@article{KaltdorfSrivastavaGuptaetal.2016,
  author    = {Kaltdorf, Martin and Srivastava, Mugdha and Gupta, Shishir K. and Liang, Chunguang and Binder, Jasmin and Dietl, Anna-Maria and Meir, Zohar and Haas, Hubertus and Osherov, Nir and Krappmann, Sven and Dandekar, Thomas},
  title     = {Systematic Identification of Anti-Fungal Drug Targets by a Metabolic Network Approach},
  series = {Frontiers in Molecular Bioscience},
  volume    = {3},
  journal   = {Frontiers in Molecular Bioscience},
  doi       = {10.3389/fmolb.2016.00022},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147396},
  pages     = {22},
  year      = {2016},
  abstract  = {New antimycotic drugs are challenging to find, as potential target proteins may have close human orthologs. We here focus on identifying metabolic targets that are critical for fungal growth and have minimal similarity to targets among human proteins. We compare and combine here: (I) direct metabolic network modeling using elementary mode analysis and flux estimates approximations using expression data, (II) targeting metabolic genes by transcriptome analysis of condition-specific highly expressed enzymes, and (III) analysis of enzyme structure, enzyme interconnectedness ("hubs"), and identification of pathogen-specific enzymes using orthology relations. We have identified 64 targets including metabolic enzymes involved in vitamin synthesis, lipid, and amino acid biosynthesis including 18 targets validated from the literature, two validated and five currently examined in own genetic experiments, and 38 further promising novel target proteins which are non-orthologous to human proteins, involved in metabolism and are highly ranked drug targets from these pipelines.},
  language  = {en}
}
@article{NaseemSrivastavaDandekar2014,
  author    = {Naseem, Muhammad and Srivastava, Mugdha and Dandekar, Thomas},
  title     = {Stem-cell-triggered immunity safeguards cytokinin enriched plant shoot apexes from pathogen infection},
  series = {Frontiers in Plant Science},
  volume    = {5},
  journal   = {Frontiers in Plant Science},
  issn      = {1664-462X},
  doi       = {10.3389/fpls.2014.00588},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118247},
  pages     = {588},
  year      = {2014},
  abstract  = {Intricate mechanisms discriminate between friends and foes in plants. Plant organs deploy overlapping and distinct protection strategies. Despite vulnerability to a plethora of pathogens, the growing tips of plants grow bacteria free. The shoot apical meristem (SAM) is among three stem cells niches, a self-renewable reservoir for the future organogenesis of leaf, stem, and flowers. How plants safeguard this high value growth target from infections was not known until now. Recent reports find the stem cell secreted 12-amino acid peptide CLV3p (CLAVATA3 peptide) is perceived by FLS2 (FLAGELLIN SENSING 2) receptor and activates the transcription of immunity and defense marker genes. No infection in the SAM of wild type plants and bacterial infection in clv3 and fls2 mutants illustrate this natural protection against infections. Cytokinins (CKs) are enriched in the SAM and regulate meristem activities by their involvement in stem cell signaling networks. Auxin mediates plant susceptibility to pathogen infections while CKs boost plant immunity. Here, in addition to the stem-cell-triggered immunity we also highlight a potential link between CK signaling and CLV3p mediated immune response in the SAM.},
  language  = {en}
}
@article{GuptaSrivastavaMinochaetal.2021,
  author    = {Gupta, Shishir K. and Srivastava, Mugdha and Minocha, Rashmi and Akash, Aman and Dangwal, Seema and Dandekar, Thomas},
  title     = {Alveolar regeneration in COVID-19 patients: a network perspective},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {20},
  issn      = {1422-0067},
  doi       = {10.3390/ijms222011279},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284307},
  year      = {2021},
  abstract  = {A viral infection involves entry and replication of viral nucleic acid in a host organism, subsequently leading to biochemical and structural alterations in the host cell. In the case of SARS-CoV-2 viral infection, over-activation of the host immune system may lead to lung damage. Albeit the regeneration and fibrotic repair processes being the two protective host responses, prolonged injury may lead to excessive fibrosis, a pathological state that can result in lung collapse. In this review, we discuss regeneration and fibrosis processes in response to SARS-CoV-2 and provide our viewpoint on the triggering of alveolar regeneration in coronavirus disease 2019 (COVID-19) patients.},
  language  = {en}
}
@article{NaseemOsmanoğluKaltdorfetal.2020,
  author    = {Naseem, Muhammad and Osmanoğlu, {\"O}zge and Kaltdorf, Martin and Alblooshi, Afnan Ali M. A. and Iqbal, Jibran and Howari, Fares M. and Srivastava, Mugdha and Dandekar, Thomas},
  title     = {Integrated framework of the immune-defense transcriptional signatures in the Arabidopsis shoot apical meristem},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {16},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21165745},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285730},
  year      = {2020},
  abstract  = {The growing tips of plants grow sterile; therefore, disease-free plants can be generated from them. How plants safeguard growing apices from pathogen infection is still a mystery. The shoot apical meristem (SAM) is one of the three stem cells niches that give rise to the above ground plant organs. This is very well explored; however, how signaling networks orchestrate immune responses against pathogen infections in the SAM remains unclear. To reconstruct a transcriptional framework of the differentially expressed genes (DEGs) pertaining to various SAM cellular populations, we acquired large-scale transcriptome datasets from the public repository Gene Expression Omnibus (GEO). We identify here distinct sets of genes for various SAM cellular populations that are enriched in immune functions, such as immune defense, pathogen infection, biotic stress, and response to salicylic acid and jasmonic acid and their biosynthetic pathways in the SAM. We further linked those immune genes to their respective proteins and identify interactions among them by mapping a transcriptome-guided SAM-interactome. Furthermore, we compared stem-cells regulated transcriptome with innate immune responses in plants showing transcriptional separation among their DEGs in Arabidopsis. Besides unleashing a repertoire of immune-related genes in the SAM, our analysis provides a SAM-interactome that will help the community in designing functional experiments to study the specific defense dynamics of the SAM-cellular populations. Moreover, our study promotes the essence of large-scale omics data re-analysis, allowing a fresh look at the SAM-cellular transcriptome repurposing data-sets for new questions.},
  language  = {en}
}
@article{GuptaSrivastavaOsmanogluetal.2021,
  author    = {Gupta, Shishir K. and Srivastava, Mugdha and Osmanoglu, {\"O}zge and Xu, Zhuofei and Brakhage, Axel A. and Dandekar, Thomas},
  title     = {Aspergillus fumigatus versus genus Aspergillus: conservation, adaptive evolution and specific virulence genes},
  series = {Microorganisms},
  volume    = {9},
  journal   = {Microorganisms},
  number    = {10},
  issn      = {2076-2607},
  doi       = {10.3390/microorganisms9102014},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246318},
  year      = {2021},
  abstract  = {Aspergillus is an important fungal genus containing economically important species, as well as pathogenic species of animals and plants. Using eighteen fungal species of the genus Aspergillus, we conducted a comprehensive investigation of conserved genes and their evolution. This also allows us to investigate the selection pressure driving the adaptive evolution in the pathogenic species A. fumigatus. Among single-copy orthologs (SCOs) for A. fumigatus and the closely related species A. fischeri, we identified 122 versus 50 positively selected genes (PSGs), respectively. Moreover, twenty conserved genes of unknown function were established to be positively selected and thus important for adaption. A. fumigatus PSGs interacting with human host proteins show over-representation of adaptive, symbiosis-related, immunomodulatory and virulence-related pathways, such as the TGF-β pathway, insulin receptor signaling, IL1 pathway and interfering with phagosomal GTPase signaling. Additionally, among the virulence factor coding genes, secretory and membrane protein-coding genes in multi-copy gene families, 212 genes underwent positive selection and also suggest increased adaptation, such as fungal immune evasion mechanisms (aspf2), siderophore biosynthesis (sidD), fumarylalanine production (sidE), stress tolerance (atfA) and thermotolerance (sodA). These genes presumably contribute to host adaptation strategies. Genes for the biosynthesis of gliotoxin are shared among all the close relatives of A. fumigatus as an ancient defense mechanism. Positive selection plays a crucial role in the adaptive evolution of A. fumigatus. The genome-wide profile of PSGs provides valuable targets for further research on the mechanisms of immune evasion, antimycotic targeting and understanding fundamental virulence processes.},
  language  = {en}
}
@article{GuptaOsmanogluMinochaetal.2022,
  author    = {Gupta, Shishir K. and Osmanoglu, {\"O}zge and Minocha, Rashmi and Bandi, Sourish Reddy and Bencurova, Elena and Srivastava, Mugdha and Dandekar, Thomas},
  title     = {Genome-wide scan for potential CD4+ T-cell vaccine candidates in Candida auris by exploiting reverse vaccinology and evolutionary information},
  series = {Frontiers in Medicine},
  volume    = {9},
  journal   = {Frontiers in Medicine},
  issn      = {2296-858X},
  doi       = {10.3389/fmed.2022.1008527},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-293953},
  year      = {2022},
  abstract  = {Candida auris is a globally emerging fungal pathogen responsible for causing nosocomial outbreaks in healthcare associated settings. It is known to cause infection in all age groups and exhibits multi-drug resistance with high potential for horizontal transmission. Because of this reason combined with limited therapeutic choices available, C. auris infection has been acknowledged as a potential risk for causing a future pandemic, and thus seeking a promising strategy for its treatment is imperative. Here, we combined evolutionary information with reverse vaccinology approach to identify novel epitopes for vaccine design that could elicit CD4+ T-cell responses against C. auris. To this end, we extensively scanned the family of proteins encoded by C. auris genome. In addition, a pathogen may acquire substitutions in epitopes over a period of time which could cause its escape from the immune response thus rendering the vaccine ineffective. To lower this possibility in our design, we eliminated all rapidly evolving genes of C. auris with positive selection. We further employed highly conserved regions of multiple C. auris strains and identified two immunogenic and antigenic T-cell epitopes that could generate the most effective immune response against C. auris. The antigenicity scores of our predicted vaccine candidates were calculated as 0.85 and 1.88 where 0.5 is the threshold for prediction of fungal antigenic sequences. Based on our results, we conclude that our vaccine candidates have the potential to be successfully employed for the treatment of C. auris infection. However, in vivo experiments are imperative to further demonstrate the efficacy of our design.},
  language  = {en}
}
@article{GuptaSrivastavaOsmanogluetal.2020,
  author    = {Gupta, Shishir K. and Srivastava, Mugdha and Osmanoglu, Oezge and Dandekar, Thomas},
  title     = {Genome-wide inference of the Camponotus floridanus protein-protein interaction network using homologous mapping and interacting domain profile pairs},
  series = {Scientific Reports},
  volume    = {10},
  journal   = {Scientific Reports},
  number    = {1},
  doi       = {10.1038/s41598-020-59344-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229406},
  year      = {2020},
  abstract  = {Apart from some model organisms, the interactome of most organisms is largely unidentified. High-throughput experimental techniques to determine protein-protein interactions (PPIs) are resource intensive and highly susceptible to noise. Computational methods of PPI determination can accelerate biological discovery by identifying the most promising interacting pairs of proteins and by assessing the reliability of identified PPIs. Here we present a first in-depth study describing a global view of the ant Camponotus floridanus interactome. Although several ant genomes have been sequenced in the last eight years, studies exploring and investigating PPIs in ants are lacking. Our study attempts to fill this gap and the presented interactome will also serve as a template for determining PPIs in other ants in future. Our C. floridanus interactome covers 51,866 non-redundant PPIs among 6,274 proteins, including 20,544 interactions supported by domain-domain interactions (DDIs), 13,640 interactions supported by DDIs and subcellular localization, and 10,834 high confidence interactions mediated by 3,289 proteins. These interactions involve and cover 30.6\% of the entire C. floridanus proteome.},
  language  = {en}
}
@article{SrivastavaBencurovaGuptaetal.2019,
  author    = {Srivastava, Mugdha and Bencurova, Elena and Gupta, Shishir K. and Weiss, Esther and L{\"o}ffler, J{\"u}rgen and Dandekar, Thomas},
  title     = {Aspergillus fumigatus challenged by human dendritic cells: metabolic and regulatory pathway responses testify a tight battle},
  series = {Frontiers in Cellular and Infection Microbiology},
  volume    = {9},
  journal   = {Frontiers in Cellular and Infection Microbiology},
  doi       = {10.3389/fcimb.2019.00168},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201368},
  pages     = {168},
  year      = {2019},
  abstract  = {Dendritic cells (DCs) are antigen presenting cells which serve as a passage between the innate and the acquired immunity. Aspergillosis is a major lethal condition in immunocompromised patients caused by the adaptable saprophytic fungus Aspergillus fumigatus. The healthy human immune system is capable to ward off A. fumigatus infections however immune-deficient patients are highly vulnerable to invasive aspergillosis. A. fumigatus can persist during infection due to its ability to survive the immune response of human DCs. Therefore, the study of the metabolism specific to the context of infection may allow us to gain insight into the adaptation strategies of both the pathogen and the immune cells. We established a metabolic model of A. fumigatus central metabolism during infection of DCs and calculated the metabolic pathway (elementary modes; EMs). Transcriptome data were used to identify pathways activated when A. fumigatus is challenged with DCs. In particular, amino acid metabolic pathways, alternative carbon metabolic pathways and stress regulating enzymes were found to be active. Metabolic flux modeling identified further active enzymes such as alcohol dehydrogenase, inositol oxygenase and GTP cyclohydrolase participating in different stress responses in A. fumigatus. These were further validated by qRT-PCR from RNA extracted under these different conditions. For DCs, we outlined the activation of metabolic pathways in response to the confrontation with A. fumigatus. We found the fatty acid metabolism plays a crucial role, along with other metabolic changes. The gene expression data and their analysis illuminate additional regulatory pathways activated in the DCs apart from interleukin regulation. In particular, Toll-like receptor signaling, NOD-like receptor signaling and RIG-I-like receptor signaling were active pathways. Moreover, we identified subnetworks and several novel key regulators such as UBC, EGFR, and CUL3 of DCs to be activated in response to A. fumigatus. In conclusion, we analyze the metabolic and regulatory responses of A. fumigatus and DCs when confronted with each other.},
  language  = {en}
}
@article{FuhrHeidenreichSrivastavaetal.2022,
  author    = {Fuhr, Viktoria and Heidenreich, Shanice and Srivastava, Mugdha and Riedel, Angela and D{\"u}ll, Johannes and Gerhard-Hartmann, Elena and Rosenwald, Andreas and Rauert-Wunderlich, Hilka},
  title     = {CD52 and OXPHOS-potential targets in ibrutinib-treated mantle cell lymphoma},
  series = {Cell Death Discovery},
  volume    = {8},
  journal   = {Cell Death Discovery},
  issn      = {2058-7716},
  doi       = {10.1038/s41420-022-01289-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300817},
  year      = {2022},
  abstract  = {Altered features of tumor cells acquired across therapy can result in the survival of treatment-resistant clones that may cause minimal residual disease (MRD). Despite the efficacy of ibrutinib in treating relapsed/refractory mantle cell lymphoma, the obstacle of residual cells contributes to relapses of this mature B-cell neoplasm, and the disease remains incurable. RNA-seq analysis of an ibrutinib-sensitive mantle cell lymphoma cell line following ibrutinib incubation of up to 4 d, corroborated our previously postulated resistance mechanism of a metabolic switch to reliance on oxidative phosphorylation (OXPHOS) in surviving cells. Besides, we had shown that treatment-persisting cells were characterized by increased CD52 expression. Therefore, we hypothesized that combining ibrutinib with another agent targeting these potential escape mechanisms could minimize the risk of survival of ibrutinib-resistant cells. Concomitant use of ibrutinib with OXPHOS-inhibitor IACS-010759 increased toxicity compared to ibrutinib alone. Targeting CD52 was even more efficient, as addition of CD52 mAb in combination with human serum following ibrutinib pretreatment led to rapid complement-dependent-cytotoxicity in an ibrutinib-sensitive cell line. In primary mantle cell lymphoma cells, a higher toxic effect with CD52 mAb was obtained, when cells were pretreated with ibrutinib, but only in an ibrutinib-sensitive cohort. Given the challenge of treating multi-resistant mantle cell lymphoma patients, this work highlights the potential use of anti-CD52 therapy as consolidation after ibrutinib treatment in patients who responded to the BTK inhibitor to achieve MRD negativity and prolong progression-free survival.},
  language  = {en}
}
@article{GuptaMinochaThapaetal.2022,
  author    = {Gupta, Shishir K. and Minocha, Rashmi and Thapa, Prithivi Jung and Srivastava, Mugdha and Dandekar, Thomas},
  title     = {Role of the pangolin in origin of SARS-CoV-2: an evolutionary perspective},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {16},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23169115},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285995},
  year      = {2022},
  abstract  = {After the recent emergence of SARS-CoV-2 infection, unanswered questions remain related to its evolutionary history, path of transmission or divergence and role of recombination. There is emerging evidence on amino acid substitutions occurring in key residues of the receptor-binding domain of the spike glycoprotein in coronavirus isolates from bat and pangolins. In this article, we summarize our current knowledge on the origin of SARS-CoV-2. We also analyze the host ACE2-interacting residues of the receptor-binding domain of spike glycoprotein in SARS-CoV-2 isolates from bats, and compare it to pangolin SARS-CoV-2 isolates collected from Guangdong province (GD Pangolin-CoV) and Guangxi autonomous regions (GX Pangolin-CoV) of South China. Based on our comparative analysis, we support the view that the Guangdong Pangolins are the intermediate hosts that adapted the SARS-CoV-2 and represented a significant evolutionary link in the path of transmission of SARS-CoV-2 virus. We also discuss the role of intermediate hosts in the origin of Omicron.},
  language  = {en}
}
@article{DelgoboHeinrichsHapkeetal.2021,
  author    = {Delgobo, Murilo and Heinrichs, Margarete and Hapke, Nils and Ashour, DiyaaElDin and Appel, Marc and Srivastava, Mugdha and Heckel, Tobias and Spyridopoulos, Ioakim and Hofmann, Ulrich and Frantz, Stefan and Ramos, Gustavo Campos},
  title     = {Terminally Differentiated CD4\(^+\) T Cells Promote Myocardial Inflammaging},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.584538},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229612},
  year      = {2021},
  abstract  = {The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4\(^+\) T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4\(^+\) T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4\(^+\) T cell compartment was primarily composed of na{\"i}ve cells defined as CCR7\(^+\)CD45RO\(^-\). However, when transplanted into young lymphocyte-deficient mice, CD4\(^+\) T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7\(^-\) CD45RO\(^+\)) and terminally-differentiated phenotypes (CCR7\(^-\)CD45RO\(^-\)), as typically seen in elderly. Differentiated CD4\(^+\) T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4\(^+\) T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4\(^+\) T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.},
  language  = {en}
}
@article{SalihogluSrivastavaLiangetal.2023,
  author    = {Salihoglu, Rana and Srivastava, Mugdha and Liang, Chunguang and Schilling, Klaus and Szalay, Aladar and Bencurova, Elena and Dandekar, Thomas},
  title     = {PRO-Simat: Protein network simulation and design tool},
  series = {Computational and Structural Biotechnology Journal},
  volume    = {21},
  journal   = {Computational and Structural Biotechnology Journal},
  issn      = {2001-0370},
  doi       = {10.1016/j.csbj.2023.04.023},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350034},
  pages     = {2767-2779},
  year      = {2023},
  abstract  = {PRO-Simat is a simulation tool for analysing protein interaction networks, their dynamic change and pathway engineering. It provides GO enrichment, KEGG pathway analyses, and network visualisation from an integrated database of more than 8 million protein-protein interactions across 32 model organisms and the human proteome. We integrated dynamical network simulation using the Jimena framework, which quickly and efficiently simulates Boolean genetic regulatory networks. It enables simulation outputs with in-depth analysis of the type, strength, duration and pathway of the protein interactions on the website. Furthermore, the user can efficiently edit and analyse the effect of network modifications and engineering experiments. In case studies, applications of PRO-Simat are demonstrated: (i) understanding mutually exclusive differentiation pathways in Bacillus subtilis, (ii) making Vaccinia virus oncolytic by switching on its viral replication mainly in cancer cells and triggering cancer cell apoptosis and (iii) optogenetic control of nucleotide processing protein networks to operate DNA storage. Multilevel communication between components is critical for efficient network switching, as demonstrated by a general census on prokaryotic and eukaryotic networks and comparing design with synthetic networks using PRO-Simat. The tool is available at https://prosimat.heinzelab.de/ as a web-based query server.},
  language  = {en}
}