TY - JOUR AU - Tóth, Eszter AU - Györffy, Dániel AU - Posta, Máté AU - Hupuczi, Petronella AU - Balogh, Andrea AU - Szalai, Gábor AU - Orosz, Gergő Balázs AU - Orosz, László AU - Szilágyi, András AU - Oravecz, Orsolya AU - Veress, Lajos AU - Nagy, Sándor AU - Török, Olga AU - Murthi, Padma AU - Erez, Offer AU - Papp, Zoltán AU - Ács, Nándor AU - Than, Nándor Gábor TI - Decreased Expression of Placental Proteins in Recurrent Pregnancy Loss: Functional Relevance and Diagnostic Value JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 3 PG - 23 SN - 1661-6596 DO - 10.3390/ijms25031865 UR - https://m2.mtmt.hu/api/publication/34563187 ID - 34563187 N1 - Funding Agency and Grant Number: Hungarian Academy of Sciences; Thermo Fisher Scientific Funding text: Pascaline Caruhel, Kathrin Matischak, Elena Uliyanova, and Arnaud Vernier from Thermo Fisher Scientific (Hennigsdorf, Germany) for providing the daily medians of the related proteins. AB - Miscarriages affect 50–70% of all conceptions and 15–20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL, ≥2 miscarriages) affects 1–5% of recognized pregnancies. Nevertheless, our knowledge about the etiologies and pathophysiology of RPL is incomplete, and thus, reliable diagnostic/preventive tools are not yet available. Here, we aimed to define the diagnostic value of three placental proteins for RPL: human chorionic gonadotropin free beta-subunit (free-β-hCG), pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF). Blood samples were collected from women with RPL (n = 14) and controls undergoing elective termination of pregnancy (n = 30) at the time of surgery. Maternal serum protein concentrations were measured by BRAHMS KRYPTOR Analyzer. Daily multiple of median (dMoM) values were calculated for gestational age-specific normalization. To obtain classifiers, logistic regression analysis was performed, and ROC curves were calculated. There were differences in changes of maternal serum protein concentrations with advancing healthy gestation. Between 6 and 13 weeks, women with RPL had lower concentrations and dMoMs of free β-hCG, PAPP-A, and PlGF than controls. PAPP-A dMoM had the best discriminative properties (AUC = 0.880). Between 9 and 13 weeks, discriminative properties of all protein dMoMs were excellent (free β-hCG: AUC = 0.975; PAPP-A: AUC = 0.998; PlGF: AUC = 0.924). In conclusion, free-β-hCG and PAPP-A are valuable biomarkers for RPL, especially between 9 and 13 weeks. Their decreased concentrations indicate the deterioration of placental functions, while lower PlGF levels indicate problems with placental angiogenesis after 9 weeks. LA - English DB - MTMT ER - TY - JOUR AU - Than, Nándor Gábor AU - Romero, Roberto AU - Posta, Máté AU - Györffy, Dániel AU - Szalai, Gábor AU - Rossi, Simona W AU - Szilágyi, András AU - Hupuczi, Petronella AU - Nagy, Sándor AU - Török, Olga AU - Tarca, Adi L AU - Erez, Offer AU - Ács, Nándor AU - Papp, Zoltán TI - Classification of preeclampsia according to molecular clusters with the goal of achieving personalized prevention JF - JOURNAL OF REPRODUCTIVE IMMUNOLOGY J2 - J REPROD IMMUNOL VL - 161 PY - 2024 PG - 8 SN - 0165-0378 DO - 10.1016/j.jri.2023.104172 UR - https://m2.mtmt.hu/api/publication/34477407 ID - 34477407 N1 - Journal Article; Review AB - The prevention of pre-eclampsia is difficult due to the syndromic nature and multiple underlying mechanisms of this severe complication of pregnancy. The current clinical distinction between early- and late-onset disease, although clinically useful, does not reflect the true nature and complexity of the pathologic processes leading to pre-eclampsia. The current gaps in knowledge on the heterogeneous molecular pathways of this syndrome and the lack of adequate, specific diagnostic methods are major obstacles to early screening and tailored preventive strategies. The development of novel diagnostic tools for detecting the activation of the identified disease pathways would enable early, accurate screening and personalized preventive therapies. We implemented a holistic approach that includes the utilization of different proteomic profiling methods of maternal plasma samples collected from various ethnic populations and the application of systems biology analysis to plasma proteomic, maternal demographic, clinical characteristic, and placental histopathologic data. This approach enabled the identification of four molecular subclasses of pre-eclampsia in which distinct and shared disease mechanisms are activated. The current review summarizes the results and conclusions from these studies and the research and clinical implications of our findings. LA - English DB - MTMT ER - TY - JOUR AU - Györffy, Dániel AU - Závodszky, Péter AU - Szilágyi, András TI - A Kinetic Transition Network Model Reveals the Diversity of Protein Dimer Formation Mechanisms JF - BIOMOLECULES J2 - BIOMOLECULES VL - 13 PY - 2023 IS - 12 SN - 2218-273X DO - 10.3390/biom13121708 UR - https://m2.mtmt.hu/api/publication/34410484 ID - 34410484 N1 - Export Date: 10 January 2024; Cited By: 0; Correspondence Address: A. Szilágyi; Systems Biology of Reproduction Research Group, Institute of Enzymology, HUN-REN Research Centre for Natural Sciences, Budapest, 1117, Hungary; email: szilagyi.andras@ttk.hu AB - Protein homodimers have been classified as three-state or two-state dimers depending on whether a folded monomer forms before association, but the details of the folding–binding mechanisms are poorly understood. Kinetic transition networks of conformational states have provided insight into the folding mechanisms of monomeric proteins, but extending such a network to two protein chains is challenging as all the relative positions and orientations of the chains need to be included, greatly increasing the number of degrees of freedom. Here, we present a simplification of the problem by grouping all states of the two chains into two layers: a dissociated and an associated layer. We combined our two-layer approach with the Wako–Saito–Muñoz–Eaton method and used Transition Path Theory to investigate the dimer formation kinetics of eight homodimers. The analysis reveals a remarkable diversity of dimer formation mechanisms. Induced folding, conformational selection, and rigid docking are often simultaneously at work, and their contribution depends on the protein concentration. Pre-folded structural elements are always present at the moment of association, and asymmetric binding mechanisms are common. Our two-layer network approach can be combined with various methods that generate discrete states, yielding new insights into the kinetics and pathways of flexible binding processes. LA - English DB - MTMT ER - TY - JOUR AU - Than, Nándor Gábor AU - Romero, Roberto AU - Györffy, Dániel AU - Posta, Máté AU - Bhatti, Gaurav AU - Done, Bogdan AU - Chaemsaithong, Piya AU - Jung, Eunjung AU - Suksai, Manaphat AU - Gotsch, Francesca AU - Gallo, Dahiana M. AU - Bosco, Mariachiara AU - Kim, Bomi AU - Kim, Yeon Mee AU - Chaiworapongsa, Tinnakorn AU - Rossi, Simona W. AU - Szilágyi, András AU - Erez, Offer AU - Tarca, Adi L. AU - Papp, Zoltán TI - Molecular subclasses of preeclampsia characterized by a longitudinal maternal proteomics study: distinct biomarkers, disease pathways and options for prevention JF - JOURNAL OF PERINATAL MEDICINE J2 - J PERINAT MED VL - 51 PY - 2023 IS - 1 SP - 51 EP - 68 PG - 18 SN - 0300-5577 DO - 10.1515/jpm-2022-0433 UR - https://m2.mtmt.hu/api/publication/33186504 ID - 33186504 N1 - Systems Biology of Reproduction Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Maternity Private Clinic of Obstetrics and Gynecology, Budapest, Hungary Genesis Theranostix Group, Budapest, Hungary First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, United States Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, United States Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States Detroit Medical Center, Detroit, MI, United States Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary Károly Rácz Doctoral School of Clinical Medicine, Semmelweis University, Budapest, Hungary Department of Obstetrics and Gynecology, Wayne State University, School of Medicine, Detroit, MI, United States Department of Obstetrics and Gynecology, Universidad Del Valle, Cali, Colombia Department of Pathology, Wayne State University, School of Medicine, Detroit, MI, United States Department of Pathology, Haeundae Paik Hospital, Inje University, College of Medicine, Busan, South Korea Department of Obstetrics and Gynecology, HaEmek Medical Center, Afula, Israel Department of Computer Science, Wayne State University, College of Engineering, Detroit, MI, United States Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Detroit, MI, United States Cited By :4 Export Date: 25 October 2023 CODEN: JPEMA Correspondence Address: Than, N.G.; Perinatology Research Branch, United States; email: than.gabor@ttk.hu Correspondence Address: Papp, Z.; Maternity Private Clinic of Obstetrics and GynecologyHungary; email: pzorvosihetilap@maternity.hu LA - English DB - MTMT ER - TY - JOUR AU - Than, Nándor Gábor AU - Posta, Máté AU - Györffy, Dániel AU - Orosz, László AU - Orosz, Gergő Balázs AU - Rossi, Simona W. AU - Ambrus-Aikelin, Géza AU - Szilágyi, András AU - Nagy, Sándor AU - Hupuczi, Petronella AU - Török, Olga AU - Tarca, Adi L. AU - Erez, Offer AU - Papp, Zoltán AU - Romero, Roberto TI - Early pathways, biomarkers, and four distinct molecular subclasses of preeclampsia: The intersection of clinical, pathological, and high-dimensional biology studies JF - PLACENTA J2 - PLACENTA VL - 125 PY - 2022 SP - 10 EP - 19 PG - 10 SN - 0143-4004 DO - 10.1016/j.placenta.2022.03.009 UR - https://m2.mtmt.hu/api/publication/32760816 ID - 32760816 N1 - Systems Biology of Reproduction Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Maternity Private Clinic of Obstetrics and Gynecology, Budapest, Hungary Genesis Theranostix Group, Budapest, Hungary Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary Vividion Therapeutics, Inc., San Diego, CA, United States Faculty of Health and Sport Sciences, Széchenyi István University, Győr, Hungary Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, Maryland, and Detroit, Michigan, United States Department of Obstetrics and Gynecology, HAEMEK Medical Center, Afula, Israel Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, United States Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, United States Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States Detroit Medical Center, Detroit, MI, United States Cited By :10 Export Date: 11 September 2023 CODEN: PLACD Correspondence Address: Than, N.G.; Systems Biology of Reproduction Research Group, Magyar Tudósok körútja 2. H-1117, Hungary; email: than.gabor@ttk.hu LA - English DB - MTMT ER - TY - JOUR AU - Than, Nándor Gábor AU - Posta, Máté AU - Györffy, Dániel AU - Orosz, László AU - Orosz, Gergő AU - Rossi, Simona Wilma AU - Ambrus-Aikelin, Géza AU - Szilágyi, András AU - Nagy, Sándor AU - Hupuczi, Petronella AU - Török, Olga AU - Tarca, Adi Laurentiu AU - Erez, Offer AU - Papp, Zoltán AU - Romero, Roberto TI - A praeeclampsia korai betegségútvonalai, biomarkerei és négy különböző molekuláris alosztálya JF - NŐGYÓGYÁSZATI ÉS SZÜLÉSZETI TOVÁBBKÉPZŐ SZEMLE J2 - NŐGYÓGYÁSZATI ÉS SZÜLÉSZETI TOVÁBBKÉPZŐ SZEMLE VL - 24 PY - 2022 IS - 1 SP - 6 EP - 16 PG - 11 SN - 1585-8731 UR - https://m2.mtmt.hu/api/publication/32725682 ID - 32725682 N1 - A dolgozat angol nyelven a Placenta (Trophoblast Research) folyóiratban 2022-ben jelenik meg, jelenleg elfogadás alatt áll. A magyar változat közlése az Elsevier kiadó hozzájárulásával történik. LA - Hungarian DB - MTMT ER - TY - JOUR AU - Tarca, A.L. AU - Pataki, Bálint Ármin AU - Romero, R. AU - Sirota, M. AU - Guan, Y. AU - Kutum, R. AU - Gomez-Lopez, N. AU - Done, B. AU - Bhatti, G. AU - Yu, T. AU - Andreoletti, G. AU - Chaiworapongsa, T. AU - Hassan, S.S. AU - Hsu, C.-D. AU - Aghaeepour, N. AU - Stolovitzky, G. AU - Csabai, István AU - Costello, J.C. ED - Györffy, Dániel / Collaborator ED - Szilágyi, András / Collaborator ED - Than, Nándor Gábor / Collaborator TI - Crowdsourcing assessment of maternal blood multi-omics for predicting gestational age and preterm birth JF - CELL REPORTS MEDICINE J2 - CELL REP MED VL - 2 PY - 2021 IS - 6 SN - 2666-3791 DO - 10.1016/j.xcrm.2021.100323 UR - https://m2.mtmt.hu/api/publication/32124679 ID - 32124679 N1 - Funding Agency and Grant Number: Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and H; NICHD/NIH/DHHS [HHSN275201300006C]; Wayne State University Perinatal Initiative in Maternal, Perinatal, and Child Health; Bill and Melinda Gates Foundation [OPP1112382, OPP1113682]; March of Dimes Prematurity Research Center at Stanford University; Burroughs Wellcome Fund; National Center for Advancing Translational Sciences; Robertson Family Foundation [KL2TR003143]; National Research, Development, and Innovation Fund of Hungary [FIEK_16-1-2016-0005]; National Institutes of Health [NIH/NIGMS R35GM133346-01]; National Science Foundation (NSF/DBI) [1452656]; Council of Scientific and Industrial Research of India [HCP00013]; March of Dimes; Bill and Melinda Gates Foundation [OPP1112382] Funding Source: Bill and Melinda Gates Foundation Funding text: This research was supported, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services (NICHD/NIH/DHHS) and, in part, with federal funds from NICHD/NIH/DHHS under contract no. HHSN275201300006C. A.L.T. and N.G.-L. were also supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal, and Child Health. R.R. has contributed to this work as part of his official duties as an employee of the US federal government. The authors acknowledge Alison Paquette for insightful discussions about available maternal omics datasets in preterm birth and Maureen McGerty (Wayne State University) and Corina Ghita for proofreading and copyediting this manuscript. N.A. was supported by the Bill and Melinda Gates Foundation (OPP1112382 and OPP1113682), the March of Dimes Prematurity Research Center at Stanford University, the Burroughs Wellcome Fund, the National Center for Advancing Translational Sciences, and the Robertson Family Foundation (KL2TR003143). I.C. and B.A.P. were supported by the National Research, Development, and Innovation Fund of Hungary (project no. FIEK_16-1-2016-0005). Y.G. was supported by grants from the National Institutes of Health (NIH/NIGMS R35GM133346-01) and the National Science Foundation (NSF/DBI #1452656). R.K. was supported by a Senior Research Fellowship Award from the Council of Scientific and Industrial Research of India (HCP00013). G.A. and M.S. were supported by the March of Dimes. AB - Identification of pregnancies at risk of preterm birth (PTB), the leading cause of newborn deaths, remains challenging given the syndromic nature of the disease. We report a longitudinal multi-omics study coupled with a DREAM challenge to develop predictive models of PTB. The findings indicate that whole-blood gene expression predicts ultrasound-based gestational ages in normal and complicated pregnancies (r = 0.83) and, using data collected before 37 weeks of gestation, also predicts the delivery date in both normal pregnancies (r = 0.86) and those with spontaneous preterm birth (r = 0.75). Based on samples collected before 33 weeks in asymptomatic women, our analysis suggests that expression changes preceding preterm prelabor rupture of the membranes are consistent across time points and cohorts and involve leukocyte-mediated immunity. Models built from plasma proteomic data predict spontaneous preterm delivery with intact membranes with higher accuracy and earlier in pregnancy than transcriptomic models (AUROC = 0.76 versus AUROC = 0.6 at 27–33 weeks of gestation). © 2021 The Author(s) LA - English DB - MTMT ER - TY - JOUR AU - Hajdú, István AU - Szilágyi, András AU - Végh, Barbara AU - Wacha, András Ferenc AU - Györffy, Dániel AU - Gráczer, Éva Laura AU - Somogyi, Márk AU - Gál, Péter AU - Závodszky, Péter TI - Ligand-induced conformational rearrangements regulate the switch between membrane-proximal and distal functions of Rho kinase 2. JF - COMMUNICATIONS BIOLOGY J2 - COMMUN BIOL VL - 3 PY - 2020 IS - 1 SN - 2399-3642 DO - 10.1038/s42003-020-01450-x UR - https://m2.mtmt.hu/api/publication/31677587 ID - 31677587 N1 - Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Budapest, Hungary Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary Export Date: 16 December 2020 Correspondence Address: Hajdú, I.; Institute of Enzymology, Research Centre for Natural Sciences, Institute of Enzymology, Research Centre for Natural SciencesHungary; email: hajdu.istvan@ttk.hu Funding details: National Research, Development and Innovation Office Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH Funding text 1: The authors greatly thank Mária Vas (Institute of Enzymology, Research Center for Natural Sciences) for her critical review of the manuscript, Attila Bóta (Institute of Materials and Environmental Chemistry, Research Center for Natural Sciences) for his expert help in preliminary SAXS experiments. We also thank Nelly R. Hajizadeh and Dmitri I. Svergun at the EMBL SAXS facility for their professional help. The present work was supported by grants K108642, K128262, K134711, PD124451, and 2017-1.2.1-NKP-2017-00002 provided by National Research, Development and Innovation Office (NKFIH). AB - Rho-associated protein kinase 2 (ROCK2) is a membrane-anchored, long, flexible, multidomain, multifunctional protein. Its functions can be divided into two categories: membrane-proximal and membrane-distal. A recent study concluded that membrane-distal functions require the fully extended conformation, and this conclusion was supported by electron microscopy. The present solution small-angle X-ray scattering (SAXS) study revealed that ROCK2 population is a dynamic mixture of folded and partially extended conformers. Binding of RhoA to the coiled-coil domain shifts the equilibrium towards the partially extended state. Enzyme activity measurements suggest that the binding of natural protein substrates to the kinase domain breaks up the interaction between the N-terminal kinase and C-terminal regulatory domains, but smaller substrate analogues do not. The present study reveals the dynamic behaviour of this long, dimeric molecule in solution, and our structural model provides a mechanistic explanation for a set of membrane-proximal functions while allowing for the existence of an extended conformation in the case of membrane-distal functions. LA - English DB - MTMT ER - TY - JOUR AU - Szimler, Tamás AU - Gráczer, Éva Laura AU - Györffy, Dániel AU - Végh, Barbara AU - Szilágyi, András AU - Hajdú, István AU - Závodszky, Péter AU - Kazinczyné Vas, Mária TI - New type of interaction between the SARAH domain of the tumour suppressor RASSF1A and its mitotic kinase Aurora A JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 9 PY - 2019 PG - 12 SN - 2045-2322 DO - 10.1038/s41598-019-41972-x UR - https://m2.mtmt.hu/api/publication/30625253 ID - 30625253 LA - English DB - MTMT ER - TY - JOUR AU - Szilágyi, András AU - Györffy, Dániel AU - Závodszky, Péter TI - Segment swapping aided the evolution of enzyme function: The case of uroporphyrinogen III synthase. JF - PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS J2 - PROTEINS VL - 85 PY - 2017 IS - 1 SP - 46 EP - 53 PG - 8 SN - 0887-3585 DO - 10.1002/prot.25190 UR - https://m2.mtmt.hu/api/publication/3168308 ID - 3168308 AB - In an earlier study, we showed that two-domain segment-swapped proteins can evolve by domain swapping and fusion, resulting in a protein with two linkers connecting its domains. We proposed that a potential evolutionary advantage of this topology may be the restriction of interdomain motions, which may facilitate domain closure by a hinge-like movement, crucial for the function of many enzymes. Here, we test this hypothesis computationally on uroporphyrinogen III synthase, a two-domain segment-swapped enzyme essential in porphyrin metabolism. To compare the interdomain flexibility between the wild-type, segment-swapped enzyme (having two interdomain linkers) and circular permutants of the same enzyme having only one interdomain linker, we performed geometric and molecular dynamics simulations for these species in their ligand-free and ligand-bound forms. We find that in the ligand-free form, interdomain motions in the wild-type enzyme are significantly more restricted than they would be with only one interdomain linker, while the flexibility difference is negligible in the ligand-bound form. We also estimated the entropy costs of ligand binding associated with the interdomain motions, and find that the change in domain connectivity due to segment swapping results in a reduction of this entropy cost, corresponding to approximately 20% of the total ligand binding free energy. In addition, the restriction of interdomain motions may also help the functional domain-closure motion required for catalysis. This suggests that the evolution of the segment-swapped topology facilitated the evolution of enzyme function for this protein by influencing its dynamic properties. Proteins 2016; 85:46-53. (c) 2016 Wiley Periodicals, Inc. LA - English DB - MTMT ER -