Affinage

DEFA1

Neutrophil defensin 1 · UniProt P59665

Round 2 corrected
Length
94 aa
Mass
10.2 kDa
Annotated
2026-04-28
130 papers in source corpus 19 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DEFA1 encodes neutrophil defensin 1 (HNP-1), a cationic antimicrobial peptide of the innate immune system that is synthesized as a preprodefensin precursor, sequentially processed via signal peptide removal and anionic propiece cleavage in acidic granular compartments, and stored as a mature 29-residue peptide in neutrophil azurophil granules (PMID:2997278, PMID:3174637, PMID:1339298). The anionic propiece functions as an intramolecular inhibitor that prevents autocytotoxicity during biosynthesis, while the mature peptide kills bacteria through dual mechanisms: binding the cell wall precursor lipid II to inhibit cell wall synthesis and forming amphiphilic dimeric channels that permeabilize membranes (PMID:8601627, PMID:20214904, PMID:2006422). Beyond direct microbicidal activity, HNP-1 chemoattracts naive T cells and immature dendritic cells via a Gαi-coupled receptor, neutralizes adenovirus by blocking endosomal capsid disassembly, inhibits HIV-1 replication through PKC-dependent suppression of nuclear import, and triggers P2X7/NLRP3-dependent caspase-1 activation and pyroptosis in macrophages and endothelial cells—with elevated DEFA1/DEFA3 gene copy number worsening sepsis severity in vivo (PMID:10914484, PMID:18191790, PMID:15719067, PMID:30718392).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1985 High

    Identification and sequencing of HNP-1 from azurophil granules established it as a small, cystine- and arginine-rich antimicrobial peptide and founding member of the defensin family.

    Evidence Chromatographic purification, immunogold EM localization to azurophil granules, Edman degradation sequencing of HNP-1/2/3

    PMID:2997278 PMID:4056036

    Open questions at the time
    • Mechanism of microbial killing undefined
    • Gene structure and biosynthetic pathway unknown
  2. 1988 High

    Cloning of DEFA1 cDNA revealed that HNP-1 is synthesized as a ~94-residue preprodefensin precursor requiring proteolytic maturation, with expression restricted to bone marrow myeloid precursors.

    Evidence cDNA library screening from HL-60 cells, Northern blot of bone marrow vs. peripheral blood

    PMID:3174637

    Open questions at the time
    • Identity of the processing protease(s) unknown
    • Subcellular site of each processing step undefined
  3. 1991 High

    The crystal structure of HNP-3 (differing from HNP-1 only at residue 1) at 1.9 Å resolution revealed a dimeric amphiphilic β-sheet fold, providing a structural basis for how defensins insert into and permeabilize lipid bilayers.

    Evidence X-ray crystallography of HNP-3 at 1.9 Å

    PMID:2006422

    Open questions at the time
    • Structure solved for HNP-3, not HNP-1 directly
    • In-membrane conformation and channel stoichiometry unresolved
  4. 1992 High

    Pulse-chase metabolic labeling dissected the two-step precursor processing pathway—signal peptide removal yielding a 75-aa intermediate followed by propiece cleavage in acidic compartments yielding a 56-aa species en route to mature HNP-1.

    Evidence [35S]-methionine pulse-chase in HL-60 cells, subcellular fractionation, lysosomotropic agent blockade

    PMID:1339298

    Open questions at the time
    • Specific protease responsible for propiece cleavage not identified
    • Whether processing differs across neutrophil lineage stages unclear
  5. 1996 High

    Reconstitution experiments demonstrated that the anionic propiece acts as an intramolecular chaperone-inhibitor, blocking HNP-1 binding to target membranes and preventing premature cytotoxicity during biosynthesis.

    Evidence Recombinant proHNP-1 expression in baculovirus, cyanogen bromide cleavage, bactericidal and cell-permeabilization assays with exogenous propiece

    PMID:8601627

    Open questions at the time
    • Structural basis of propiece-mediated inhibition not defined
    • Whether propiece has independent biological function unknown
  6. 2000 High

    HNP-1 was shown to function as a chemoattractant for naive T cells and immature dendritic cells through a pertussis toxin-sensitive Gαi-coupled receptor, linking defensins to adaptive immune cell recruitment.

    Evidence Chemotaxis assays with primary human T cell subsets and dendritic cells, pertussis toxin inhibition

    PMID:10914484

    Open questions at the time
    • Identity of the Gαi-coupled receptor not determined
    • In vivo relevance of defensin-mediated chemotaxis not established at this time
  7. 2005 High

    HNP-1 was found to inhibit HIV-1 through both direct virucidal effects and a cellular mechanism involving PKC suppression that blocks viral nuclear import and transcription after integration.

    Evidence HIV-1 replication kinetics, PKC phosphorylation analysis, pharmacological epistasis with bryostatin-1, analysis of HIV-1 DNA intermediates in primary CD4+ T cells

    PMID:15719067

    Open questions at the time
    • Specific PKC isoform targeted not identified
    • In vivo relevance at physiological HNP-1 concentrations uncertain
  8. 2008 High

    The molecular mechanism of adenovirus neutralization was defined: HNP-1 binds the virion vertex and prevents capsid disassembly, blocking pVI release and endosomal escape, trapping virions in endosomes/lysosomes.

    Evidence Infectivity assays, confocal tracking of endosomal trafficking, capsid disassembly and pVI release assays

    PMID:18191790

    Open questions at the time
    • Exact binding site on vertex proteins not resolved at atomic level
    • Breadth across other non-enveloped virus families untested
  9. 2009 High

    ART1-mediated ADP-ribosylation of HNP-1 at arginines 14 and 24 was identified as a post-translational modification that attenuates antimicrobial potency, with nonenzymatic conversion of ADP-ribosylarginine-14 to ornithine confirmed in patient bronchoalveolar lavage fluid.

    Evidence In vitro ADP-ribosylation with ART1, site identification by mass spectrometry, detection of ADP-ribosyl-HNP-ornithine in IPF patient BALF

    PMID:19897717

    Open questions at the time
    • Physiological regulation of ART1-HNP-1 interaction not characterized
    • Whether ornithine conversion alters immunomodulatory functions unknown
  10. 2010 High

    Discovery that HNP-1 binds lipid II and that lipid II depletion abrogates bacterial killing established inhibition of cell wall biosynthesis as a primary antibacterial mechanism, distinct from membrane permeabilization alone.

    Evidence Direct lipid II binding assay, killing assays in lipid II-depleted bacteria, dissociation of killing from membrane permeabilization

    PMID:20214904

    Open questions at the time
    • Structural basis of HNP-1–lipid II interaction unresolved
    • Relative contribution of lipid II binding vs. pore formation across different species not quantified
  11. 2010 High

    HNP-1 was positioned downstream of NOD2 in intestinal innate immunity: NOD2 stimulation with MDP induces HNP-1 secretion from epithelial cells, and HNP-1 is required for NOD2-dependent NF-κB activation and antibacterial activity against Salmonella.

    Evidence siRNA knockdown of HNP-1 in epithelial cells, NF-κB reporter assays, gentamicin protection assay, NOD2 mutagenesis

    PMID:19856414

    Open questions at the time
    • How HNP-1 feeds back to activate NF-κB mechanistically is unclear
    • Relevance to Crohn's disease-associated NOD2 mutations not directly tested
  12. 2013 High

    The inflammasome-activating mechanism of HNP-1 was delineated: direct binding to P2X7 receptor triggers K+ efflux, NLRP3/caspase-1 activation, pyroptotic pore formation, and IL-1β release in macrophages.

    Evidence P2X7 pharmacological inhibition, GST pulldown, confocal co-localization, NLRP3 siRNA, caspase-1 and ethidium bromide uptake assays in THP-1 cells

    PMID:23792296

    Open questions at the time
    • Binding interface between HNP-1 and P2X7 not structurally defined
    • Whether other defensins share this pathway untested
  13. 2019 High

    In vivo validation in transgenic mice demonstrated that DEFA1/DEFA3 copy number drives sepsis severity through HNP-1-induced endothelial pyroptosis via P2X7/NLRP3/caspase-1, and a P2X7-blocking antibody rescued high-copy-number animals from lethal sepsis.

    Evidence Neutrophil-specific DEFA1/DEFA3 transgenic mice, CLP sepsis model, endothelial permeability and pyroptosis assays, therapeutic anti-P2X7 antibody

    PMID:30718392

    Open questions at the time
    • Translational relevance of DEFA1 copy number variation to human sepsis outcomes requires clinical validation
    • Whether anti-P2X7 blockade impairs necessary defensin antimicrobial functions in vivo unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the Gαi-coupled chemotactic receptor for HNP-1, the structural basis of HNP-1–lipid II and HNP-1–P2X7 interactions, and the protease(s) responsible for propiece cleavage during biosynthetic maturation.
  • Chemotactic receptor identity unknown
  • HNP-1–lipid II co-crystal structure lacking
  • Propiece-processing protease not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0090729 toxin activity 3 GO:0048018 receptor ligand activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2
Partners
ART1NLRP3NOD2P2RX7

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 HNP-1 (DEFA1 gene product) was isolated from human neutrophil azurophil granules and shown to be a small antimicrobial peptide (~3,500 Da) with broad-spectrum bactericidal, antifungal, and antiviral activity; immunogold electron microscopy confirmed its localization specifically to azurophil granules. Chromatographic/electrophoretic purification, antimicrobial killing assays, immunoperoxidase and immunogold electron microscopy The Journal of clinical investigation High 2997278
1985 The primary amino acid sequences of HNP-1, HNP-2, and HNP-3 were determined; all three are 29-30 residues, rich in cystine and arginine, devoid of free sulfhydryls, and differ only at their amino-terminal residues, defining a multigene defensin family. Protein sequencing (Edman degradation), amino acid analysis The Journal of clinical investigation High 4056036
1988 Defensin cDNA clones encoding HNP-1 were isolated from an HL-60 library, establishing that defensins are synthesized as ~94 amino acid precursor proteins (preprodefensins) that require proteolytic processing to yield the mature 29-30 residue peptides; defensin mRNA was detected in bone marrow but not peripheral blood leukocytes. cDNA library screening, Northern blot, sequence analysis Proceedings of the National Academy of Sciences of the United States of America High 3174637
1991 The crystal structure of defensin HNP-3 (a closely related paralog differing from HNP-1 only at position 1) was solved at 1.9 Å resolution, revealing a dimeric amphiphilic beta-sheet architecture; the dimer structure suggested a mechanism of membrane permeabilization in which defensins bind and intercalate into lipid bilayers to form channels. X-ray crystallography (1.9 Å resolution) Science (New York, N.Y.) High 2006422
1992 Metabolic labeling in HL-60 promyelocytes showed that preprodefensins are processed to mature HNP-1 (~29-30 aa) via two sequential intermediates: a 75 aa prodefensin (after signal sequence cleavage, found in cytoplasmic/microsomal fraction) and a 56 aa prodefensin (after preaspartate cleavage, found in granule-enriched fraction); neutralization of acidic compartments with monensin/chloroquine partially blocked conversion, implicating acidic vesicles in processing. Metabolic radiolabeling ([35S]-methionine), subcellular fractionation, SDS-PAGE, treatment with lysosomotropic agents Blood High 1339298
1993 Defensins (including HNP-1) kill microorganisms and mammalian cells through a common mechanism involving initial electrostatic interaction with negatively charged membrane lipid head groups, followed by membrane insertion and formation of voltage-regulated channels; defensins also act as opsonins, inhibit protein kinase C, and act as chemoattractants for monocytes. Review synthesizing lipid bilayer reconstitution, electrophysiology (voltage-regulated channels), and functional assays Annual review of immunology High 8476558
1996 The anionic propiece (residues 20-64) of HNP-1 acts as an intramolecular inhibitor of HNP-1 cytotoxicity: proHNP-1(20-94) is virtually inactive against bacteria and in permeabilizing cells, and the unlinked propiece inhibits bactericidal and cell-permeabilizing activity of mature HNP-1 in a dose-dependent manner by interfering with HNP-1 binding to target cells. Recombinant baculovirus expression of preproHNP-1, cyanogen bromide cleavage, microbicidal assays against Listeria monocytogenes, K562 cell permeabilization assay, HPLC, mass spectrometry, acid-urea PAGE The Journal of clinical investigation High 8601627
2000 Human neutrophil defensins (including HNP-1) selectively chemoattract naive CD4+/CD45RA+ T cells, CD8+ T cells, and immature (but not mature) dendritic cells; the chemotactic effect is pertussis toxin-sensitive, indicating signaling through a Gαi protein-coupled receptor. Chemotaxis assays with human primary T cells and dendritic cell subsets, pertussis toxin inhibition Journal of leukocyte biology High 10914484
2001 HNP-1 inhibits adenoviral infection of 293 cells with IC50 ~15 µg/ml and >95% inhibition at 50 µg/ml, suggesting that alpha-defensin-1 present in bronchoalveolar lavage can neutralize adenovirus infectivity. Adenovirus type-5 infection assay in 293 cells, dose-response analysis Regulatory peptides Medium 11495691
2005 Alpha-defensin-1 (HNP-1) inhibits HIV-1 at two levels: (1) a direct virucidal effect on HIV-1 virions at low MOI in the absence of serum, and (2) a cellular effect in which it inhibits PKC activity in primary CD4+ T cells, blocking HIV-1 nuclear import and transcription steps following reverse transcription and integration; bryostatin-1 (PKC activator) partially reversed this inhibition. HIV-1 replication kinetics assay, PKC phosphorylation analysis, pharmacological PKC inhibitors/activators, analysis of HIV-1 DNA intermediates in primary CD4+ T cells The Journal of clinical investigation High 15719067
2005 Quantitative antimicrobial comparison showed that among human alpha-defensins, HNP-1 (DEFA1 product) has intermediate potency: against S. aureus the order is HNP2 > HNP1 > HNP3 > HNP4, while against gram-negative bacteria HNP4 > HNP2 > HNP1 = HNP3. Kinetic 96-well turbidimetric antimicrobial assay with synthetic peptides; virtual LD50/90/99 determination Antimicrobial agents and chemotherapy High 15616305
2007 Truncated HNP-1 analogues modeled on the C-terminal beta-hairpin region but lacking disulfide bridges retained antimicrobial activity; the analogue 2Abz(23)S(29) displayed broad-spectrum antibacterial activity against all bacterial strains tested, suggesting the C-terminal beta-hairpin is a key antimicrobial pharmacophore. Solid-phase peptide synthesis, antimicrobial MIC assays against multiple bacterial strains including oral pathogens Molecular immunology Medium 17548109
2008 Human alpha-defensins (including HNP-1) inhibit adenovirus infection by directly binding the virus and blocking disassembly at the vertex region, thereby preventing release of the internal capsid protein pVI required for endosomal membrane penetration; this results in virion accumulation in early endosomes and lysosomes. Virus infectivity assays, confocal microscopy of endosomal trafficking, capsid disassembly assay, pVI release assay Cell host & microbe High 18191790
2009 ART1 (ADP-ribosyltransferase 1) on airway epithelial cell surfaces ADP-ribosylates HNP-1 specifically on arginines 14 and 24; this modification decreases antimicrobial activity. Furthermore, ADP-ribosylation of arginine 14 undergoes nonenzymatic hydrolysis to yield the non-coded amino acid ornithine, and ADP-ribosyl-HNP-ornithine was detected in bronchoalveolar lavage fluid from IPF patients, indicating this conversion occurs in vivo. In vitro ADP-ribosylation assay with ART1, mass spectrometry, amino acid analysis, incubation at 37°C for nonenzymatic hydrolysis, analysis of patient BALF by MS Proceedings of the National Academy of Sciences of the United States of America High 19897717
2010 HNP-1 binds to the bacterial cell wall precursor lipid II; reduction of lipid II levels in bacterial membranes significantly reduces HNP-1 killing, establishing inhibition of cell wall synthesis (via lipid II binding) as a novel antibacterial mechanism distinct from simple membrane disruption. Lipid II binding assay, bacterial killing assays with lipid II-depleted strains, membrane permeabilization assays (showing no correlation between membrane disruption and killing) FEBS letters High 20214904
2010 The three-dimensional structure of HNP-1 was determined in the microcrystalline state by solid-state NMR; the structure closely resembles the crystal structure of the HNP family but reveals flexibility in the loop region between the first and second beta-strands, suggesting this segment may regulate HNP-1 interaction with phospholipid membranes. Solid-state magic-angle spinning NMR (2D and 3D), 13C/15N chemical shift torsion angle constraints, inter-residue distance measurements Journal of molecular biology High 20097206
2010 HNP-1 secretion by intestinal epithelial cells is induced specifically by NOD2 stimulation with MDP (muramyl dipeptide); HNP-1 is required for NOD2-dependent NF-κB activation and for NOD2-mediated antibacterial activity against S. typhimurium, as demonstrated by siRNA knockdown of HNP-1 abrogating both responses. qRT-PCR, Western blot, ELISA, NF-κB luciferase reporter assay, siRNA knockdown, gentamicin protection assay (bacterial killing), NOD2 site-directed mutagenesis Inflammatory bowel diseases High 19856414
2013 HNP-1 induces IL-1β release and pyroptotic pore formation in LPS-primed THP-1 macrophages through a P2X7 receptor → K+ efflux → caspase-1 activation pathway; GST pulldown and confocal microscopy demonstrated direct binding of HNP-1 to P2X7. NLRP3 knockdown decreased caspase-1 activation and pore formation but not IL-1β release, indicating NLRP3 plays different roles in these two HNP-1-induced outcomes. P2X7 inhibitor pharmacology, GST pulldown, confocal co-localization, caspase-1 activity assay, KCl efflux experiments, ethidium bromide uptake (pore formation), NLRP3 siRNA knockdown, ELISA Innate immunity High 23792296
2019 In DEFA1/DEFA3 transgenic mice with neutrophil-specific expression, higher DEFA1/DEFA3 copy number caused more severe sepsis-related organ damage and mortality via endothelial barrier dysfunction and endothelial cell pyroptosis; mechanistically, HNP-1 induces endothelial pyroptosis via P2X7 receptor-mediated canonical caspase-1 activation in an NLRP3 inflammasome-dependent manner; a monoclonal antibody blocking HNP-1/P2X7 interaction protected high-copy-number mice from lethal sepsis. Transgenic mouse generation (neutrophil-specific DEFA1/DEFA3 expression), cecal ligation and puncture sepsis model, endothelial permeability assays, pyroptosis assays (caspase-1, NLRP3), P2X7 blocking antibody experiment Proceedings of the National Academy of Sciences of the United States of America High 30718392

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1985 Defensins. Natural peptide antibiotics of human neutrophils. The Journal of clinical investigation 1192 2997278
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1993 Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annual review of immunology 820 8476558
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1996 Widespread expression of beta-defensin hBD-1 in human secretory glands and epithelial cells. FEBS letters 468 8915011
1991 Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization. Science (New York, N.Y.) 444 2006422
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1985 Primary structures of three human neutrophil defensins. The Journal of clinical investigation 434 4056036
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
1997 Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes. The Journal of neuroscience : the official journal of the Society for Neuroscience 413 9030614
2000 Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells. Journal of leukocyte biology 385 10914484
2011 Glutamate in schizophrenia: a focused review and meta-analysis of ¹H-MRS studies. Schizophrenia bulletin 356 21746807
1996 Inhibition of N-acetylaspartate production: implications for 1H MRS studies in vivo. Neuroreport 356 8856684
2010 Fluorine (19F) MRS and MRI in biomedicine. NMR in biomedicine 350 20842758
2005 Antibacterial activity and specificity of the six human {alpha}-defensins. Antimicrobial agents and chemotherapy 263 15616305
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2007 Absolute quantification of phosphorus metabolite concentrations in human muscle in vivo by 31P MRS: a quantitative review. NMR in biomedicine 251 17628042
2009 Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). Journal of proteome research 237 19199708
2010 Proteomics characterization of extracellular space components in the human aorta. Molecular & cellular proteomics : MCP 231 20551380
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2011 13C MRS studies of neuroenergetics and neurotransmitter cycling in humans. NMR in biomedicine 216 21882281
2012 Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington's disease. PloS one 207 23284644
2005 Dual role of alpha-defensin-1 in anti-HIV-1 innate immunity. The Journal of clinical investigation 191 15719067
2002 A Rad26-Def1 complex coordinates repair and RNA pol II proteolysis in response to DNA damage. Nature 188 11859374
2010 Functional interaction of human neutrophil peptide-1 with the cell wall precursor lipid II. FEBS letters 185 20214904
2006 Crystal structures of human alpha-defensins HNP4, HD5, and HD6. Protein science : a publication of the Protein Society 174 17088326
1992 Posttranslational processing of defensins in immature human myeloid cells. Blood 161 1339298
2014 The alpha defensin-1 biomarker assay can be used to evaluate the potentially infected total joint arthroplasty. Clinical orthopaedics and related research 158 25256621
2008 Mechanism of adenovirus neutralization by Human alpha-defensins. Cell host & microbe 155 18191790
2005 Copy number polymorphism and expression level variation of the human alpha-defensin genes DEFA1 and DEFA3. Human molecular genetics 152 15944200
2003 Antimicrobial peptides in amniotic fluid: defensins, calprotectin and bacterial/permeability-increasing protein in patients with microbial invasion of the amniotic cavity, intra-amniotic inflammation, preterm labor and premature rupture of membranes. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 150 12710851
1988 Isolation and characterization of human defensin cDNA clones. Proceedings of the National Academy of Sciences of the United States of America 140 3174637
2013 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics 138 23533145
2001 Human alpha-defensin 1 (HNP-1) inhibits adenoviral infection in vitro. Regulatory peptides 132 11495691
2014 GABA and glutamate in schizophrenia: a 7 T ¹H-MRS study. NeuroImage. Clinical 131 25379453
1995 Corticosterone, brain mineralocorticoid receptors (MRs) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis: the Lewis rat as an example of increased central MR capacity and a hyporesponsive HPA axis. Psychoneuroendocrinology 130 8584606
1996 Intramolecular inhibition of human defensin HNP-1 by its propiece. The Journal of clinical investigation 111 8601627
2005 A review of the possible relevance of inositol and the phosphatidylinositol second messenger system (PI-cycle) to psychiatric disorders--focus on magnetic resonance spectroscopy (MRS) studies. Human psychopharmacology 107 15880397
2012 Altered neurochemical profile after traumatic brain injury: (1)H-MRS biomarkers of pathological mechanisms. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 95 22892723
2001 Direct determination of the N-acetyl-L-aspartate synthesis rate in the human brain by (13)C MRS and [1-(13)C]glucose infusion. Journal of neurochemistry 95 11279290
2009 Changes in MRS neuronal markers and T cell phenotypes observed during early HIV infection. Neurology 77 19398702
2013 Proteasome-mediated processing of Def1, a critical step in the cellular response to transcription stress. Cell 71 23993092
2019 Dynamic Imaging of Glucose and Lactate Metabolism by 13C-MRS without Hyperpolarization. Scientific reports 68 30833588
2019 Increased gene copy number of DEFA1/DEFA3 worsens sepsis by inducing endothelial pyroptosis. Proceedings of the National Academy of Sciences of the United States of America 63 30718392
2015 MRI/MRS in neuroinflammation: methodology and applications. Clinical and translational imaging 63 26705534
2021 Prodromal neuroinflammatory, cholinergic and metabolite dysfunction detected by PET and MRS in the TgF344-AD transgenic rat model of AD: a collaborative multi-modal study. Theranostics 60 34093845
2005 Heterogeneity in 1H-MRS profiles of presymptomatic and early manifest Huntington's disease. Brain research 60 15621015
2017 Insights into brain microstructure from in vivo DW-MRS. NeuroImage 58 29155183
2012 Gamma-aminobutyric acid and glutamic acid levels in the auditory pathway of rats with chronic tinnitus: a direct determination using high resolution point-resolved proton magnetic resonance spectroscopy (H-MRS). Frontiers in systems neuroscience 57 22383901
1997 Behavioral and neuroendocrine responses controlled by the concerted action of central mineralocorticoid (MRS) and glucocorticoid receptors (GRS). Psychoneuroendocrinology 55 9264153
2022 MRSCloud: A cloud-based MRS tool for basis set simulation. Magnetic resonance in medicine 52 35775808
2015 The use of dynamic nuclear polarization (13)C-pyruvate MRS in cancer. American journal of nuclear medicine and molecular imaging 51 26550544
2005 Quantitative proton MRS of Pelizaeus-Merzbacher disease: evidence of dys- and hypomyelination. Neurology 51 16157902
1992 The contribution made by cell death and oxygenation to 31P MRS observations of tumour energy metabolism. NMR in biomedicine 51 1449969
2012 Correlation of a priori DCE-MRI and (1)H-MRS data with molecular markers in neck nodal metastases: Initial analysis. Oral oncology 50 22366441
1999 Sjögren-Larsson syndrome: clinical and MRI/MRS findings in FALDH-deficient patients. Neurology 49 10227616
2018 Integrated imaging of [11C]-PBR28 PET, MR diffusion and magnetic resonance spectroscopy 1H-MRS in amyotrophic lateral sclerosis. NeuroImage. Clinical 47 30112276
2007 Ha-DEF1, a sunflower defensin, induces cell death in Orobanche parasitic plants. Planta 47 17375322
2004 DNA damage-induced Def1-RNA polymerase II interaction and Def1 requirement for polymerase ubiquitylation in vitro. The Journal of biological chemistry 47 15166235
2017 Diabetic db/db mice do not develop heart failure upon pressure overload: a longitudinal in vivo PET, MRI, and MRS study on cardiac metabolic, structural, and functional adaptations. Cardiovascular research 46 28549111
2016 Activation of Phosphatidylcholine-Specific Phospholipase C in Breast and Ovarian Cancer: Impact on MRS-Detected Choline Metabolic Profile and Perspectives for Targeted Therapy. Frontiers in oncology 46 27532027
2009 ADP-ribosylation of human defensin HNP-1 results in the replacement of the modified arginine with the noncoded amino acid ornithine. Proceedings of the National Academy of Sciences of the United States of America 44 19897717
2007 Antimicrobial activity of truncated alpha-defensin (human neutrophil peptide (HNP)-1) analogues without disulphide bridges. Molecular immunology 44 17548109
2004 Time course of NAA T2 and ADC(w) in ischaemic stroke patients: 1H MRS imaging and diffusion-weighted MRI. Journal of the neurological sciences 44 15140601
2021 Anterior cingulate cortex neurometabolites in bipolar disorder are influenced by mood state and medication: A meta-analysis of 1H-MRS studies. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 43 33581932
2018 Imaging features (CT, MRI, MRS, and PET/CT) of primary central nervous system lymphoma in immunocompetent patients. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 41 30580380
2013 Alarmin HNP-1 promotes pyroptosis and IL-1β release through different roles of NLRP3 inflammasome via P2X7 in LPS-primed macrophages. Innate immunity 41 23792296
2007 Response of choline metabolites to docetaxel therapy is quantified in vivo by localized (31)P MRS of human breast cancer xenografts and in vitro by high-resolution (31)P NMR spectroscopy of cell extracts. Magnetic resonance in medicine 41 17654590
2020 Functions of lactate in the brain of rat with intracerebral hemorrhage evaluated with MRI/MRS and in vitro approaches. CNS neuroscience & therapeutics 40 32488963
1998 An MRI and MRS study of Pelizaeus-Merzbacher disease. Pediatric neurology 40 9588530
2016 Associations between Dietary Nutrient Intakes and Hepatic Lipid Contents in NAFLD Patients Quantified by ¹H-MRS and Dual-Echo MRI. Nutrients 39 27618908
2002 Glycolysis as a metabolic marker in orthotopic breast cancer, monitored by in vivo (13)C MRS. American journal of physiology. Endocrinology and metabolism 39 12217878
2010 MRS in presymptomatic MAPT mutation carriers: a potential biomarker for tau-mediated pathology. Neurology 38 20805522
2004 In vivo cardiac 1H-MRS in the mouse. Magnetic resonance in medicine 37 15508174
2019 Task-related measures of short-interval intracortical inhibition and GABA levels in healthy young and older adults: A multimodal TMS-MRS study. NeuroImage 36 31863914
2010 Resonance assignment and three-dimensional structure determination of a human alpha-defensin, HNP-1, by solid-state NMR. Journal of molecular biology 36 20097206
2004 Neuroradiological findings (MRS, MRI, SPECT) in infantile neuronal ceroid-lipofuscinosis (infantile CLN1) at different stages of the disease. Neuropediatrics 35 15002049
1999 DEF-1, a novel Src SH3 binding protein that promotes adipogenesis in fibroblastic cell lines. Molecular and cellular biology 35 10022919
2014 Def1 promotes the degradation of Pol3 for polymerase exchange to occur during DNA-damage--induced mutagenesis in Saccharomyces cerevisiae. PLoS biology 32 24465179
2010 Pyruvate carboxylation in different model systems studied by (13)C MRS. Neurochemical research 32 20842423
2022 Selenium-Enriched Pediococcus acidilactici MRS-7 Alleviates Patulin-Induced Jejunum Injuries in Mice and Its Possible Mechanisms. Journal of agricultural and food chemistry 31 35394776
2007 Quantitative correlation between (1)H MRS and dynamic contrast-enhanced MRI of human breast cancer. Magnetic resonance imaging 31 18060716
2016 The recovery trajectory of adolescent social defeat stress-induced behavioral, (1)H-MRS metabolites and myelin changes in Balb/c mice. Scientific reports 30 27283029
2008 Non-invasive detection of hippocampal sclerosis: correlation between metabolite alterations detected by (1)H-MRS and neuropathology. NMR in biomedicine 30 18035849
2018 Metabolic Heterogeneity Evidenced by MRS among Patient-Derived Glioblastoma Multiforme Stem-Like Cells Accounts for Cell Clustering and Different Responses to Drugs. Stem cells international 28 29531533
2010 MDP-NOD2 stimulation induces HNP-1 secretion, which contributes to NOD2 antibacterial function. Inflammatory bowel diseases 28 19856414
2017 PPBP and DEFA1/DEFA3 genes in hyperlipidaemia as feasible synergistic inflammatory biomarkers for coronary heart disease. Lipids in health and disease 26 28420383
2014 Evaluation of dietary effects on hepatic lipids in high fat and placebo diet fed rats by in vivo MRS and LC-MS techniques. PloS one 26 24638096
2014 Biochemical changes in the brain of hemiplegic migraine patients measured with 7 tesla 1H-MRS. Cephalalgia : an international journal of headache 26 24651393
2013 Proton magnetic resonance spectroscopy ((1)H-MRS) reveals geniculocalcarine and striate area degeneration in primary glaucoma. PloS one 26 24009739
2010 Trypanosoma cruzi infection modulates the expression of Triatoma brasiliensis def1 in the midgut. Vector borne and zoonotic diseases (Larchmont, N.Y.) 26 20925526
2007 Fucosidosis: MRI and MRS findings. Pediatric radiology 26 17704911
2021 Diffusion-weighted MR spectroscopy (DW-MRS) is sensitive to LPS-induced changes in human glial morphometry: A preliminary study. Brain, behavior, and immunity 25 34673176
2017 Applications of high-resolution magic angle spinning MRS in biomedical studies I-cell line and animal models. NMR in biomedicine 25 28301071
2016 (13)C MRS and LC-MS Flux Analysis of Tumor Intermediary Metabolism. Frontiers in oncology 25 27379200
2013 An 1H-MRS framework predicts the onset of Alzheimer's disease symptoms in PSEN1 mutation carriers. Alzheimer's & dementia : the journal of the Alzheimer's Association 25 24239247
2011 The respective and interaction effects of spinal GRs and MRs on radicular pain induced by chronic compression of the dorsal root ganglion in the rat. Brain research 25 21550593
2020 Age-related GABAergic differences in the primary sensorimotor cortex: A multimodal approach combining PET, MRS and TMS. NeuroImage 24 33186716
2013 Clinical protocols for ³¹P MRS of the brain and their use in evaluating optic pathway gliomas in children. European journal of radiology 23 24331847
2004 Utility of 19F MRS detection of the hypoxic cell marker EF5 to assess cellular hypoxia in solid tumors. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 23 15588883
1997 Differentiation between cortical atrophy and hydrocephalus using 1H MRS. Magnetic resonance in medicine 23 9055230
2002 Proton MRS in Kennedy disease: absolute metabolite and macromolecular concentrations. Journal of magnetic resonance imaging : JMRI 22 12203763
1999 Short TE proton MRS and neurofibromatosis type 1 intracranial lesions. Journal of computer assisted tomography 22 10589584
2021 Kynurenines increase MRS metabolites in basal ganglia and decrease resting-state connectivity in frontostriatal reward circuitry in depression. Translational psychiatry 21 34482366
2010 Correlation between lactate and neuronal cell damage in the rat brain after focal ischemia: An in vivo 1H magnetic resonance spectroscopic (1H-MRS) study. Acta radiologica (Stockholm, Sweden : 1987) 21 20144147
2007 1H MRS identifies specific metabolite profiles associated with MYCN-amplified and non-amplified tumour subtypes of neuroblastoma cell lines. NMR in biomedicine 21 17506115
2018 Involvement of the def-1 Mutation in the Response of Tomato Plants to Arbuscular Mycorrhizal Symbiosis Under Well-Watered and Drought Conditions. Plant & cell physiology 19 29165704
2017 Hyperpolarized 13C Diffusion MRS of Co-Polarized Pyruvate and Fumarate to Measure Lactate Export and Necrosis. Journal of Cancer 19 28928899
2007 In vivo monitoring response to chemotherapy of human diffuse large B-cell lymphoma xenografts in SCID mice by 1H and 31P MRS. Academic radiology 19 18035282
2006 MRS as endogenous molecular imaging for brain and prostate tumors: FP6 project "eTUMOR". Advances in experimental medicine and biology 19 17163172
1996 Introduction to in vivo MRS of cancer: new perspectives and open problems. Anticancer research 19 8694519
2022 UBAP2/UBAP2L regulate UV-induced ubiquitylation of RNA polymerase II and are the human orthologues of yeast Def1. DNA repair 18 35633597
2018 Multifaceted assessment of the APP/PS1 mouse model for Alzheimer's disease: Applying MRS, DTI, and ASL. Brain research 18 30077647
2016 MRS studies of neuroenergetics and glutamate/glutamine exchange in rats: Extensions to hyperammonemic models. Analytical biochemistry 18 28017739
2013 Enhancing the [13C]bicarbonate signal in cardiac hyperpolarized [1-13C]pyruvate MRS studies by infusion of glucose, insulin and potassium. NMR in biomedicine 18 23794521
2009 Identification of mobile lipids in human cancer tissues by ex vivo diffusion edited HR-MAS MRS. Oncology reports 18 19885604
2013 Combined MRI and ³¹P-MRS investigations of the ACTA1(H40Y) mouse model of nemaline myopathy show impaired muscle function and altered energy metabolism. PloS one 17 23613869
2012 (1)H-MRS evaluation of therapeutic effect of neural stem cell transplantation on Alzheimer's disease in AβPP/PS1 double transgenic mice. Journal of Alzheimer's disease : JAD 17 21955813
2013 Multimodal MRI and (31)P-MRS investigations of the ACTA1(Asp286Gly) mouse model of nemaline myopathy provide evidence of impaired in vivo muscle function, altered muscle structure and disturbed energy metabolism. PloS one 16 23977274
2016 The intergenic region of the maize defensin-like protein genes Def1 and Def2 functions as an embryo-specific asymmetric bidirectional promoter. Journal of experimental botany 15 27279278
2015 MRI and MRS findings in fucosidosis; a rare lysosomal storage disease. Brain & development 15 26515723
2010 Pretreatment and early intratreatment prediction of clinicopathologic response of head and neck cancer to chemoradiotherapy using 1H-MRS. Journal of magnetic resonance imaging : JMRI 15 20578027
2005 Parkinson's disease, chronic hydrocarbon exposure and striatal neuronal damage: a 1-H MRS study. Neurotoxicology 15 16246421
2017 Def1 interacts with TFIIH and modulates RNA polymerase II transcription. Proceedings of the National Academy of Sciences of the United States of America 14 29180430
2009 Proton MRS detects metabolic changes in hormone sensitive and resistant human prostate cancer models CWR22 and CWR22r. Magnetic resonance in medicine 14 19780165
1992 Correlations between in vivo 31P MRS measurements, tumor size, cell survival, and hypoxic fraction in the murine EMT6 tumor. Magnetic resonance in medicine 13 1614307