (Pt) nanoparticles (NPs) towards methanol electrooxidation in alkaline media was demonstrated to be dependent on their interactions with their nanostructured ceria support. Ceria nanorods (NRs) with diameters of 5 to 10 nm and lengths of 15 to 50 nm as well as ceria NPs with diameters of 2 to 6 nm were applied as supports for similarly sized Pt NPs with diameters of 2 to 5 nm. Cyclic voltammetry data showed that Pt NPs supported on ceria NPs exhibited a 2-to-5-fold higher catalytic current density versus ceria NRs. X-ray photoelectron spectroscopic data indicated that Pt NPs deposited onto ceria NRs were disproportionally composed of oxidized species (Pt2+, Pt4+ and Pt–O–M) rather than Pt0 while Pt NPs on ceria NPs mainly consisted of Pt0. Stronger metal-support interactions between Pt NPs and ceria NRs are postulated to induce preferential oxidation of Pt NPs and consequently decrease the catalytic sites and overall activity

Life in the surf-zone: Variations of faunal assemblage structure in temperate sandy beaches of the Southwestern Atlantic coast

This study explores the changes of biological descriptors -richness, diversity and abundance-of faunal surf-zone assemblage along a temperate coastal fringe. Three mesotidal sandy beaches with different morphodynamic states, adjacent to an estuarine zone, were seasonally sampled during a year. Zooplankton, zoobenthos and fish samples were taken in the surf-zone and a set of potential explanatory environmental variables were measured and/or quantified. Generalized linear models (GLM) were employed to compare environmental and biological variables between beaches and seasons. Beaches varied from tide-dominated flat to tide-modified reflective to intermediate. The assemblage included 108 taxa, of which few were numerically dominant. Richness of each biological group was similar along the shore and higher values of α-diversity were associated with minimum values of total abundance. β-diversity was mainly a consequence of species turnover, mostly due to changes in zoobenthic and zooplanktonic taxa. Results of GLM test showed that seasons and beaches have an interdependent effect on the abundance of the surf-zone assemblage. All biological groups showed marked seasonal variability in its occurrence, possibly associated with environmental variables, such as temperature and photosynthetic pigment concentrations. Zooplankton and fish groups reached maximum abundance, during autumn and spring respectively, in tide-modified beaches where the surf-zone was well developed and waves reached higher heights. Zoobenthic abundance peaked in beaches with narrower surf-zone and lower wave energy, during autumn, winter and spring, which could be advantageous for those taxa that escape from predators by burying or for species that actively swim near the seafloor. The copepod Acartia tonsa, the clupeidae fish Ramnogaster arcuata and the mysids Arthromysis magellanica and Neomysis americana all typical species of the neighboring estuary, were the main responsibles for these distribution patterns. The connection of the surf-zone with the adjacent estuarine area is also evident by its role in enriching the dissolved organic matter of surf-waters.Fil: Fiori, Sandra Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Lopez Cazorla, Andrea Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; ArgentinaFil: Martinez, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur. Departamento de Química; ArgentinaFil: Carcedo, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Blasina, Gabriela Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Molina, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Garzon Cardona, John Edison. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; Argentina. Universidad Nacional del Sur. Departamento de Química; ArgentinaFil: Moyano, Jessica Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; Argentina. Universidad Nacional del Sur. Departamento de Química; ArgentinaFil: Menendez, Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; Argentin

Challenges in Quantifying Air‐Water Carbon Dioxide Flux Using Estuarine Water Quality Data: Case Study for Chesapeake Bay

Estuaries play an uncertain but potentially important role in the global carbon cycle via CO2 outgassing. The uncertainty mainly stems from the paucity of studies that document the full spatial and temporal variability of estuarine surface water partial pressure of carbon dioxide ( pCO2). Here, we explore the potential of utilizing the abundance of pH data from historical water quality monitoring programs to fill the data void via a case study of the mainstem Chesapeake Bay (eastern United States). We calculate pCO2 and the air-water CO2 flux at monthly resolution from 1998 to 2018 from tidal fresh to polyhaline waters, paying special attention to the error estimation. The biggest error is due to the pH measurement error, and errors due to the gas transfer velocity, temporal sampling, the alkalinity mixing model, and the organic alkalinity estimation are 72%, 27%, 15%, and 5%, respectively, of the error due to pH. Seasonal, interannual, and spatial variability in the air-water flux and surface pCO2 is high, and a correlation analysis with oxygen reveals that this variability is driven largely by biological processes. Averaged over 1998–2018, the mainstem bay is a weak net source of CO2 to the atmosphere of 1.2 (1.1, 1.4) mol m−2 yr−1 (best estimate and 95% confidence interval). Our findings suggest that the abundance of historical pH measurements in estuaries around the globe should be mined in order to constrain the large spatial and temporal variability of the CO2 exchange between estuaries and the atmosphere

The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer

Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification