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Article ; Online: Duration of SARS-CoV-2 mRNA vaccine persistence and factors associated with cardiac involvement in recently vaccinated patients.

Krauson, Aram J / Casimero, Faye Victoria C / Siddiquee, Zakir / Stone, James R

NPJ vaccines

2023 Volume 8, Issue 1, Page(s) 141

Abstract: At the start of the COVID-19 pandemic, the BNT162b2 (BioNTech-Pfizer) and mRNA-1273 (Moderna) mRNA vaccines were expediently designed and mass produced. Both vaccines produce the full-length SARS-CoV-2 spike protein for gain of immunity and have greatly ... ...

Abstract	At the start of the COVID-19 pandemic, the BNT162b2 (BioNTech-Pfizer) and mRNA-1273 (Moderna) mRNA vaccines were expediently designed and mass produced. Both vaccines produce the full-length SARS-CoV-2 spike protein for gain of immunity and have greatly reduced mortality and morbidity from SARS-CoV-2 infection. The distribution and duration of SARS-CoV-2 mRNA vaccine persistence in human tissues is unclear. Here, we developed specific RT-qPCR-based assays to detect each mRNA vaccine and screened lymph nodes, liver, spleen, and myocardium from recently vaccinated deceased patients. Vaccine was detected in the axillary lymph nodes in the majority of patients dying within 30 days of vaccination, but not in patients dying more than 30 days from vaccination. Vaccine was not detected in the mediastinal lymph nodes, spleen, or liver. Vaccine was detected in the myocardium in a subset of patients vaccinated within 30 days of death. Cardiac ventricles in which vaccine was detected had healing myocardial injury at the time of vaccination and had more myocardial macrophages than the cardiac ventricles in which vaccine was not detected. These results suggest that SARS-CoV-2 mRNA vaccines routinely persist up to 30 days from vaccination and can be detected in the heart.
Language	English
Publishing date	2023-09-27
Publishing country	England
Document type	Journal Article
ISSN	2059-0105
ISSN (online)	2059-0105
DOI	10.1038/s41541-023-00742-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The Thumb Domain Mediates Acid-sensing Ion Channel Desensitization.

Krauson, Aram J / Carattino, Marcelo D

The Journal of biological chemistry

2016 Volume 291, Issue 21, Page(s) 11407–11419

Abstract: Acid-sensing ion channels (ASICs) are cation-selective proton-gated channels expressed in neurons that participate in diverse physiological processes, including nociception, synaptic plasticity, learning, and memory. ASIC subunits contain intracellular N ...

Abstract	Acid-sensing ion channels (ASICs) are cation-selective proton-gated channels expressed in neurons that participate in diverse physiological processes, including nociception, synaptic plasticity, learning, and memory. ASIC subunits contain intracellular N and C termini, two transmembrane domains that constitute the pore, and a large extracellular loop with defined domains termed the finger, β-ball, thumb, palm, and knuckle. Here we examined the contribution of the finger, β-ball, and thumb domains to activation and desensitization through the analysis of chimeras and the assessment of the effect of covalent modification of introduced Cys at the domain-domain interfaces. Our studies with ASIC1a-ASIC2a chimeras showed that swapping the thumb domain between subunits results in faster channel desensitization. Likewise, the covalent modification of Cys residues at selected positions in the β-ball-thumb interface accelerates the desensitization of the mutant channels. Studies of accessibility with thiol-reactive reagents revealed that the β-ball and thumb domains reside apart in the resting state but that they become closer to each other in response to extracellular acidification. We propose that the thumb domain moves upon continuous exposure to an acidic extracellular milieu, assisting with the closing of the pore during channel desensitization.
MeSH term(s)	Acid Sensing Ion Channels/chemistry ; Acid Sensing Ion Channels/genetics ; Acid Sensing Ion Channels/metabolism ; Amino Acid Substitution ; Animals ; Electrochemical Techniques ; Female ; Mice ; Models, Molecular ; Mutagenesis, Site-Directed ; Oocytes/metabolism ; Protein Interaction Domains and Motifs ; Protein Subunits ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Xenopus laevis
Chemical Substances	ASIC1 protein, mouse ; ASIC2 protein, mouse ; Acid Sensing Ion Channels ; Protein Subunits ; Recombinant Fusion Proteins
Language	English
Publishing date	2016-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M115.702316
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Article ; Online: Molecular basis of inhibition of acid sensing ion channel 1A by diminazene.

Krauson, Aram J / Rooney, James G / Carattino, Marcelo D

PloS one

2018 Volume 13, Issue 5, Page(s) e0196894

Abstract: Acid-sensing ion channels (ASICs) are trimeric proton-gated cation permeable ion channels expressed primarily in neurons. Here we employed site-directed mutagenesis and electrophysiology to investigate the mechanism of inhibition of ASIC1a by diminazene. ...

Abstract	Acid-sensing ion channels (ASICs) are trimeric proton-gated cation permeable ion channels expressed primarily in neurons. Here we employed site-directed mutagenesis and electrophysiology to investigate the mechanism of inhibition of ASIC1a by diminazene. This compound inhibits mouse ASIC1a with a half-maximal inhibitory concentration (IC50) of 2.4 μM. At first, we examined whether neutralizing mutations of Glu79 and Glu416 alter diminazene block. These residues form a hexagonal array in the lower palm domain that was previously shown to contribute to pore opening in response to extracellular acidification. Significantly, single Gln substitutions at positions 79 and 416 in ASIC1a reduced diminazene apparent affinity by 6-7 fold. This result suggests that diminazene inhibits ASIC1a in part by limiting conformational rearrangement in the lower palm domain. Because diminazene is charged at physiological pHs, we assessed whether it inhibits ASIC1a by blocking the ion channel pore. Consistent with the notion that diminazene binds to a site within the membrane electric field, diminazene block showed a strong dependence with the membrane potential. Moreover, a Gly to Ala mutation at position 438, in the ion conduction pathway of ASIC1a, increased diminazene IC50 by one order of magnitude and eliminated the voltage dependence of block. Taken together, our results indicate that the inhibition of ASIC1a by diminazene involves both allosteric modulation and blocking of ion flow through the conduction pathway. Our findings provide a foundation for the development of more selective and potent ASIC pore blockers.
MeSH term(s)	Acid Sensing Ion Channel Blockers/pharmacology ; Acid Sensing Ion Channels/chemistry ; Acid Sensing Ion Channels/genetics ; Acid Sensing Ion Channels/metabolism ; Amino Acid Sequence ; Animals ; Binding Sites ; Cells, Cultured ; Conserved Sequence ; Diminazene/pharmacology ; Hydrogen-Ion Concentration ; Mice ; Oocytes/drug effects ; Oocytes/metabolism ; Protein Binding ; Xenopus laevis
Chemical Substances	ASIC1 protein, mouse ; Acid Sensing Ion Channel Blockers ; Acid Sensing Ion Channels ; Diminazene (Y5G36EEA5Z)
Language	English
Publishing date	2018-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0196894
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Article ; Online: Molecular basis of inhibition of acid sensing ion channel 1A by diminazene.

Aram J Krauson / James G Rooney / Marcelo D Carattino

PLoS ONE, Vol 13, Iss 5, p e

2018 Volume 0196894

Abstract	Acid-sensing ion channels (ASICs) are trimeric proton-gated cation permeable ion channels expressed primarily in neurons. Here we employed site-directed mutagenesis and electrophysiology to investigate the mechanism of inhibition of ASIC1a by diminazene. This compound inhibits mouse ASIC1a with a half-maximal inhibitory concentration (IC50) of 2.4 μM. At first, we examined whether neutralizing mutations of Glu79 and Glu416 alter diminazene block. These residues form a hexagonal array in the lower palm domain that was previously shown to contribute to pore opening in response to extracellular acidification. Significantly, single Gln substitutions at positions 79 and 416 in ASIC1a reduced diminazene apparent affinity by 6-7 fold. This result suggests that diminazene inhibits ASIC1a in part by limiting conformational rearrangement in the lower palm domain. Because diminazene is charged at physiological pHs, we assessed whether it inhibits ASIC1a by blocking the ion channel pore. Consistent with the notion that diminazene binds to a site within the membrane electric field, diminazene block showed a strong dependence with the membrane potential. Moreover, a Gly to Ala mutation at position 438, in the ion conduction pathway of ASIC1a, increased diminazene IC50 by one order of magnitude and eliminated the voltage dependence of block. Taken together, our results indicate that the inhibition of ASIC1a by diminazene involves both allosteric modulation and blocking of ion flow through the conduction pathway. Our findings provide a foundation for the development of more selective and potent ASIC pore blockers.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.

American journal of human genetics

2023 Volume 110, Issue 3, Page(s) 531–547

Abstract: Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in elongator acetyltransferase complex subunit 1 (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1, mainly in the ... ...

Abstract	Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in elongator acetyltransferase complex subunit 1 (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 production in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in individuals with FD. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the nervous system. We demonstrate that the novel compound PTC258 efficiently restores correct ELP1 splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse model TgFD9;Elp1
MeSH term(s)	Mice ; Animals ; Dysautonomia, Familial/genetics ; Kinetin ; Gait Ataxia ; Retinal Degeneration ; Neurodegenerative Diseases ; Administration, Oral
Chemical Substances	Kinetin (P39Y9652YJ)
Language	English
Publishing date	2023-02-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2023.01.019
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Article: Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage.

Morini, Elisabetta / Gao, Dadi / Logan, Emily M / Salani, Monica / Krauson, Aram J / Chekuri, Anil / Chen, Yei-Tsung / Ragavendran, Ashok / Chakravarty, Probir / Erdin, Serkan / Stortchevoi, Alexei / Svejstrup, Jesper Q / Talkowski, Michael E / Slaugenhaupt, Susan A

Journal of genetics and genomics = Yi chuan xue bao

2021 Volume 49, Issue 7, Page(s) 654–665

Abstract: Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1 (ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for ...

Abstract	Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1 (ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse (Elp1
MeSH term(s)	Animals ; Carrier Proteins/genetics ; Disease Models, Animal ; Dysautonomia, Familial/genetics ; Dysautonomia, Familial/metabolism ; Gene Expression ; Homozygote ; Humans ; Mice ; Sequence Deletion
Chemical Substances	Carrier Proteins
Language	English
Publishing date	2021-12-09
Publishing country	China
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2374568-X
ISSN	1873-5533 ; 1673-8527
ISSN (online)	1873-5533
ISSN	1673-8527
DOI	10.1016/j.jgg.2021.11.011
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Article ; Online: Selective retinal ganglion cell loss and optic neuropathy in a humanized mouse model of familial dysautonomia.

Chekuri, Anil / Logan, Emily M / Krauson, Aram J / Salani, Monica / Ackerman, Sophie / Kirchner, Emily G / Bolduc, Jessica M / Wang, Xia / Dietrich, Paula / Dragatsis, Ioannis / Vandenberghe, Luk H / Slaugenhaupt, Susan A / Morini, Elisabetta

Human molecular genetics

2021 Volume 31, Issue 11, Page(s) 1776–1787

Abstract: Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease caused by a splicing mutation in the gene encoding Elongator complex protein 1 (ELP1, also known as IKBKAP). This mutation results in tissue-specific skipping of exon 20 with ... ...

Abstract	Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease caused by a splicing mutation in the gene encoding Elongator complex protein 1 (ELP1, also known as IKBKAP). This mutation results in tissue-specific skipping of exon 20 with a corresponding reduction of ELP1 protein, predominantly in the central and peripheral nervous system. Although FD patients have a complex neurological phenotype caused by continuous depletion of sensory and autonomic neurons, progressive visual decline leading to blindness is one of the most problematic aspects of the disease, as it severely affects their quality of life. To better understand the disease mechanism as well as to test the in vivo efficacy of targeted therapies for FD, we have recently generated a novel phenotypic mouse model, TgFD9; IkbkapΔ20/flox. This mouse exhibits most of the clinical features of the disease and accurately recapitulates the tissue-specific splicing defect observed in FD patients. Driven by the dire need to develop therapies targeting retinal degeneration in FD, herein, we comprehensively characterized the progression of the retinal phenotype in this mouse, and we demonstrated that it is possible to correct ELP1 splicing defect in the retina using the splicing modulator compound (SMC) BPN-15477.
MeSH term(s)	Animals ; Disease Models, Animal ; Dysautonomia, Familial/pathology ; Humans ; Intracellular Signaling Peptides and Proteins ; Mice ; Neurodegenerative Diseases/pathology ; Optic Nerve Diseases/pathology ; Retinal Ganglion Cells/pathology
Chemical Substances	Ikbkap protein, mouse ; Intracellular Signaling Peptides and Proteins
Language	English
Publishing date	2021-12-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddab359
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Article ; Online: Independent contribution of extracellular proton binding sites to ASIC1a activation.

Krauson, Aram J / Rued, Anna C / Carattino, Marcelo D

The Journal of biological chemistry

2013 Volume 288, Issue 48, Page(s) 34375–34383

Abstract: Acid-sensing ion channels (ASICs) are a group of trimeric cation permeable channels gated by extracellular protons that are mainly expressed in the nervous system. Despite the structural information available for ASIC1, there is limited understanding of ... ...

Abstract	Acid-sensing ion channels (ASICs) are a group of trimeric cation permeable channels gated by extracellular protons that are mainly expressed in the nervous system. Despite the structural information available for ASIC1, there is limited understanding of the molecular mechanism that allows these channels to sense and respond to drops in extracellular pH. In this report, we employed the substituted cysteine accessibility method and site-directed mutagenesis to examine the mechanism of activation of ASIC1a by extracellular protons. We found that the modification of E238C and D345C channels by MTSET reduced proton apparent affinity for activation. Furthermore, the introduction of positively charged residues at position 345 rendered shifted biphasic proton activation curves. Likewise, channels bearing mutations at positions 79 and 416 in the palm domain of the channel showed reduced proton apparent affinity and biphasic proton activation curves. Of significance, the effect of the mutations at positions 79 and 345 on channel activation was additive. E79K-D345K required a change to a pH lower than 2 for maximal activation. In summary, this study provides direct evidence for the presence of two distinct proton coordination sites in the extracellular region of ASIC1a, which jointly facilitate pore opening in response to extracellular acidification.
MeSH term(s)	Acid Sensing Ion Channels/chemistry ; Acid Sensing Ion Channels/genetics ; Acid Sensing Ion Channels/metabolism ; Amino Acids/chemistry ; Amino Acids/metabolism ; Animals ; Binding Sites ; Cysteine/chemistry ; Cysteine/metabolism ; Hydrogen-Ion Concentration ; Mice ; Mutagenesis, Site-Directed ; Mutation ; Nervous System/metabolism ; Oocytes/cytology ; Oocytes/metabolism ; Protein Conformation ; Protein Subunits/chemistry ; Protein Subunits/genetics ; Protein Subunits/metabolism ; Protons ; Structure-Activity Relationship ; Transcriptional Activation/genetics ; Xenopus laevis
Chemical Substances	ASIC1 protein, mouse ; Acid Sensing Ion Channels ; Amino Acids ; Protein Subunits ; Protons ; Cysteine (K848JZ4886)
Language	English
Publishing date	2013-10-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M113.504324
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Article ; Online: Toward the de novo design of antimicrobial peptides: Lack of correlation between peptide permeabilization of lipid vesicles and antimicrobial, cytolytic, or cytotoxic activity in living cells.

He, Jing / Krauson, Aram J / Wimley, William C

Biopolymers

2013 Volume 102, Issue 1, Page(s) 1–6

Abstract: We previously performed a lipid vesicle-based, high-throughput screen on a 26-residue combinatorial peptide library that was designed de novo to yield membrane-permeabilizing peptides that fold into β-sheets. The most active and soluble library members ... ...

Abstract	We previously performed a lipid vesicle-based, high-throughput screen on a 26-residue combinatorial peptide library that was designed de novo to yield membrane-permeabilizing peptides that fold into β-sheets. The most active and soluble library members that were identified permeabilized lipid vesicles detectably, but not with high potency. Nonetheless, they were broad-spectrum, membrane-permeabilizing antibiotics with minimum sterilizing activity at low µM concentrations. In an expansion of that work, we recently performed an iterative screen in which an active consensus sequence from that first-generation library was used as a template to design a second-generation library which was then screened against lipid vesicles at very high stringency. Compared to the consensus sequence from the first library, the most active second-generation peptides are highly potent, equilibrium pore-formers in synthetic lipid vesicles. Here, we use these first- and second-generation families of peptides to test the hypothesis that a large increase in potency in bacteria-like lipid vesicles will correlate with a large improvement in antimicrobial activity. The results do not support the hypothesis. Despite a 20-fold increase in potency against bacteria-like lipid vesicles, the second-generation peptides are only slightly more active against bacteria, and at the same time, are also more toxic against mammalian cells. The results suggest that a "pipeline" strategy toward the optimization of antimicrobial peptides could begin with a vesicle-based screen for identifying families with broad-spectrum activity, but will also need to include screening or optimization steps that are done under conditions that are more directly relevant to possible therapeutic applications.
MeSH term(s)	Amino Acid Sequence ; Animals ; Antimicrobial Cationic Peptides/chemical synthesis ; Antimicrobial Cationic Peptides/chemistry ; Antimicrobial Cationic Peptides/pharmacology ; Bacteria/drug effects ; CHO Cells ; Cell Death/drug effects ; Cell Survival/drug effects ; Cricetinae ; Cricetulus ; Drug Design ; Lipid Bilayers/chemistry ; Microbial Sensitivity Tests ; Molecular Sequence Data ; Permeability
Chemical Substances	Antimicrobial Cationic Peptides ; Lipid Bilayers
Language	English
Publishing date	2013-07-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1123-x
ISSN	1097-0282 ; 0006-3525
ISSN (online)	1097-0282
ISSN	0006-3525
DOI	10.1002/bip.22281
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Article ; Online: Gain-of-function analogues of the pore-forming peptide melittin selected by orthogonal high-throughput screening.

Krauson, Aram J / He, Jing / Wimley, William C

Journal of the American Chemical Society

2012 Volume 134, Issue 30, Page(s) 12732–12741

Abstract: We recently developed an orthogonal, high-throughput assay to identify peptides that self-assemble into potent, equilibrium pores in synthetic lipid bilayers. Here, we use this assay as a high-throughput screen to select highly potent pore-forming ... ...

Abstract	We recently developed an orthogonal, high-throughput assay to identify peptides that self-assemble into potent, equilibrium pores in synthetic lipid bilayers. Here, we use this assay as a high-throughput screen to select highly potent pore-forming peptides from a 7776-member rational combinatorial peptide library based on the sequence of the natural pore-forming peptide toxin melittin. In the library we varied ten critical residues in the melittin sequence, chosen to test specific structural hypotheses about the mechanism of pore formation. Using the new high-throughput assay, we screened the library for gain-of-function sequences at a peptide to lipid ratio of 1:1000 where native melittin is not active. More than 99% of the library sequences were also inactive under these conditions. A small number of library members (0.1%) were highly active. From these we identified 14 potent, gain-of-function, pore-forming sequences. These sequences differed from melittin in only 2-6 amino acids out of 26. Some native residues were highly conserved and others were consistently changed. The two factors that were essential for gain-of-function were the preservation of melittin's proline-dependent break in the middle of the helix and the improvement and extension the amphipathic nature of the α-helix. In particular the highly cationic carboxyl-terminal sequence of melittin, is consistently changed in the gain-of-function variants to a sequence that it is capable of participating in an extended amphipathic α-helix. The most potent variants reside in a membrane-spanning orientation, in contrast to the parent melittin, which is predominantly surface bound. This structural information, taken together with the high-throughput tools developed for this work, enable the identification, refinement and optimization of pore-forming peptides for many potential applications.
MeSH term(s)	Amino Acid Sequence ; Conserved Sequence ; High-Throughput Screening Assays ; Melitten/analogs & derivatives ; Melitten/pharmacology ; Molecular Sequence Data ; Peptide Library ; Phospholipids/metabolism ; Unilamellar Liposomes/metabolism
Chemical Substances	Peptide Library ; Phospholipids ; Unilamellar Liposomes ; Melitten (20449-79-0)
Language	English
Publishing date	2012-07-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/ja3042004
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