Evaluation of receptorâ ligand mechanisms of dualâ targeted particles to an inflamed endothelium

Vascularâ targeted carriers (VTCs) are designed as leukocyte mimics, decorated with ligands that target leukocyte adhesion molecules (LAMs) and facilitate adhesion to diseased endothelium. VTCs require different design considerations than other targeted particle therapies; adhesion of VTCs in regions with dynamic blood flow requires multiple ligandâ receptor (LR) pairs that provide particle adhesion and disease specificity. Despite the ultimate goal of leukocyte mimicry, the specificity of multiple LAMâ targeted VTCs remains poorly understood, especially in physiological environments. Here, we investigate particle binding to an inflamed mesentery via intravital microscopy using a series of particles with wellâ controlled ligand properties. We find that the total number of sites of a single ligand can drive particle adhesion to the endothelium, however, combining ligands that target multiple LR pairs provides a more effective approach. Combining sites of sialyl Lewis A (sLeA) and antiâ intercellular adhesion moleculeâ 1 (aICAM), two adhesive molecules, resulted in â ¼3â 7â fold increase of adherent particles at the endothelium over singleâ ligand particles. At a constant total ligand density, a particle with a ratio of 75% sLeA: 25% aICAM resulted in more than 3â fold increase over all over other ligand ratios tested in our in vivo model. Combined with in vivo and in silico data, we find the best dualâ ligand design of a particle is heavily dependent on the surface expression of the endothelial cells, producing superior adhesion with more particle ligand for the lesserâ expressed receptor. These results establish the importance of considering LRâ kinetics in intelligent VTC ligand design for future therapeutics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/133573/1/btm210008-sup-0007-suppinfo07.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/133573/2/btm210008_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/133573/3/btm210008.pd

The Nancy Grace Roman Space Telescope Coronagraph Instrument (CGI) technology demonstration

The Coronagraph Instrument (CGI) on the Nancy Grace Roman Space Telescope will demonstrate the highcontrast technology necessary for visible-light exoplanet imaging and spectroscopy from space via direct imaging of Jupiter-size planets and debris disks. This in-space experience is a critical step toward future, larger missions targeted at direct imaging of Earth-like planets in the habitable zones of nearby stars. This paper presents an overview of the current instrument design and requirements, highlighting the critical hardware, algorithms, and operations being demonstrated. We also describe several exoplanet and circumstellar disk science cases enabled by these capabilities. A competitively selected Community Participation Program team will be an integral part of the technology demonstration and could perform additional CGI observations beyond the initial tech demo if the instrument performance warrants it

Data to knowledge: how to get meaning from your result

Structural and functional studies require the development of sophisticated `Big Data' technologies and software to increase the knowledge derived and ensure reproducibility of the data. This paper presents summaries of the Structural Biology Knowledge Base, the VIPERdb Virus Structure Database, evaluation of homology modeling by the Protein Model Portal, the ProSMART tool for conformation-independent structure comparison, the LabDB `super' laboratory information management system and the Cambridge Structural Database. These techniques and technologies represent important tools for the transformation of crystallographic data into knowledge and information, in an effort to address the problem of non-reproducibility of experimental results

Carbon budget of tidal wetlands, estuaries, and shelf waters of eastern North America

Author Posting. © American Geophysical Union, 2018. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 32 (2018): 389-416, doi:10.1002/2017GB005790.Carbon cycling in the coastal zone affects global carbon budgets and is critical for understanding the urgent issues of hypoxia, acidification, and tidal wetland loss. However, there are no regional carbon budgets spanning the three main ecosystems in coastal waters: tidal wetlands, estuaries, and shelf waters. Here we construct such a budget for eastern North America using historical data, empirical models, remote sensing algorithms, and process‐based models. Considering the net fluxes of total carbon at the domain boundaries, 59 ± 12% (± 2 standard errors) of the carbon entering is from rivers and 41 ± 12% is from the atmosphere, while 80 ± 9% of the carbon leaving is exported to the open ocean and 20 ± 9% is buried. Net lateral carbon transfers between the three main ecosystem types are comparable to fluxes at the domain boundaries. Each ecosystem type contributes substantially to exchange with the atmosphere, with CO2 uptake split evenly between tidal wetlands and shelf waters, and estuarine CO2 outgassing offsetting half of the uptake. Similarly, burial is about equal in tidal wetlands and shelf waters, while estuaries play a smaller but still substantial role. The importance of tidal wetlands and estuaries in the overall budget is remarkable given that they, respectively, make up only 2.4 and 8.9% of the study domain area. This study shows that coastal carbon budgets should explicitly include tidal wetlands, estuaries, shelf waters, and the linkages between them; ignoring any of them may produce a biased picture of coastal carbon cycling.NASA Interdisciplinary Science program Grant Number: NNX14AF93G; NASA Carbon Cycle Science Program Grant Number: NNX14AM37G; NASA Ocean Biology and Biogeochemistry Program Grant Number: NNX11AD47G; National Science Foundation's Chemical Oceanography Program Grant Number: OCE‐12605742018-10-0

The Application of Archival Concepts to a Data-Intensive Environment: Working with Scientists to Understand Data Management and Preservation Needs

The collection, organization, and long-term preservation of resources are the raison d’être of archives and archivists. The archival community, however, has largely neglected science data, assuming they were outside the bounds of their professional concerns. Scientists, on the other hand, increasingly recognize that they lack the skills and expertise needed to meet the demands being placed on them with regard to data curation and are seeking the help of “data archivists” and “data curators.” This represents a significant opportunity for archivists and archival scholars but one that can only be realized if they better understand the scientific context.National Science Foundation under Grant No. 0724300Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86738/1/Akmonetal2011.pd

The Structural Biology Knowledgebase: a portal to protein structures, sequences, functions, and methods

The Protein Structure Initiative’s Structural Biology Knowledgebase (SBKB, URL: http://sbkb.org) is an open web resource designed to turn the products of the structural genomics and structural biology efforts into knowledge that can be used by the biological community to understand living systems and disease. Here we will present examples on how to use the SBKB to enable biological research. For example, a protein sequence or Protein Data Bank (PDB) structure ID search will provide a list of related protein structures in the PDB, associated biological descriptions (annotations), homology models, structural genomics protein target status, experimental protocols, and the ability to order available DNA clones from the PSI:Biology-Materials Repository. A text search will find publication and technology reports resulting from the PSI’s high-throughput research efforts. Web tools that aid in research, including a system that accepts protein structure requests from the community, will also be described. Created in collaboration with the Nature Publishing Group, the Structural Biology Knowledgebase monthly update also provides a research library, editorials about new research advances, news, and an events calendar to present a broader view of structural genomics and structural biology

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008

SCOPUS: ar.jinfo:eu-repo/semantics/publishe