@article{MTMT:34477407, title = {Classification of preeclampsia according to molecular clusters with the goal of achieving personalized prevention}, url = {https://m2.mtmt.hu/api/publication/34477407}, author = {Than, Nándor Gábor and Romero, Roberto and Posta, Máté and Györffy, Dániel and Szalai, Gábor and Rossi, Simona W and Szilágyi, András and Hupuczi, Petronella and Nagy, Sándor and Török, Olga and Tarca, Adi L and Erez, Offer and Ács, Nándor and Papp, Zoltán}, doi = {10.1016/j.jri.2023.104172}, journal-iso = {J REPROD IMMUNOL}, journal = {JOURNAL OF REPRODUCTIVE IMMUNOLOGY}, volume = {161}, unique-id = {34477407}, issn = {0165-0378}, abstract = {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.}, keywords = {proteomics; personalized medicine; Screening; Prenatal Diagnosis; liquid biopsy; Extracellular matrix-related pre-eclampsia; Maternal anti-fetal rejection-type pre-eclampsia; Metabolic pre-eclampsia; Placental pre-eclampsia}, year = {2024}, eissn = {1872-7603}, orcid-numbers = {Szilágyi, András/0000-0002-1773-6861; Ács, Nándor/0000-0002-1919-1869} } @article{MTMT:34563187, title = {Decreased Expression of Placental Proteins in Recurrent Pregnancy Loss: Functional Relevance and Diagnostic Value}, url = {https://m2.mtmt.hu/api/publication/34563187}, author = {Tóth, Eszter and Györffy, Dániel and Posta, Máté and Hupuczi, Petronella and Balogh, Andrea and Szalai, Gábor and Orosz, Gergő Balázs and Orosz, László and Szilágyi, András and Oravecz, Orsolya and Veress, Lajos and Nagy, Sándor and Török, Olga and Murthi, Padma and Erez, Offer and Papp, Zoltán and Ács, Nándor and Than, Nándor Gábor}, doi = {10.3390/ijms25031865}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {25}, unique-id = {34563187}, issn = {1661-6596}, abstract = {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.}, year = {2024}, eissn = {1422-0067}, orcid-numbers = {Tóth, Eszter/0000-0001-7149-1482; Balogh, Andrea/0000-0003-0322-1522; Szilágyi, András/0000-0002-1773-6861; Murthi, Padma/0000-0003-2535-5134; Ács, Nándor/0000-0002-1919-1869} } @article{MTMT:34410484, title = {A Kinetic Transition Network Model Reveals the Diversity of Protein Dimer Formation Mechanisms}, url = {https://m2.mtmt.hu/api/publication/34410484}, author = {Györffy, Dániel and Závodszky, Péter and Szilágyi, András}, doi = {10.3390/biom13121708}, journal-iso = {BIOMOLECULES}, journal = {BIOMOLECULES}, volume = {13}, unique-id = {34410484}, issn = {2218-273X}, abstract = {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.}, year = {2023}, eissn = {2218-273X}, orcid-numbers = {Szilágyi, András/0000-0002-1773-6861} } @article{MTMT:34083456, title = {Beta-Secretase 1 Recruits Amyloid-Beta Precursor Protein to ROCK2 Kinase, Resulting in Erroneous Phosphorylation and Beta-Amyloid Plaque Formation}, url = {https://m2.mtmt.hu/api/publication/34083456}, author = {Hajdú, István and Végh, Barbara and Szilágyi, András and Závodszky, Péter}, doi = {10.3390/ijms241310416}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {34083456}, issn = {1661-6596}, abstract = {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.}, keywords = {Humans; PHOSPHORYLATION; PHOSPHORYLATION; PHOSPHORYLATION; metabolism; human; AMYLOID PRECURSOR PROTEIN; Alzheimer disease; Alzheimer disease; Aspartic proteinase; rho-Associated Kinases; amyloid beta protein; Amyloid beta-Peptides; Rho kinase; Plaque, Amyloid; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; SECRETASE; amyloid plaque; Aspartic Acid Endopeptidases; amyloid precursor protein (APP); beta-secretase (BACE1); Rho-kinase (ROCK); allosteric binding site; ROCK2 protein, human}, year = {2023}, eissn = {1422-0067}, orcid-numbers = {Végh, Barbara/0000-0002-1405-4136; Szilágyi, András/0000-0002-1773-6861} } @article{MTMT:33186504, title = {Molecular subclasses of preeclampsia characterized by a longitudinal maternal proteomics study: distinct biomarkers, disease pathways and options for prevention}, url = {https://m2.mtmt.hu/api/publication/33186504}, author = {Than, Nándor Gábor and Romero, Roberto and Györffy, Dániel and Posta, Máté and Bhatti, Gaurav and Done, Bogdan and Chaemsaithong, Piya and Jung, Eunjung and Suksai, Manaphat and Gotsch, Francesca and Gallo, Dahiana M. and Bosco, Mariachiara and Kim, Bomi and Kim, Yeon Mee and Chaiworapongsa, Tinnakorn and Rossi, Simona W. and Szilágyi, András and Erez, Offer and Tarca, Adi L. and Papp, Zoltán}, doi = {10.1515/jpm-2022-0433}, journal-iso = {J PERINAT MED}, journal = {JOURNAL OF PERINATAL MEDICINE}, volume = {51}, unique-id = {33186504}, issn = {0300-5577}, year = {2023}, eissn = {1619-3997}, pages = {51-68}, orcid-numbers = {Szilágyi, András/0000-0002-1773-6861} } @article{MTMT:32760816, title = {Early pathways, biomarkers, and four distinct molecular subclasses of preeclampsia: The intersection of clinical, pathological, and high-dimensional biology studies}, url = {https://m2.mtmt.hu/api/publication/32760816}, author = {Than, Nándor Gábor and Posta, Máté and Györffy, Dániel and Orosz, László and Orosz, Gergő Balázs and Rossi, Simona W. and Ambrus-Aikelin, Géza and Szilágyi, András and Nagy, Sándor and Hupuczi, Petronella and Török, Olga and Tarca, Adi L. and Erez, Offer and Papp, Zoltán and Romero, Roberto}, doi = {10.1016/j.placenta.2022.03.009}, journal-iso = {PLACENTA}, journal = {PLACENTA}, volume = {125}, unique-id = {32760816}, issn = {0143-4004}, year = {2022}, eissn = {1532-3102}, pages = {10-19}, orcid-numbers = {Szilágyi, András/0000-0002-1773-6861; Tarca, Adi L./0000-0003-1712-7588} } @article{MTMT:32725682, title = {A praeeclampsia korai betegségútvonalai, biomarkerei és négy különböző molekuláris alosztálya}, url = {https://m2.mtmt.hu/api/publication/32725682}, author = {Than, Nándor Gábor and Posta, Máté and Györffy, Dániel and Orosz, László and Orosz, Gergő and Rossi, Simona Wilma and Ambrus-Aikelin, Géza and Szilágyi, András and Nagy, Sándor and Hupuczi, Petronella and Török, Olga and Tarca, Adi Laurentiu and Erez, Offer and Papp, Zoltán and Romero, Roberto}, journal-iso = {NŐGYÓGYÁSZATI ÉS SZÜLÉSZETI TOVÁBBKÉPZŐ SZEMLE}, journal = {NŐGYÓGYÁSZATI ÉS SZÜLÉSZETI TOVÁBBKÉPZŐ SZEMLE}, volume = {24}, unique-id = {32725682}, issn = {1585-8731}, year = {2022}, pages = {6-16}, orcid-numbers = {Szilágyi, András/0000-0002-1773-6861} } @article{MTMT:32546517, title = {Epigenetic Dysregulation of Trophoblastic Gene Expression in Gestational Trophoblastic Disease}, url = {https://m2.mtmt.hu/api/publication/32546517}, author = {Szabolcsi, Zoltan and Demeter, Amanda and Király, Péter and Balogh, Andrea and Wilson, Melissa L. and King, Jennifer R. and Hetey, Szabolcs and Gelencsér, Zsolt and Matsuo, Koji and Hargitai, Beáta and Mhawech-Fauceglia, Paulette and Hupuczi, Petronella and Szilágyi, András and Papp, Zoltán and Roman, Lynda D. and Cortessis, Victoria K. and Than, Nándor Gábor}, doi = {10.3390/biomedicines9121935}, journal-iso = {BIOMEDICINES}, journal = {BIOMEDICINES}, volume = {9}, unique-id = {32546517}, year = {2021}, eissn = {2227-9059}, orcid-numbers = {Szabolcsi, Zoltan/0000-0003-0937-9857; Balogh, Andrea/0000-0003-0322-1522; Hetey, Szabolcs/0000-0002-5948-8501; Hargitai, Beáta/0000-0002-3699-6562; Szilágyi, András/0000-0002-1773-6861} } @article{MTMT:32124679, title = {Crowdsourcing assessment of maternal blood multi-omics for predicting gestational age and preterm birth}, url = {https://m2.mtmt.hu/api/publication/32124679}, author = {Tarca, A.L. and Pataki, Bálint Ármin and Romero, R. and Sirota, M. and Guan, Y. and Kutum, R. and Gomez-Lopez, N. and Done, B. and Bhatti, G. and Yu, T. and Andreoletti, G. and Chaiworapongsa, T. and Hassan, S.S. and Hsu, C.-D. and Aghaeepour, N. and Stolovitzky, G. and Csabai, István and Costello, J.C.}, doi = {10.1016/j.xcrm.2021.100323}, journal-iso = {CELL REP MED}, journal = {CELL REPORTS MEDICINE}, volume = {2}, unique-id = {32124679}, issn = {2666-3791}, abstract = {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)}, keywords = {machine learning; APTAMERS; spontaneous preterm birth; Predictive modeling; plasma proteomics; collaborative competition; human transcriptome arrays; preterm labor and delivery; whole blood transcriptomics}, year = {2021}, eissn = {2666-3791}, orcid-numbers = {Csabai, István/0000-0001-9232-9898; Szilágyi, András/0000-0002-1773-6861} } @article{MTMT:31601846, title = {Decreased Expression ofZNF554in Gliomas is Associated with the Activation of Tumor Pathways and Shorter Patient Survival}, url = {https://m2.mtmt.hu/api/publication/31601846}, author = {Balogh, Andrea and Reiniger, Lilla and Hetey, Szabolcs and Király, Péter and Tóth, Eszter and Karászi, Katalin and Juhász, Kata and Gelencsér, Zsolt and Zvara, Ágnes and Szilágyi, András and Puskás, László and Matkó, János and Papp, Zoltán and Kovalszky, Ilona and Juhasz, Csaba and Than, Nándor Gábor}, doi = {10.3390/ijms21165762}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {21}, unique-id = {31601846}, issn = {1661-6596}, abstract = {Zinc finger protein 554 (ZNF554), a member of the Kruppel-associated box domain zinc finger protein subfamily, is predominantly expressed in the brain and placenta in humans. Recently, we unveiled that ZNF554 regulates trophoblast invasion during placentation and its decreased expression leads to the early pathogenesis of preeclampsia. Since ZNF proteins are immensely implicated in the development of several tumors including malignant tumors of the brain, here we explored the pathological role of ZNF554 in gliomas. We examined the expression of ZNF554 at mRNA and protein levels in normal brain and gliomas, and then we searched for genome-wide transcriptomic changes in U87 glioblastoma cells transiently overexpressingZNF554. Immunohistochemistry of brain tissues in our cohort (n= 62) and analysis of large TCGA RNA-Seq data (n= 687) of control, oligodendroglioma, and astrocytoma tissues both revealed decreased expression ofZNF554towards higher glioma grades. Furthermore, lowZNF554expression was associated with shorter survival of grade III and IV astrocytoma patients. Overexpression ofZNF554in U87 cells resulted in differential expression, mostly downregulation of 899 genes. The "PI3K-Akt signaling pathway", known to be activated during glioma development, was the most impacted among 116 dysregulated pathways. Most affected pathways were cancer-related and/or immune-related. Congruently, cell proliferation was decreased and cell cycle was arrested inZNF554-transfected glioma cells. These data collectively suggest that ZNF554 is a potential tumor suppressor and its decreased expression may lead to the loss of oncogene suppression, activation of tumor pathways, and shorter survival of patients with malignant glioma.}, keywords = {Brain; CELLS; DIFFERENTIATION; DOMAINS; FAMILY; GLIOMA; SURVIVAL; transcription factors; glioblastoma; Transcriptome; GENE-THERAPY; HUMAN GLIOBLASTOMA; Biochemistry & Molecular Biology; ZINC-FINGER PROTEINS}, year = {2020}, eissn = {1422-0067}, orcid-numbers = {Balogh, Andrea/0000-0003-0322-1522; Reiniger, Lilla/0000-0003-2248-4264; Tóth, Eszter/0000-0001-7149-1482; Szilágyi, András/0000-0002-1773-6861; Matkó, János/0000-0001-9434-934X; Kovalszky, Ilona/0000-0002-0179-3378} }