TY - JOUR AU - Gudrun, Meinhardt AU - Hanna, Waldhäusl AU - Andreas, I. Lackner AU - Jasmin, Wächter AU - Theresa, Maxian AU - Anna-Lena, Höbler AU - Sigrid, Vondra AU - Victoria, Kunihs AU - Leila, Saleh AU - Peter, Haslinger AU - Peter, Kiraly AU - Szilágyi, András AU - Than, Nándor Gábor AU - Jürgen, Pollheimer AU - Sandra, Haider AU - Martin, Knöfler TI - The multifaceted roles of the transcriptional coactivator TAZ in extravillous trophoblast development of the human placenta JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA J2 - P NATL ACAD SCI USA VL - 122 PY - 2025 IS - 16 PG - 11 SN - 0027-8424 DO - 10.1073/pnas.2426385122 UR - https://m2.mtmt.hu/api/publication/36063062 ID - 36063062 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 - Systems Biology of Reproduction Research Group, Institute of Enzymology, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary Department of Obstetrics and Gynecology, School of Medicine, Semmelweis University, Budapest, Hungary Maternity Private Clinic of Obstetrics and Gynecology, Budapest, Hungary Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States Genesis Theranostix Group, Budapest, Hungary , NICHD/NIH/DHHS, Bethesda, MD, United States 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 Semmelweis University Doctoral School, Budapest, Hungary Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary Department of Surgery, School of Medicine, University of Pécs, Pécs, Hungary Department of Anesthesiology and Intensive Therapy, Semmelweis University, Budapest, Hungary Faculty of Health and Sport Sciences, Széchenyi István University, Győr, Hungary Department of Obstetrics and Gynecology, School of Medicine, University of Debrecen, Debrecen, Hungary Department of Obstetrics and Gynecology, School of Medicine, Wayne State University School of Medicine, Detroit, MI, United States Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States Department of Obstetrics and Gynecology, Soroka University Medical Center, Ben Gurion University of the Negev, Be'er Sheva, Israel Export Date: 09 January 2025; Cited By: 2; Correspondence Address: N.G. Than; Department of Obstetrics and Gynecology, Semmelweis University, Budapest, 27 Baross Street, H-1088, Hungary; email: than.gabor@semmelweis.hu; CODEN: JRIMD 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 - 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 - Systems Biology of Reproduction Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, Budapest, H-1117, Hungary Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, H-1083, Hungary Doctoral School, Semmelweis University, Budapest, H-1085, Hungary Maternity Private Clinic of Obstetrics and Gynecology, Budapest, H-1126, Hungary Department of Surgery, Medical School, University of Pécs, Pécs, H-7624, Hungary Department of Obstetrics and Gynecology, Medical School, University of Debrecen, Debrecen, H-4032, Hungary Doctoral School of Biology, ELTE Eötvös Loránd University, Budapest, H-1117, Hungary Department of Pharmacology and Pharmacotherapy, Medical School, University of Debrecen, Debrecen, H-4032, Hungary Faculty of Health and Sport Sciences, Széchenyi István University, Győr, H-9026, Hungary Department of Pharmacology, Monash Biomedicine Discovery Institute, Clayton, 3168, Australia Department of Obstetrics and Gynaecology, University of Melbourne, Royal Women’s Hospital, Parkville, 3052, Australia Department of Obstetrics and Gynecology, Soroka University Medical Center, Ben Gurion University of the Negev, Be’er Sheva, 8410501, Israel Department of Obstetrics and Gynecology, Medical School, Wayne State University, Detroit, 48201, MI, United States Department of Obstetrics and Gynecology, Medical School, Semmelweis University, 27 Baross Street, Budapest, H-1088, Hungary Export Date: 09 January 2025; Cited By: 1; Correspondence Address: N.G. Than; Systems Biology of Reproduction Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Magyar Tudósok Körútja 2, H-1117, Hungary; email: than.gabor@semmelweis.hu 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 - 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 - Hajdú, István AU - Végh, Barbara AU - Szilágyi, András AU - Závodszky, Péter TI - Beta-Secretase 1 Recruits Amyloid-Beta Precursor Protein to ROCK2 Kinase, Resulting in Erroneous Phosphorylation and Beta-Amyloid Plaque Formation JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 13 SN - 1661-6596 DO - 10.3390/ijms241310416 UR - https://m2.mtmt.hu/api/publication/34083456 ID - 34083456 N1 - Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, 1083, Hungary Export Date: 01 August 2023; Cited By: 0; Correspondence Address: I. Hajdú; Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary; email: hajdu.istvan@ttk.hu; P. Závodszky; Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary; email: zavodszky.peter@ttk.hu AB - The amyloidogenic processing of APP depends on two events: its phosphorylation by ROCK2 (at Thr654) and the phosphorylation of the APP-cleaving enzyme BACE1 (at Ser498). However, the mechanisms and structural details of APP-ROCK2 and BACE1-ROCK2 binding are unknown. Using direct physical methods in combination with an in silico approach, we found that BACE1 binds into the substrate-binding groove of ROCK2 with a low affinity (Kd = 18 µM), while no binding of APP to ROCK2 alone could be detected. On the other hand, a strong association (Kd = 3.5 nM) of APP to the weak ROCK2-BACE1 complex was observed, although no stable ternary complex was detected, i.e., BACE1 was displaced by APP. We constructed a sequential functional model: (1) BACE1 weakly binds to ROCK2 and induces an allosteric conformational change in ROCK2; (2) APP strongly binds to the ROCK2-BACE1 complex, and BACE1 is released; and (3) ROCK2 phosphorylates APP at Thr654 (leading to a longer stay in the early endosome during APP processing). Direct fluorescence titration experiments showed that the APP646–664 or APP665–695 fragments did not bind separately to the ROCK2-BACE1 complex. Based on these observations, we conclude that two binding sites are involved in the ROCK2-APP interaction: (1) the substrate-binding groove, where the APP646–664 sequence containing Thr654 sits and (2) the allosteric binding site, where the APP665–695 sequence binds. These results open the way to attack the allosteric site to prevent APP phosphorylation at Thr654 by ROCK2 without inhibiting the activity of ROCK2 towards its other substrates. © 2023 by the authors. 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 AB - The heterogeneous nature of preeclampsia is a major obstacle to early screening and prevention, and a molecular taxonomy of disease is needed. We have previously identified four subclasses of preeclampsia based on first-trimester plasma proteomic profiles. Herein, we expanded this approach by using a more comprehensive panel of proteins profiled in longitudinal samples. 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 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 - Szabolcsi, Zoltan AU - Demeter, Amanda AU - Király, Péter AU - Balogh, Andrea AU - Wilson, Melissa L. AU - King, Jennifer R. AU - Hetey, Szabolcs AU - Gelencsér, Zsolt AU - Matsuo, Koji AU - Hargitai, Beáta AU - Mhawech-Fauceglia, Paulette AU - Hupuczi, Petronella AU - Szilágyi, András AU - Papp, Zoltán AU - Roman, Lynda D. AU - Cortessis, Victoria K. AU - Than, Nándor Gábor TI - Epigenetic Dysregulation of Trophoblastic Gene Expression in Gestational Trophoblastic Disease JF - BIOMEDICINES J2 - BIOMEDICINES VL - 9 PY - 2021 IS - 12 PG - 21 SN - 2227-9059 DO - 10.3390/biomedicines9121935 UR - https://m2.mtmt.hu/api/publication/32546517 ID - 32546517 AB - Gestational trophoblastic diseases (GTDs) have not been investigated for their epigenetic marks and consequent transcriptomic changes. Here, we analyzed genome-wide DNA methylation and transcriptome data to reveal the epigenetic basis of disease pathways that may lead to benign or malignant GTDs. RNA-Seq, mRNA microarray, and Human Methylation 450 BeadChip data from complete moles and choriocarcinoma cells were bioinformatically analyzed. Paraffin-embedded tissues from complete moles and control placentas were used for tissue microarray construction, DNMT3B immunostaining and immunoscoring. We found that DNA methylation increases with disease severity in GTDs. Differentially expressed genes are mainly upregulated in moles while predominantly downregulated in choriocarcinoma. DNA methylation principally influences the gene expression of villous trophoblast differentiation-related or predominantly placenta-expressed genes in moles and choriocarcinoma cells. Affected genes in these subsets shared focal adhesion and actin cytoskeleton pathways in moles and choriocarcinoma. In moles, cell cycle and differentiation regulatory pathways, essential for trophoblast/placental development, were enriched. In choriocarcinoma cells, hormone biosynthetic, extracellular matrix-related, hypoxic gene regulatory, and differentiation-related signaling pathways were enriched. In moles, we found slight upregulation of DNMT3B protein, a developmentally important de novo DNA methylase, which is strongly overexpressed in choriocarcinoma cells that may partly be responsible for the large DNA methylation differences. Our findings provide new insights into the shared and disparate molecular pathways of disease in GTDs and may help in designing new diagnostic and therapeutic tools. LA - English 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 PG - 20 SN - 2666-3791 DO - 10.1016/j.xcrm.2021.100323 UR - https://m2.mtmt.hu/api/publication/32124679 ID - 32124679 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 -