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Erik C. B. Johnson

Bio: Erik C. B. Johnson is an academic researcher from Johns Hopkins University Applied Physics Laboratory. The author has contributed to research in topics: Computer science & Medicine. The author has an hindex of 18, co-authored 62 publications receiving 1665 citations. Previous affiliations of Erik C. B. Johnson include Emory University & University of Illinois at Urbana–Champaign.


Papers
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Journal ArticleDOI
TL;DR: The most common thiol catalysts used to date have been either a mixture of thiophenol/benzyl mercaptan, or the alkanethiol MESNA.
Abstract: Native chemical ligation of unprotected peptide segments involves reaction between a peptide-α-thioester and a cysteine-peptide, to yield a product with a native amide bond at the ligation site. Peptide-α-thioalkyl esters are commonly used because of their ease of preparation. These thioalkyl esters are rather unreactive so the ligation reaction is catalyzed by in situ transthioesterification with thiol additives. The most common thiol catalysts used to date have been either a mixture of thiophenol/benzyl mercaptan, or the alkanethiol MESNA. Despite the use of these thiol catalysts, ligation reactions typically take 24−48 h. To gain insight into the mechanism of native chemical ligaton and in order to find a better catalyst, we investigated the use of a number of thiol compounds. Substituted thiophenols with pKa > 6 were found to best combine the ability to exchange rapidly and completely with thioalkyl esters, and to then act as effective leaving groups in reaction of the peptide-thioester with the thiol...

542 citations

Journal ArticleDOI
TL;DR: Large-scale, comprehensive proteomic profiling of Alzheimer’s disease brain and cerebrospinal fluid reveals disease-associated protein coexpression modules and highlights the importance of glia and energy metabolism in disease pathogenesis.
Abstract: Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.

472 citations

Journal ArticleDOI
TL;DR: It is shown that elevating klotho expression decreases premature mortality and network dysfunction in human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD.
Abstract: Aging is the principal demographic risk factor for Alzheimer disease (AD), the most common neurodegenerative disorder. Klotho is a key modulator of the aging process and, when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition. Whether klotho can counteract deficits related to neurodegenerative diseases, such as AD, is unknown. Here we show that elevating klotho expression decreases premature mortality and network dysfunction in human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Increasing klotho levels prevented depletion of NMDA receptor (NMDAR) subunits in the hippocampus and enhanced spatial learning and memory in hAPP mice. Klotho elevation in hAPP mice increased the abundance of the GluN2B subunit of NMDAR in postsynaptic densities and NMDAR-dependent long-term potentiation, which is critical for learning and memory. Thus, increasing wild-type klotho levels or activities improves synaptic and cognitive functions, and may be of therapeutic benefit in AD and other cognitive disorders.

146 citations

Journal ArticleDOI
TL;DR: A new proteomic systems-level analysis of AD brain based on 6,533 proteins measured across AD, AsymAD, and controls using an analysis pipeline consisting of isobaric tandem mass tag (TMT) mass spectrometry and offline prefractionation is reported.
Abstract: The complicated cellular and biochemical changes that occur in brain during Alzheimer’s disease are poorly understood. In a previous study we used an unbiased label-free quantitative mass spectrometry-based proteomic approach to analyze these changes at a systems level in post-mortem cortical tissue from patients with Alzheimer’s disease (AD), asymptomatic Alzheimer’s disease (AsymAD), and controls. We found modules of co-expressed proteins that correlated with AD phenotypes, some of which were enriched in proteins identified as risk factors for AD by genetic studies. The amount of information that can be obtained from such systems-level proteomic analyses is critically dependent upon the number of proteins that can be quantified across a cohort. We report here a new proteomic systems-level analysis of AD brain based on 6,533 proteins measured across AD, AsymAD, and controls using an analysis pipeline consisting of isobaric tandem mass tag (TMT) mass spectrometry and offline prefractionation. Our new TMT pipeline allowed us to more than double the depth of brain proteome coverage. This increased depth of coverage greatly expanded the brain protein network to reveal new protein modules that correlated with disease and were unrelated to those identified in our previous network. Differential protein abundance analysis identified 350 proteins that had altered levels between AsymAD and AD not caused by changes in specific cell type abundance, potentially reflecting biochemical changes that are associated with cognitive decline in AD. RNA binding proteins emerged as a class of proteins altered between AsymAD and AD, and were enriched in network modules that correlated with AD pathology. We developed a proteogenomic approach to investigate RNA splicing events that may be altered by RNA binding protein changes in AD. The increased proteome depth afforded by our TMT pipeline allowed us to identify and quantify a large number of alternatively spliced protein isoforms in brain, including AD risk factors such as BIN1, PICALM, PTK2B, and FERMT2. Many of the new AD protein network modules were enriched in alternatively spliced proteins and correlated with molecular markers of AD pathology and cognition. Further analysis of the AD brain proteome will continue to yield new insights into the biological basis of AD.

143 citations

Journal ArticleDOI
TL;DR: Results are a promising step toward a network-based biomarker tool for AD clinical applications and identify cerebrospinal fluid biomarkers representing a wide spectrum of AD pathophysiology.
Abstract: Alzheimer's disease (AD) lacks protein biomarkers reflective of its diverse underlying pathophysiology, hindering diagnostic and therapeutic advancements. Here, we used integrative proteomics to identify cerebrospinal fluid (CSF) biomarkers representing a wide spectrum of AD pathophysiology. Multiplex mass spectrometry identified ~3500 and ~12,000 proteins in AD CSF and brain, respectively. Network analysis of the brain proteome resolved 44 biologically diverse modules, 15 of which overlapped with the CSF proteome. CSF AD markers in these overlapping modules were collapsed into five protein panels representing distinct pathophysiological processes. Synaptic and metabolic panels were decreased in AD brain but increased in CSF, while glial-enriched myelination and immunity panels were increased in brain and CSF. The consistency and disease specificity of panel changes were confirmed in >500 additional CSF samples. These panels also identified biological subpopulations within asymptomatic AD. Overall, these results are a promising step toward a network-based biomarker tool for AD clinical applications.

134 citations


Cited by
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Proceedings ArticleDOI
22 Jan 2006
TL;DR: Some of the major results in random graphs and some of the more challenging open problems are reviewed, including those related to the WWW.
Abstract: We will review some of the major results in random graphs and some of the more challenging open problems. We will cover algorithmic and structural questions. We will touch on newer models, including those related to the WWW.

7,116 citations

01 Jan 2002
TL;DR: In this paper, the interactions learners have with each other build interpersonal skills, such as listening, politely interrupting, expressing ideas, raising questions, disagreeing, paraphrasing, negotiating, and asking for help.
Abstract: 1. Interaction. The interactions learners have with each other build interpersonal skills, such as listening, politely interrupting, expressing ideas, raising questions, disagreeing, paraphrasing, negotiating, and asking for help. 2. Interdependence. Learners must depend on one another to accomplish a common objective. Each group member has specific tasks to complete, and successful completion of each member’s tasks results in attaining the overall group objective.

2,171 citations

Journal Article
TL;DR: Alk-3-en-1-ols are produced in good yields from isobutylene and formaldehyde in the presence of organic carboxylic acid salts of Group IB metals.
Abstract: The yield of alkenols and cycloalkenols is substantially improved by carrying out the reaction of olefins with formaldehyde in the presence of selected catalysts. In accordance with one embodiment, alk-3-en-1-ols are produced in good yields from isobutylene and formaldehyde in the presence of organic carboxylic acid salts of Group IB metals.

851 citations

Journal ArticleDOI
TL;DR: This tutorial review outlines the modern ligation methods that enable the efficient total chemical synthesis of enzymes and other protein molecules through the chemoselective reaction of unprotected synthetic peptides.
Abstract: This tutorial review outlines the modern ligation methods that enable the efficient total chemical synthesis of enzymes and other protein molecules. Key to this success is the chemoselective reaction of unprotected synthetic peptides (‘chemical ligation’). Notably, native chemical ligation enables the reaction of two unprotected peptides in aqueous solution at neutral pH to form a single product in near quantitative yield. Full-length synthetic polypeptides are folded to form the defined tertiary structure of the target protein molecule, which is characterized by mass spectrometry, NMR, and X-ray crystallography, in addition to biochemical and/or biological activity.

764 citations

Journal ArticleDOI
TL;DR: This Review summarizes recent developments in the field of chemoselective ligation and modification strategies and illustrates their application, with examples ranging from the total synthesis of proteins to the semisynthesis of naturally modified proteins.
Abstract: The investigation of biological processes by chemical methods, commonly referred to as chemical biology, often requires chemical access to biologically relevant macromolecules such as peptides and proteins. Building upon solid-phase peptide synthesis, investigations have focused on the development of chemoselective ligation and modification strategies to link synthetic peptides or other functional units to larger synthetic and biologically relevant macromolecules. This Review summarizes recent developments in the field of chemoselective ligation and modification strategies and illustrates their application, with examples ranging from the total synthesis of proteins to the semisynthesis of naturally modified proteins.

676 citations