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1.

001-es BibID:BIBFORM113131
035-os BibID:(cikkazonosító)121 (scopus)85160315499 (wos)000994418900002
Első szerző:Ashwood, Lauren M.
Cím:Genomic, functional and structural analyses elucidate evolutionary innovation within the sea anemone 8 toxin family / Ashwood Lauren M., Elnahriry Khaled A., Stewart Zachary K., Shafee Thomas, Naseem Muhammad Umair, Szanto Tibor G., van der Burg Chloé A., Smith Hayden L., Surm Joachim M., Undheim Eivind A. B., Madio Bruno, Hamilton Brett R., Guo Shaodong, Wai Dorothy C. C., Coyne Victoria L., Phillips Matthew J., Dudley Kevin J., Hurwood David A., Panyi Gyorgy, King Glenn F., Pavasovic Ana, Norton Raymond S., Prentis Peter J.
Dátum:2023
ISSN:1741-7007
Megjegyzések:Background The ShK toxin from Stichodactyla helianthus has established the therapeutic potential of sea anemone venom peptides, but many lineage-specific toxin families in Actiniarians remain uncharacterised. One such peptide family, sea anemone 8 (SA8), is present in all five sea anemone superfamilies. We explored the genomic arrangement and evolution of the SA8 gene family in Actinia tenebrosa and Telmatactis stephensoni, characterised the expression patterns of SA8 sequences, and examined the structure and function of SA8 from the venom of T. stephensoni. Results We identified ten SA8-family genes in two clusters and six SA8-family genes in five clusters for T. stephen- soni and A. tenebrosa, respectively. Nine SA8 T. stephensoni genes were found in a single cluster, and an SA8 peptide encoded by an inverted SA8 gene from this cluster was recruited to venom. We show that SA8 genes in both spe- cies are expressed in a tissue-specific manner and the inverted SA8 gene has a unique tissue distribution. While the functional activity of the SA8 putative toxin encoded by the inverted gene was inconclusive, its tissue localisation is similar to toxins used for predator deterrence. We demonstrate that, although mature SA8 putative toxins have similar cysteine spacing to ShK, SA8 peptides are distinct from ShK peptides based on structure and disulfide connectivity. Conclusions Our results provide the first demonstration that SA8 is a unique gene family in Actiniarians, evolving through a variety of structural changes including tandem and proximal gene duplication and an inversion event that together allowed SA8 to be recruited into the venom of T. stephensoni.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:BMC Biology. - 21 : 1 (2023), p. 1-25. -
További szerzők:Elnahriry, Khaled A. Stewart, Zachary K. Shafee, Thomas Naseem, Muhammad Umair (1993-) (biofizikus, molekuláris biológus) Szántó Gábor Tibor (1980-) (vegyész) van der Burg, Chloé A. Smith, Hayden L. Surm, Joachim M. Undheim, Eivind A. B. Madio, Bruno Hamilton, Brett R. Guo, Shaodong Wai, Dorothy C. C. Coyne, Victoria L. Phillips, Matthew J. Dudley, Kevin J. Hurwood, David A. Panyi György (1966-) (biofizikus) King, Glenn F. Pavasovic, Ana Norton, Raymond S. Prentis, Peter
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2.

001-es BibID:BIBFORM114859
035-os BibID:(cikkazonosító)140952 (scopus)85170288156
Első szerző:Elnahriry, Khaled A.
Cím:Structural and functional characterisation of Tst2, a novel TRPV1 inhibitory peptide from the Australian sea anemone Telmatactis stephensoni / Elnahriry Khaled A., Wai Dorothy C. C., Ashwood Lauren M., Naseem Muhammad Umair, Szanto Tibor G., Guo Shaodong, Panyi Gyorgy, Prentis Peter J., Norton Raymond S.
Dátum:2024
ISSN:1570-9639
Megjegyzések:Sea anemone venoms are complex mixtures of biologically active compounds, including disulfide-rich peptides, some of which have found applications as research tools, and others as therapeutic leads. Our recent transcriptomic and proteomic studies of the Australian sea anemone Telmatactis stephensoni identified a transcript for a peptide designated Tst2. Tst2 is a 38-residue peptide showing sequence similarity to peptide toxins known to interact with a range of ion channels (NaV, TRPV1, KV and CaV). Recombinant Tst2 (rTst2, which contains an additional Gly at the N-terminus) was produced by periplasmic expression in Escherichia coli, enabling the production of both unlabelled and uniformly 13C,15N?labelled peptide for functional assays and structural studies. The LC-MS profile of the recombinant Tst2 showed a pure peak with molecular mass 6 Da less than that of the reduced form of the peptide, indicating the successful formation of three disulfide bonds from its six cysteine residues. The solution structure of rTst2 was determined using multidimensional NMR spectroscopy and revealed that rTst2 adopts an inhibitor cystine knot (ICK) structure. rTst2 was screened using various functional assays, including patch?clamp electrophysiological and cytotoxicity assays. rTst2 was inactive against voltagegated sodium channels (NaV) and the human voltage-gated proton (hHv1) channel. rTst2 also did not possess cytotoxic activity when assessed against Drosophila melanogaster flies. However, the recombinant peptide at 100 nM showed >50% inhibition of the transient receptor potential subfamily V member 1 (TRPV1) and slight (~10%) inhibition of transient receptor potential subfamily A member 1 (TRPA1). Tst2 is thus a novel ICK inhibitor of the TRPV1 channel.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Sea anemone
Disulfide-rich peptides
Recombinant expression
NMR spectroscopy
ICK scaffold
TRPV1 channel
Megjelenés:Biochimica et Biophysica Acta (BBA). Proteins and Proteomics. - 1872 : 1 (2024), p. 1-13. -
További szerzők:Wai, Dorothy C. C. Ashwood, Lauren M. Naseem, Muhammad Umair (1993-) (biofizikus, molekuláris biológus) Szántó Gábor Tibor (1980-) (vegyész) Guo, Shaodong Panyi György (1966-) (biofizikus) Prentis, Peter Norton, Raymond S.
Pályázati támogatás:K143071
OTKA
Stipendium Hungaricum Scholarship from the Tempus Public Foundation
Egyéb
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Intézményi repozitóriumban (DEA) tárolt változat
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3.

001-es BibID:BIBFORM091922
035-os BibID:(cikkazonosító)107692
Első szerző:Krishnarjuna, Bankala
Cím:A disulfide-stabilised helical hairpin fold in acrorhagin I : an emerging structural motif in peptide toxins / Bankala Krishnarjuna, Punnepalli Sunanda, Jessica Villegas-Moreno, Agota Csoti, Rodrigo A. V. Morales, Dorothy C. C. Wai, Gyorgy Panyi, Peter Prentis, Raymond S. Norton
Dátum:2021
ISSN:1047-8477
Megjegyzések:Acrorhagin I (U-AITX-Aeq5a) is a disulfide-rich peptide identified in the aggressive organs (acrorhagi) of the sea anemone Actinia equina. Previous studies (Toxicon 2005, 46:768-74) found that the peptide is toxic in crabs, although the structural and functional properties of acrorhagin I have not been reported. In this work, an Escherichia coli (BL21 strain) expression system was established for the preparation of 13C,15N-labelled acrorhagin I, and the solution structure was determined using NMR spectroscopy. Structurally, acrorhagin I is similar to B-IV toxin from the marine worm Cerebratulus lacteus (PDB id 1VIB), with a well-defined helical hairpin structure stabilised by four intramolecular disulfide bonds. The recombinant peptide was tested in patch-clamp electrophysiology assays against voltage-gated potassium and sodium channels, and in bacterial and fungal growth inhibitory assays and haemolytic assays. Acrorhagin I was not active against any of the ion channels tested and showed no activity in functional assays, indicating that this peptide may possess a different biological function. Metal ion interaction studies using NMR spectroscopy showed that acrorhagin I bound zinc and nickel, suggesting that its function might be modulated by metal ions or that it may be involved in regulating metal ion levels and their transport. The similarity between the structure of acrorhagin I and that of B-IV toxin from a marine worm suggests that this fold may prove to be a recurring motif in disulfide-rich peptides from marine organisms.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
acrorhagin I
NMR
disulfides
hairpin structure
metal ion interaction
sea anemone
Megjelenés:Journal Of Structural Biology. - 213 : 2 (2021), p. 1-37. -
További szerzők:Sunanda, Punnepalli Villegas-Moreno, Jessica Csóti Ágota (1989-) (biológus) Morales, Rodrigo A. V. Wai, Dorothy C. C. Panyi György (1966-) (biofizikus) Prentis, Peter Norton, Raymond S.
Pályázati támogatás:K119417
OTKA
EFOP-3.6.1-16-2016-00022
EFOP
GINOP-2.3.2-15-2016-00015
GINOP
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Intézményi repozitóriumban (DEA) tárolt változat
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4.

001-es BibID:BIBFORM107302
035-os BibID:(scopus)85141712265 (wos)000882982200001
Első szerző:Reddiar, Sanjeevini Babu
Cím:A Biodistribution Study of the Radiolabeled Kv1.3-Blocking Peptide DOTA-HsTX1[R14A] Demonstrates Brain Uptake in a Mouse Model of Neuroinflammation / Reddiar Sanjeevini Babu, de Veer Michael, Paterson Brett M., Sepehrizadeh Tara, Wai Dorothy C. C., Csoti Agota, Panyi Gyorgy, Nicolazzo Joseph A., Norton Raymond S.
Dátum:2023
ISSN:1543-8384 1543-8392
Megjegyzések:The voltage-gated potassium channel Kv1.3 regulates the pro-inflammatory function of microglia and is highly expressed in the post-mortem brains of individuals with Alzheimer's and Parkinson's diseases. HsTX1[R14A] is a selective and potent peptide inhibitor of the Kv1.3 channel (IC50 ? 45 pM) that has been shown to decrease cytokine levels in a lipopolysaccharide (LPS)-induced mouse model of inflammation. Central nervous system exposure to HsTX1[R14A] was previously detected in this mouse model using liquid chromatography with tandem mass spectrometry, but this technique does not report on the spatial distribution of the peptide in the different brain regions or peripheral organs. Herein, the in vivo distribution of a [64Cu]Cu-labeled DOTA conjugate of HsTX1[R14A] was observed for up to 48 h by positron emission tomography (PET) in mice. After subcutaneous administration to untreated C57BL/6J mice, considerable uptake of the radiolabeled peptide was observed in the kidney, but it was undetectable in the brain. Biodistribution of a [68Ga]Ga-DOTA conjugate of HsTX1[R14A] was then investigated in the LPS-induced mouse model of neuroinflammation to assess the effects of inflammation on uptake of the peptide in the brain. A control peptide with very weak Kv1.3 binding, [68Ga]Ga-DOTA-HsTX1[R14A,Y21A,K23A] (IC50 ? 6 ?M), was also tested. Significantly increased uptake of [68Ga]Ga-DOTA-HsTX1[R14A] was observed in the brains of LPS-treated mice compared to mice treated with control peptide, implying that the enhanced uptake was due to increased Kv1.3 expression rather than simply increased blood?brain barrier disruption. PET imaging also showed accumulation of [68Ga]Ga-DOTA-HsTX1[R14A] in inflamed joints and decreased clearance from the kidneys in LPS-treated mice. These biodistribution data highlight the potential of HsTX1[R14A] as a therapeutic for the treatment of neuroinflammatory diseases mediated by overexpression of Kv1.3.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Biodistribution
Central nervous system
Inflammation
Peptides and proteins
Rodent models
Megjelenés:Molecular Pharmaceutics. - 20 : 1 (2023), p. 255-266. -
További szerzők:de Veer, Michael Paterson, Brett M. Sepehrizadeh, Tara Wai, Dorothy C. C. Csóti Ágota (1989-) (biológus) Panyi György (1966-) (biofizikus) Nicolazzo, Joseph A. Norton, Raymond S.
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Intézményi repozitóriumban (DEA) tárolt változat
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5.

001-es BibID:BIBFORM100131
Első szerző:Reddiar, Sanjeevini Babu
Cím:Lipopolysaccharide influences the plasma and brain pharmacokinetics of subcutaneously-administered HsTX1[R14A], a KV1.3-blocking peptide / Reddiar Sanjeevini Babu, Jin Liang, Wai Dorothy C. C., Csoti Agota, Panyi Gyorgy, Norton Raymond S., Nicolazzo Joseph A.
Dátum:2021
ISSN:0041-0101
Megjegyzések:KV1.3 is a voltage-gated potassium channel that is upregulated in neuroinflammatory conditions, such as Alzheimer's disease and Parkinson's disease. HsTX1[R14A] is a potent and selective peptide blocker of KV1.3 with the potential to block microglial KV1.3, but its brain uptake is expected to be limited owing to the restrictive nature of the blood-brain barrier. To assess its peripheral and brain exposure, a LC-MS/MS assay was developed to quantify HsTX1[R14A] concentrations in mouse plasma and brain homogenate that was reliable and reproducible in the range of 6.7?66.7 nM (r2 = 0.9765) and 15?150 pmol/g (r2 = 0.9984), respectively. To assess if neuroinflammation affected HsTX1[R14A] disposition, C57BL/6 mice were administered HsTX1[R14A] subcutaneously (2 mg/kg) 24 h after an intraperitoneal dose of Escherichia coli lipopolysaccharide (LPS), which is commonly used to induce neuroinflammation; brain and plasma concentrations of HsTX1[R14A] were then quantified over 120 min. LPS treatment significantly retarded the decline in HsTX1[R14A] plasma concentrations, presumably as a result of reducing renal clearance, and led to substantial brain uptake of HsTX1[R14A], presumably through disruption of brain inter-endothelial tight junctions. This study suggests that HsTX1[R14A] may reach microglia in sufficient concentrations to block KV1.3 in neuroinflammatory conditions, and therefore has the potential to reduce neurodegenerative diseases.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Toxicon. - 195 (2021), p. 29-36. -
További szerzők:Jin, Liang Wai, Dorothy C. C. Csóti Ágota (1989-) (biológus) Panyi György (1966-) (biofizikus) Norton, Raymond S. Nicolazzo, Joseph A.
Pályázati támogatás:K119417
OTKA
EFOP-3.6.1-16-2016-00022
EFOP
GINOP-2.3.2-15-2016-00015
GINOP
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Intézményi repozitóriumban (DEA) tárolt változat
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6.

001-es BibID:BIBFORM116513
035-os BibID:(Scopus)85173464630 (WOS)001077676500001
Első szerző:Sanches, Karoline
Cím:Structure-function relationships in domain peptides : from the sea anemone / Sanches Karoline, Ashwood Lauren M., Olushola-Siedoks Abisola Ave-Maria, Wai Dorothy C. C., Rahman Arfatur, Shakeel Kashmala, Naseem Muhammad Umair, Panyi Gyorgy, Prentis Peter J., Norton Raymond S.
Dátum:2024
ISSN:0887-3585
Megjegyzések:Diverse structural scaffolds have been described in peptides from sea anemones, with the ShKT domain being a common scaffold first identified in ShK toxin from Stichodactyla helianthus. ShK is a potent blocker of voltage-gated potassium channels (KV1.x), and an analog, ShK-186 (dalazatide), has completed Phase 1 clinical trials in plaque psoriasis. The ShKT domain has been found in numerous other species, but only a tiny fraction of ShKT domains has been characterized functionally. Despite adopting the canonical ShK fold, some ShKT peptides from sea anemones inhibit KV1.x, while others do not. Mutagenesis studies have shown that a Lys-Tyr (KY) dyad plays a key role in KV1.x blockade, although a cationic residue followed by a hydrophobic residue may also suffice. Nevertheless, ShKT peptides displaying an ShK-like fold and containing a KY dyad do not necessarily block potassium channels, so additional criteria are needed to determine whether new ShKT peptides might show activity against potassium channels. In this study, we used a combination of NMR and molecular dynamics (MD) simulations to assess the potential activity of a new ShKT peptide. We determined the structure of ShKT-Ts1, from the sea anemone Telmatactis stephensoni, examined its tissue localization, and investigated its activity against a range of ion channels. As ShKT-Ts1 showed no activity against KV1.x channels, we used MD simulations to investigate whether solvent exposure of the dyad residues may be informative in rationalizing and potentially predicting the ability of ShKT peptides to block KV1.x channels. We show that either a buried dyad that does not become exposed during MD simulations, or a partially exposed dyad that becomes buried during MD simulations, correlates with weak or absent activity against KV1.x channels. Therefore, structure determination coupled with MD simulations, may be used to predict whether new sequences belonging to the ShKT family may act as potassium channel blockers.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
molecular dynamics
NMR
peptide
potassium channel
sea anemone
ShKT domain
structure determination
Megjelenés:Proteins-Structure Function And Bioinformatics. - 92 : 2 (2023), p. 192-205. -
További szerzők:Ashwood, Lauren M. Olushola-Siedoks, Abisola Ave-Maria Wai, Dorothy C. C. Rahman, Arfatur Shakeel, Kashmala Naseem, Muhammad Umair (1993-) (biofizikus, molekuláris biológus) Panyi György (1966-) (biofizikus) Prentis, Peter Norton, Raymond S.
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Intézményi repozitóriumban (DEA) tárolt változat
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7.

001-es BibID:BIBFORM090993
Első szerző:Tajti Gábor (gyógyszerész, biofizikus, sejtbiológus)
Cím:The voltage-gated potassium channel KV1.3 as a therapeutic target for venom-derived peptides / Gábor Tajti, Dorothy C. C. Wai, György Panyi, Raymond S. Norton
Dátum:2020
ISSN:0006-2952
Megjegyzések:The voltage-gated potassium channel KV1.3 is a well-established therapeutic target for a range of autoimmune diseases, in addition to being the site of action of many venom-derived peptides. Numerous studies have documented the efficacy of venom peptides that target KV1.3, in particular from sea anemones and scorpions, in animal models of autoimmune diseases such as rheumatoid arthritis, psoriasis and multiple sclerosis. Moreover, an analogue of the sea anemone peptide ShK (known as dalazatide) has successfully completed Phase 1 clinical trials in mild-to-moderate plaque psoriasis. In this article we consider other potential therapeutic applications of inhibitors of KV1.3, including in inflammatory bowel disease and neuroinflammatory conditions such as Alzheimer's and Parkinson's diseases, as well as fibrotic diseases. We also summarise strategies for facilitating the entry of peptides to the central nervous system, given that this will be a pre-requisite for the treatment of most neuroinflammatory diseases. Venom-derived peptides that have been reported recently to target KV1.3 are also described. The increasing number of autoimmune and other conditions in which KV1.3 is upregulated and is therefore a potential therapeutic target, combined with the fact that many venom-derived peptides are potent inhibitors of KV1.3, suggests that venoms are likely to continue to serve as a rich source of new pharmacological tools and therapeutic leads targeting this channel.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Voltage-gated potassium channel
Peptide
Toxin
Inflammatory bowel disease
Neuroinflammation
Fibrosis
Therapeutic development
Megjelenés:Biochemical Pharmacology. - 181 (2020), p. 114146-. -
További szerzők:Wai, Dorothy C. C. Panyi György (1966-) (biofizikus) Norton, Raymond S.
Pályázati támogatás:EFOP-3.6.2-16-2017-00006
EFOP
GINOP-2.3.2-15-2016-00015
GINOP
NKFIH OTKA K119417
OTKA
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Intézményi repozitóriumban (DEA) tárolt változat
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8.

001-es BibID:BIBFORM105306
035-os BibID:(WoS)000883005300001 (Scopus)85141634111
Első szerző:Wai, Dorothy C. C.
Cím:A Fluorescent Peptide Toxin for Selective Visualization of the Voltage-Gated Potassium Channel Kv1.3 / Wai Dorothy C. C., Naseem Muhammad Umair, Mocsár Gábor, Babu Reddiar Sanjeevini, Pan Yijun, Csoti Agota, Hajdu Peter, Nowell Cameron, Nicolazzo Joseph A., Panyi Gyorgy, Norton Raymond S.
Dátum:2022
ISSN:1043-1802
Megjegyzések:Upregulation of the voltage-gated potassium channel K(V)1.3 is implicated in a range of autoimmune and neuroinflammatory diseases, including rheumatoid arthritis, psoriasis, multiple sclerosis, and type I diabetes. Understanding the expression, localization, and trafficking of K(V)1.3 in normal and disease states is key to developing targeted immunomodulatory therapies. HsTX1[R14A], an analogue of a 34-residue peptide toxin from the scorpion Heterometrus spinifer, binds K(V)1.3 with high affinity (IC50 of 45 pM) and selectivity (2000-fold for K(V)1.3 over K(V)1.1). We have synthesized a fluorescent analogue of HsTX1[R14A] by N-terminal conjugation of a Cy5 tag. Electrophysiology assays show that Cy5-HsTX1[R14A] retains activity against K(V)1.3 (IC50 similar to 0.9 nM) and selectivity over a range of other potassium channels (K(V)1.2, K(V)1.4, K(V)1.5, K(V)1.6, K(Ca)1.1 and K(Ca)3.1), as well as selectivity against heteromeric channels assembled from K(V)1.3/K(V)1.5 tandem dimers. Live imaging of CHO cells expressing green fluorescent protein-tagged K(V)1.3 shows co-localization of Cy5-HsTX1[R14A] and K(V)1.3 fluorescence signals at the cell membrane. Moreover, flow cytometry demonstrated that Cy5-HsTX1[R14A] can detect K(V)1.3-expressing CHO cells. Stimulation of mouse microglia by lipopolysaccharide, which enhances membrane expression of K(V)1.3, was associated with increased staining by Cy5-HsTX1[R14A], demonstrating that it can be used to identify K(V)1.3 in disease-relevant models of inflammation. Furthermore, the biodistribution of Cy5-HsTX1[R14A] could be monitored using ex vivo fluorescence imaging of organs in mice dosed subcutaneously with the peptide. These results illustrate the utility of Cy5-HsTX1[R14A] as a tool for visualizing K(V)1.3, with broad applicability in fundamental investigations of K(V)1.3 biology, and the validation of novel disease indications where K(V)1.3 inhibition may be of therapeutic value.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Fluorescence
Imaging probes
Peptides and proteins
Potassium
Selectivity
Megjelenés:Bioconjugate Chemistry. - 33 : 11 (2022), p. 2197-2212. -
További szerzők:Naseem, Muhammad Umair (1993-) (biofizikus, molekuláris biológus) Mocsár Gábor (1981-) (biofizikus) Babu Reddiar, Sanjeevini Pan, Yijun Csóti Ágota (1989-) (biológus) Hajdu Péter (1975-) (biofizikus) Nowell, Cameron Nicolazzo, Joseph A. Panyi György (1966-) (biofizikus) Norton, Raymond S.
Pályázati támogatás:K143071
OTKA
K128525
OTKA
EFOP-3.6.1-16-2016-00022
EFOP
GINOP-2.3.2-15-2016-00015
GINOP
Stipendium Hungaricum Scholarship by the Tempus Public Foundation
Egyéb
Internet cím:Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
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