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1
Sylvester, Anne W., Laurie Smith und Michael Freeling. „ACQUISITION OF IDENTITY IN THE DEVELOPING LEAF“. Annual Review of Cell and Developmental Biology 12, Nr. 1 (November 1996): 257–304. http://dx.doi.org/10.1146/annurev.cellbio.12.1.257.
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Mesman, Simone, und Marten P. Smidt. „Acquisition of the Midbrain Dopaminergic Neuronal Identity“. International Journal of Molecular Sciences 21, Nr. 13 (30.06.2020): 4638. http://dx.doi.org/10.3390/ijms21134638.
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The mesodiencephalic dopaminergic (mdDA) group of neurons comprises molecularly distinct subgroups, of which the substantia nigra (SN) and ventral tegmental area (VTA) are the best known, due to the selective degeneration of the SN during Parkinson’s disease. However, although significant research has been conducted on the molecular build-up of these subsets, much is still unknown about how these subsets develop and which factors are involved in this process. In this review, we aim to describe the life of an mdDA neuron, from specification in the floor plate to differentiation into the different subsets. All mdDA neurons are born in the mesodiencephalic floor plate under the influence of both SHH-signaling, important for floor plate patterning, and WNT-signaling, involved in establishing the progenitor pool and the start of the specification of mdDA neurons. Furthermore, transcription factors, like Ngn2, Ascl1, Lmx1a, and En1, and epigenetic factors, like Ezh2, are important in the correct specification of dopamine (DA) progenitors. Later during development, mdDA neurons are further subdivided into different molecular subsets by, amongst others, Otx2, involved in the specification of subsets in the VTA, and En1, Pitx3, Lmx1a, and WNT-signaling, involved in the specification of subsets in the SN. Interestingly, factors involved in early specification in the floor plate can serve a dual function and can also be involved in subset specification. Besides the mdDA group of neurons, other systems in the embryo contain different subsets, like the immune system. Interestingly, many factors involved in the development of mdDA neurons are similarly involved in immune system development and vice versa. This indicates that similar mechanisms are used in the development of these systems, and that knowledge about the development of the immune system may hold clues for the factors involved in the development of mdDA neurons, which may be used in culture protocols for cell replacement therapies.
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Salinno, Cota, Bastidas-Ponce, Tarquis-Medina, Lickert und Bakhti. „β-Cell Maturation and Identity in Health and Disease“. International Journal of Molecular Sciences 20, Nr. 21 (30.10.2019): 5417. http://dx.doi.org/10.3390/ijms20215417.
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The exponential increase of patients with diabetes mellitus urges for novel therapeutic strategies to reduce the socioeconomic burden of this disease. The loss or dysfunction of insulin-producing β-cells, in patients with type 1 and type 2 diabetes respectively, put these cells at the center of the disease initiation and progression. Therefore, major efforts have been taken to restore the β-cell mass by cell-replacement or regeneration approaches. Implementing novel therapies requires deciphering the developmental mechanisms that generate β-cells and determine the acquisition of their physiological phenotype. In this review, we summarize the current understanding of the mechanisms that coordinate the postnatal maturation of β-cells and define their functional identity. Furthermore, we discuss different routes by which β-cells lose their features and functionality in type 1 and 2 diabetic conditions. We then focus on potential mechanisms to restore the functionality of those β-cell populations that have lost their functional phenotype. Finally, we discuss the recent progress and remaining challenges facing the generation of functional mature β-cells from stem cells for cell-replacement therapy for diabetes treatment.
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Kinare, Veena, Archana Iyer, Hari Padmanabhan, Geeta Godbole, Tooba Khan, Zeba Khatri, Upasana Maheshwari, Bhavana Muralidharan und Shubha Tole. „An evolutionarily conserved Lhx2-Ldb1 interaction regulates the acquisition of hippocampal cell fate and regional identity“. Development 147, Nr. 20 (29.09.2020): dev187856. http://dx.doi.org/10.1242/dev.187856.
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ABSTRACTThe protein co-factor Ldb1 regulates cell fate specification by interacting with LIM-homeodomain (LIM-HD) proteins in a tetrameric complex consisting of an LDB:LDB dimer that bridges two LIM-HD molecules, a mechanism first demonstrated in the Drosophila wing disc. Here, we demonstrate conservation of this interaction in the regulation of mammalian hippocampal development, which is profoundly defective upon loss of either Lhx2 or Ldb1. Electroporation of a chimeric construct that encodes the Lhx2-HD and Ldb1-DD (dimerization domain) in a single transcript cell-autonomously rescues a comprehensive range of hippocampal deficits in the mouse Ldb1 mutant, including the acquisition of field-specific molecular identity and the regulation of the neuron-glia cell fate switch. This demonstrates that the LHX:LDB complex is an evolutionarily conserved molecular regulatory device that controls complex aspects of regional cell identity in the developing brain.
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Simon, Françoise, Anne Ramat, Sophie Louvet-Vallée, Jérôme Lacoste, Angélique Burg, Agnès Audibert und Michel Gho. „Shaping of Drosophila Neural Cell Lineages Through Coordination of Cell Proliferation and Cell Fate by the BTB-ZF Transcription Factor Tramtrack-69“. Genetics 212, Nr. 3 (09.05.2019): 773–88. http://dx.doi.org/10.1534/genetics.119.302234.
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Cell diversity in multicellular organisms relies on coordination between cell proliferation and the acquisition of cell identity. The equilibrium between these two processes is essential to assure the correct number of determined cells at a given time at a given place. Using genetic approaches and correlative microscopy, we show that Tramtrack-69 (Ttk69, a Broad-complex, Tramtrack and Bric-à-brac - Zinc Finger (BTB-ZF) transcription factor ortholog of the human promyelocytic leukemia zinc finger factor) plays an essential role in controlling this balance. In the Drosophila bristle cell lineage, which produces the external sensory organs composed by a neuron and accessory cells, we show that ttk69 loss-of-function leads to supplementary neural-type cells at the expense of accessory cells. Our data indicate that Ttk69 (1) promotes cell cycle exit of newborn terminal cells by downregulating CycE, the principal cyclin involved in S-phase entry, and (2) regulates cell-fate acquisition and terminal differentiation, by downregulating the expression of hamlet and upregulating that of Suppressor of Hairless, two transcription factors involved in neural-fate acquisition and accessory cell differentiation, respectively. Thus, Ttk69 plays a central role in shaping neural cell lineages by integrating molecular mechanisms that regulate progenitor cell cycle exit and cell-fate commitment.
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Okada, Yohei, Takuya Shimazaki, Gen Sobue und Hideyuki Okano. „Retinoic-acid-concentration-dependent acquisition of neural cell identity during in vitro differentiation of mouse embryonic stem cells“. Developmental Biology 275, Nr. 1 (November 2004): 124–42. http://dx.doi.org/10.1016/j.ydbio.2004.07.038.
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Conforti, P., D. Besusso, V. D. Bocchi, A. Faedo, E. Cesana, G. Rossetti, V. Ranzani et al. „Faulty neuronal determination and cell polarization are reverted by modulating HD early phenotypes“. Proceedings of the National Academy of Sciences 115, Nr. 4 (08.01.2018): E762—E771. http://dx.doi.org/10.1073/pnas.1715865115.
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Increasing evidence suggests that early neurodevelopmental defects in Huntington’s disease (HD) patients could contribute to the later adult neurodegenerative phenotype. Here, by using HD-derived induced pluripotent stem cell lines, we report that early telencephalic induction and late neural identity are affected in cortical and striatal populations. We show that a large CAG expansion causes complete failure of the neuro-ectodermal acquisition, while cells carrying shorter CAGs repeats show gross abnormalities in neural rosette formation as well as disrupted cytoarchitecture in cortical organoids. Gene-expression analysis showed that control organoid overlapped with mature human fetal cortical areas, while HD organoids correlated with the immature ventricular zone/subventricular zone. We also report that defects in neuroectoderm and rosette formation could be rescued by molecular and pharmacological approaches leading to a recovery of striatal identity. These results show that mutant huntingtin precludes normal neuronal fate acquisition and highlights a possible connection between mutant huntingtin and abnormal neural development in HD.
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Abenza, Juan F., Antonio Galindo, Areti Pantazopoulou, Concha Gil, Vivian de los Ríos und Miguel A. Peñalva. „Aspergillus RabBRab5 Integrates Acquisition of Degradative Identity with the Long Distance Movement of Early Endosomes“. Molecular Biology of the Cell 21, Nr. 15 (August 2010): 2756–69. http://dx.doi.org/10.1091/mbc.e10-02-0119.
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Aspergillus nidulans early endosomes display characteristic long-distance bidirectional motility. Simultaneous dual-channel acquisition showed that the two Rab5 paralogues RabB and RabA colocalize in these early endosomes and also in larger, immotile mature endosomes. However, RabB-GTP is the sole recruiter to endosomes of Vps34 PI3K (phosphatidylinositol-3-kinase) and the phosphatidylinositol-3-phosphate [PI(3)P] effector AnVps19 and rabBΔ, leading to thermosensitivity prevents multivesicular body sorting of endocytic cargo. Thus, RabB is the sole mediator of degradative endosomal identity. Importantly, rabBΔ, unlike rabAΔ, prevents early endosome movement. As affinity experiments and pulldowns showed that RabB-GTP recruits AnVps45, RabB coordinates PI(3)P-dependent endosome-to-vacuole traffic with incoming traffic from the Golgi and with long-distance endosomal motility. However, the finding that Anvps45Δ, unlike rabBΔ, severely impairs growth indicates that AnVps45 plays RabB-independent functions. Affinity chromatography showed that the CORVET complex is a RabB and, to a lesser extent, a RabA effector, in agreement with GST pulldown assays of AnVps8. rabBΔ leads to smaller vacuoles, suggesting that it impairs homotypic vacuolar fusion, which would agree with the sequential maturation of endosomal CORVET into HOPS proposed for Saccharomyces cerevisiae. rabBΔ and rabAΔ mutations are synthetically lethal, demonstrating that Rab5-mediated establishment of endosomal identity is essential for A. nidulans.
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Situmorang, Boldson Herdianto. „Identification of Biometrics Using Fingerprint Minutiae Extraction Based on Crossing Number Method“. Komputasi: Jurnal Ilmiah Ilmu Komputer dan Matematika 20, Nr. 1 (02.12.2022): 71–80. http://dx.doi.org/10.33751/komputasi.v20i1.6814.
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Biometrics based on fingerprint images is a self-recognition technique using fingerprint to represent a person's identity. Fingerprint is characteristic of someone's identity precisely and safely because there are no similarities and cannot be falsified. The purpose of this research is to develop a biometrics identification system based on fingerprint images by utilizing a cell phone camera for the acquisition of fingerprint images. This is based on its simplicity because almost everyone has a cell phone so that a person's identification system based on fingerprint can be used anytime and anywhere. The research was conducted using images generated from cell phone cameras with camera specifications of 2, 5 and 8 mega pixels. The method used in image processing consists of the minutiae crossing number method for the feature extraction process and the minutiae based matching method for the similarity measurement process. The results of the research concluded that cell phone cameras with specifications of 5 and 8 mega pixels can be used for the process of image acquisition in biometrics systems based on fingerprint. The feature extraction process of image results using the minutiae crossing number method and the match measurement process using the minutiae based matching method resulted in an accuracy value of 92.8% on a 5 mega pixel camera and 95.3% on an 8 mega pixel camera. The accuracy value depends on the results of the image acquisition stage, pre-processing, the threshold value in the identification process, and the number of images used in the training data in the database.
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Gomez, R. Ariel, Ellen Steward Pentz, Xuan Jin, Magali Cordaillat und Maria Luisa S. Sequeira Lopez. „CBP and p300 are essential for renin cell identity and morphological integrity of the kidney“. American Journal of Physiology-Heart and Circulatory Physiology 296, Nr. 5 (Mai 2009): H1255—H1262. http://dx.doi.org/10.1152/ajpheart.01266.2008.
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The mechanisms that govern the identity of renin cells are not well understood. We and others have identified cAMP as an important pathway in the regulation of renin synthesis and release. Recently, experiments in cells from the renin lineage led us to propose that acquisition and maintenance of renin cell identity are mediated by cAMP and histone acetylation at the cAMP responsive element (CRE) of the renin gene. Ultimately, the transcriptional effects of cAMP depend on binding of the appropriate transcription factors to CRE. It has been suggested that access of transcription factors to this region of the promoter is facilitated by the coactivators CREB-binding protein (CBP) and p300, which possess histone acetyltransferase activity and may be, in turn, responsible for the remodeling of chromatin underlying expression of the renin gene. We hypothesized that CBP and p300 are therefore required for expression of the renin gene and maintenance of the renin cell. Because mice homozygous for the deletion of CBP or p300 die before kidney organogenesis begins, no data on kidney or juxtaglomerular cell development in these mice are available. Therefore, to define the role of these histone acetyltransferases in renin cell identity in vivo, we used a conditional deletion approach, in which floxed CBP and p300 mice were crossed with mice expressing cre recombinase in renin cells. Results show that the histone acetyltransferases CBP and p300 are necessary for maintenance of renin cell identity and structural integrity of the kidney.
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Gaspar, Patricia, und Christina Lillesaar. „Probing the diversity of serotonin neurons“. Philosophical Transactions of the Royal Society B: Biological Sciences 367, Nr. 1601 (05.09.2012): 2382–94. http://dx.doi.org/10.1098/rstb.2011.0378.
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The serotonin (5-HT) system is generally considered as a single modulatory system, with broad and diffuse projections. However, accumulating evidence points to the existence of distinct cell groups in the raphe. Here, we review prior evidence for raphe cell heterogeneity, considering different properties of 5-HT neurons, from metabolism to anatomy, and neurochemistry to physiology. We then summarize more recent data in mice and zebrafish that support a genetic diversity of 5-HT neurons, based on differential transcription factor requirements for the acquisition of the 5-HT identity. In both species, PET1 plays a major role in the acquisition and maintenance of 5-HT identity in the hindbrain, although some 5-HT neurons do not require PET1 for their differentiation, indicating the existence of several transcriptional routes to become serotoninergic. In mice, both PET1-dependent and -independent 5-HT neurons are located in the raphe, but have distinct anatomical features, such as the morphology of axon terminals and projection patterns. In zebrafish, all raphe neurons express pet1 , but Pet1-independent 5-HT cell groups are present in the forebrain. Overall, these observations support the view that there are a number of distinct 5-HT subsystems, including within the raphe nuclei, with unique genetic programming and functions.
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Jaiswal, Sushil K., Sonam Raj und Melvin L. DePamphilis. „Developmental Acquisition of p53 Functions“. Genes 12, Nr. 11 (23.10.2021): 1675. http://dx.doi.org/10.3390/genes12111675.
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Remarkably, the p53 transcription factor, referred to as “the guardian of the genome”, is not essential for mammalian development. Moreover, efforts to identify p53-dependent developmental events have produced contradictory conclusions. Given the importance of pluripotent stem cells as models of mammalian development, and their applications in regenerative medicine and disease, resolving these conflicts is essential. Here we attempt to reconcile disparate data into justifiable conclusions predicated on reports that p53-dependent transcription is first detected in late mouse blastocysts, that p53 activity first becomes potentially lethal during gastrulation, and that apoptosis does not depend on p53. Furthermore, p53 does not regulate expression of genes required for pluripotency in embryonic stem cells (ESCs); it contributes to ESC genomic stability and differentiation. Depending on conditions, p53 accelerates initiation of apoptosis in ESCs in response to DNA damage, but cell cycle arrest as well as the rate and extent of apoptosis in ESCs are p53-independent. In embryonic fibroblasts, p53 induces cell cycle arrest to allow repair of DNA damage, and cell senescence to prevent proliferation of cells with extensive damage.
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Wille, Coral K., und Rupa Sridharan. „DOT1L inhibition enhances pluripotency beyond acquisition of epithelial identity and without immediate suppression of the somatic transcriptome“. Stem Cell Reports 17, Nr. 2 (Februar 2022): 384–96. http://dx.doi.org/10.1016/j.stemcr.2021.12.004.
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Uzquiano, Ana, Amanda J. Kedaigle, Martina Pigoni, Bruna Paulsen, Xian Adiconis, Kwanho Kim, Tyler Faits et al. „Proper acquisition of cell class identity in organoids allows definition of fate specification programs of the human cerebral cortex“. Cell 185, Nr. 20 (September 2022): 3770–88. http://dx.doi.org/10.1016/j.cell.2022.09.010.
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Schüller, Ulrich, Vivi M. Heine, Junhao Mao, Alvin T. Kho, Allison K. Dillon, Young-Goo Han, Emmanuelle Huillard et al. „Acquisition of Granule Neuron Precursor Identity Is a Critical Determinant of Progenitor Cell Competence to Form Shh-Induced Medulloblastoma“. Cancer Cell 14, Nr. 2 (August 2008): 123–34. http://dx.doi.org/10.1016/j.ccr.2008.07.005.
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Weiss, Mary C., Jean-Francois Le Garrec, Sabrina Coqueran, Helene Strick-Marchand und Margaret Buckingham. „Progressive developmental restriction, acquisition of left-right identity and cell growth behavior during lobe formation in mouse liver development“. Development 143, Nr. 7 (18.02.2016): 1149–59. http://dx.doi.org/10.1242/dev.132886.
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Carstens, Julienne L., Sujuan Yang, Pedro Correa de Sampaio, Xiaofeng Zheng, Souptik Barua, Kathleen M. McAndrews, Arvind Rao, Jared K. Burks, Andrew D. Rhim und Raghu Kalluri. „Abstract PO-059: Epithelial/mesenchymal identity dictates pancreatic cancer cell metastasis“. Cancer Research 81, Nr. 22_Supplement (15.11.2021): PO—059—PO—059. http://dx.doi.org/10.1158/1538-7445.panca21-po-059.
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Abstract Metastatic pancreatic adenocarcinoma (PDAC) is the dominant clinical presentation and highly treatment-resistant. However, not all metastasis is equal with metastatic disease in the lung having improved outcomes over the liver. These clinical differences suggest a therapeutic opportunity and urge analysis of the molecular underpinnings of PDAC metastasis. The acquisition of mesenchymal features by epithelial cancer cells is commonly associated with solid tumor metastasis and has been linked to the pancreatic cancer basal subtype and its association with treatment resistance and poorer outcomes, but its impact on pancreatic cancer metastasis needs further understanding. We explored the impact on metastasis of stabilized epithelial, partial-mesenchymal and mesenchymal cancer cells by generating several genetic mouse models based on the lineage-traced KPC mouse model (KrasLSL-G12D;p53R172H; or p53LSL; PDX1-Cre;EYFPLSL). Using single-cell RNA-sequencing we confirmed the KPC mouse model recapitulates the spectrum of epithelial-mesenchymal phenotypes observed in patients and can be genetically engineered to stabilize specific phenotypes. The stabilization of epithelial phenotypes through the homozygous loss of the mesenchymal-driving transcription factors Snail and Twist (Snai1F/F;Twist1F/F) had no impact on primary tumor progression but increased liver colonization. This increase in liver colonization was supported by a second epithelial-stabilized mouse model based on the loss of Zeb1 (Zeb1F/F). The stabilization of mesenchymal features through the heterozygous or homozygous loss of the epithelial adherin junction E-cadherin (Cdh1F/+ or Cdh1F/F) promoted lung metastasis. Interestingly, epithelial plasticity was still required for efficient lung colonization, but not rare liver metastasis. Additionally, mesenchymal gene expression correlated with an improved patient survival as well as metastatic localization, supporting the clinical observations of improved survival in lung metastasis. Using gene expression analysis of sorted bulk cancer cells and single-cells, migration assays, and multiplexed-immunohistochemistry, we observed that the epithelial/mesenchymal status of the cancer cells dictated different mechanisms for motility and interaction with the immune system. Mesenchymal cancer cells migrate as single-cells and attract fewer T-cells where epithelial cancer cells migrate collectively and have increased immune regulation gene expression. These data suggest the epithelial/mesenchymal status of cancers cells dictate the where and how of metastatic disease and could inform therapeutic interventions. Citation Format: Julienne L. Carstens, Sujuan Yang, Pedro Correa de Sampaio, Xiaofeng Zheng, Souptik Barua, Kathleen M. McAndrews, Arvind Rao, Jared K. Burks, Andrew D. Rhim, Raghu Kalluri. Epithelial/mesenchymal identity dictates pancreatic cancer cell metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-059.
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Smukler, Simon R., Susan B. Runciman, Shunbin Xu und Derek van der Kooy. „Embryonic stem cells assume a primitive neural stem cell fate in the absence of extrinsic influences“. Journal of Cell Biology 172, Nr. 1 (02.01.2006): 79–90. http://dx.doi.org/10.1083/jcb.200508085.
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The mechanisms governing the emergence of the earliest mammalian neural cells during development remain incompletely characterized. A default mechanism has been suggested to underlie neural fate acquisition; however, an instructive process has also been proposed. We used mouse embryonic stem (ES) cells to explore the fundamental issue of how an uncommitted, pluripotent mammalian cell will self-organize in the absence of extrinsic signals and what cellular fate will result. To assess this default state, ES cells were placed in conditions that minimize external influences. Individual ES cells were found to rapidly transition directly into neural cells, a process shown to be independent of suggested instructive factors (e.g., fibroblast growth factors). Further, we provide evidence that the default neural identity is that of a primitive neural stem cell (NSC). The exiguous conditions used to reveal the default state were found to present primitive NSCs with a survival challenge (limiting their persistence and proliferation), which could be mitigated by survival factors or genetic interference with apoptosis.
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Jacovetti, Cécile, und Romano Regazzi. „Mechanisms Underlying the Expansion and Functional Maturation of β-Cells in Newborns: Impact of the Nutritional Environment“. International Journal of Molecular Sciences 23, Nr. 4 (14.02.2022): 2096. http://dx.doi.org/10.3390/ijms23042096.
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The functional maturation of insulin-secreting β-cells is initiated before birth and is completed in early postnatal life. This process has a critical impact on the acquisition of an adequate functional β-cell mass and on the capacity to meet and adapt to insulin needs later in life. Many cellular pathways playing a role in postnatal β-cell development have already been identified. However, single-cell transcriptomic and proteomic analyses continue to reveal new players contributing to the acquisition of β-cell identity. In this review, we provide an updated picture of the mechanisms governing postnatal β-cell mass expansion and the transition of insulin-secreting cells from an immature to a mature state. We then highlight the contribution of the environment to β-cell maturation and discuss the adverse impact of an in utero and neonatal environment characterized by calorie and fat overload or by protein deficiency and undernutrition. Inappropriate nutrition early in life constitutes a risk factor for developing diabetes in adulthood and can affect the β-cells of the offspring over two generations. A better understanding of these events occurring in the neonatal period will help developing better strategies to produce functional β-cells and to design novel therapeutic approaches for the prevention and treatment of diabetes.
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Fort, Gabriela, Soledad Camolotto, Rushmeen Tariq, Pengshu Fang, Katherine L. Gillis, Chris Stubben und Eric L. Snyder. „Abstract 6600: Investigating molecular regulators of a dual identity state in lung adenocarcinoma“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 6600. http://dx.doi.org/10.1158/1538-7445.am2024-6600.
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Abstract Lung adenocarcinoma (LUAD) is the largest subtype of lung cancer and is the most common cause of cancer related death. LUAD progression is driven by both genetic alterations and epigenetic changes that confer increased lineage plasticity and heterogeneity, but underlying mechanisms dictating cell identity in LUAD remain incompletely understood. The lineage defining transcription factors, NKX2-1 and FoxA1/2, coordinately maintain a pulmonary identity in LUAD. Recent work suggests that NKX2-1-positive (NKX2-1+) LUAD evolves from an alveolar-like state and adopts various disparate cell fates that drive progression, including “dual-identity” states, characterized by acquisition of gastrointestinal (GI) and pulmonary-like states in the same cell. Using sophisticated genetically engineered mouse models and 3D organoid cultures, we demonstrated that the gastrointestinal transcription factor HNF4α, which robustly marks the dual-identity state, is critical for growth in NKX2-1+ LUAD. We performed bulk RNA-seq and single cell RNA-seq in vitro and in vivo, and we found that loss of HNF4α alters the differentiation state of NKX2-1+ LUAD, causing cells to shed elements of their gastric identity in favor of alternate differentiation states. Using paired chromatin immunoprecipitation sequencing and RNA-seq in dual-identity organoids, we found that HNF4α can access and activate many of its canonical gastrointestinal target genes despite being aberrantly expressed in the lung, where it is typically epigenetically silenced early in development. Surprisingly, HNF4α also colocalizes with NKX2-1 and FoxA1/2 and binds at novel sites, suggesting that HNF4α acquires expanded activity in this state beyond its canonical roles. Together, our work unveils key insights into the mechanisms by which lineage defining transcription factors regulate cellular identity and growth in LUAD. Citation Format: Gabriela Fort, Soledad Camolotto, Rushmeen Tariq, Pengshu Fang, Katherine L. Gillis, Chris Stubben, Eric L. Snyder. Investigating molecular regulators of a dual identity state in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6600.
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Douchin, J., N. Lemaire, E. Kérignard und V. Giroux. „A7 DEVELOPING NEW TOOLS TO IDENTIFY NOVELS TARGETS TO OVERCOME TREATMENT RESISTANCE IN ESOPHAGEAL CANCER“. Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (Februar 2020): 9–11. http://dx.doi.org/10.1093/jcag/gwz047.006.
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Abstract Background In Canada, patients with esophageal cancer have the 2nd worst 5-year survival rate (14%). Esophageal squamous cell carcinoma (ESCC) is the most common esophageal cancer type worldwide. Its high mortality rate is partly due to the treatment resistance acquired by patients, which has mostly been attributed to the presence of cancer stem cells (CSCs). Therefore, targeting CSCs is a promising strategy to improve treatment and survival of ESCC patients. CSCs are a subpopulation of tumor cells presenting high self-renewal and multipotent capacities, and therefore largely contribute to tumor heterogeneity in addition to treatment resistance. Aims In this study, we aim to establish human ESCC cell lines resistant to radiotherapy (TE15RR), chemotherapy (TE15CR) and both (TE15RCR), and study the relationship between resistance acquisition and CSC properties; Methods To do so, we exposed human ESCC cell line TE15 to chronic doses of radiotherapy (2 Gy/week for a total dose of 60 Gy) and/or increasing doses of chemotherapy (5-FU (1, 2, 5, 10 and 15mM)). We harvested samples at different time points to fully investigate resistance acquisition process. Then, we further validated resistance and properties of the resistant TE15 cell lines. Results We confirmed that TE15RR cells are less susceptible to radiation than control cells and showed that they are more proliferative at baseline using MTT assays. Moreover, we demonstrated that TE15RR cells comprise a higher proportion of CD24high/CD44high CSC population using flow cytometry. We also found that they express higher levels of ALDH1, another well-known CSC marker, by qPCR and Western Blot. Our preliminary observations also suggest a higher invasive phenotype in TE15RR cells in limited dilution spheroid assay than in control cells supporting that TE15RR cells display CSC-like properties. TE15CR and TE15RCR cell lines were validated using similar approaches. Finally, mass spectrometry was performed to compare the proteomic profile of the resistant cell lines to the control cell line in order to identify key players in treatment resistance acquisition. Conclusions Brief, we developed radioresistant, chemoresistant and radiochemoresistant human ESCC cell lines and demonstrated that resistance acquisition correlates with CSC enrichment. Mass spectrophotometry revealed significant proteomic differences between resistant and control cell lines, which should lead to the identification of novel targets to overcome resistance in ESCC patients. Funding Agencies Canada research chair TIER 2
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Sanz-Álvarez, Marta, Melani Luque, Miriam Morales-Gallego, Ion Cristóbal, Natalia Ramírez-Merino, Yamileth Rangel, Yann Izarzugaza et al. „Generation and Characterization of Trastuzumab/Pertuzumab-Resistant HER2-Positive Breast Cancer Cell Lines“. International Journal of Molecular Sciences 25, Nr. 1 (22.12.2023): 207. http://dx.doi.org/10.3390/ijms25010207.
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The combination of trastuzumab and pertuzumab as first-line therapy in patients with HER2-positive breast cancer has shown significant clinical benefits compared to trastuzumab alone. However, despite initial therapeutic success, most patients eventually progress, and tumors develop acquired resistance and invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance in order to develop targeted therapeutic strategies with improved efficacy. We generated four novel HER2-positive cell lines via prolonged exposure to trastuzumab and pertuzumab and determined their resistance rates. Long-term resistance was confirmed by a significant increase in the colony-forming capacity of the derived cells. We authenticated the molecular identity of the new lines via both immunohistochemistry for the clinical phenotype and molecular profiling of point mutations. HER2 overexpression was confirmed in all resistant cell lines, and acquisition of resistance to trastuzumab and pertuzumab did not translate into differences in ER, PR, and HER2 receptor expression. In contrast, changes in the expression and activity of other HER family members, particularly HER4, were observed. In the same vein, analyses of the receptor and effector kinase status of different cellular pathways revealed that the MAPK pathway may be involved in the acquisition of resistance to trastuzumab and pertuzumab. Finally, proteomic analysis confirmed a significant change in the abundance patterns of more than 600 proteins with implications in key biological processes, such as ribosome formation, mitochondrial activity, and metabolism, which could be relevant mechanisms in the generation of resistance in HER2-positive breast cancer. We concluded that these resistant BCCLs may be a valuable tool to better understand the mechanisms of acquisition of resistance to trastuzumab and pertuzumab-based anti-HER2 therapy.
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Turner, Stephen, Moshe Olshansky, Jasmine Li, Michelle Nguyen, Eddie Chen, T. H. Nguyen, Sudha Rao und Brendan Russ. „Genome wide mapping of epigenetic signatures identify novel enhancer elements that underpin virus-specific CD8+ T cell differentiation (IRM14P.445)“. Journal of Immunology 194, Nr. 1_Supplement (01.05.2015): 198.5. http://dx.doi.org/10.4049/jimmunol.194.supp.198.5.
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Abstract The molecular mechanisms that underpin acquisition and maintenance of lineage specific gene expression by virus-specific CD8+ T cells are not fully delineated. Post-translational modifications (PTMs) of genome associated histone proteins are a key mechanism for regulating gene expression. We mapped genome wide changes in histone PTM deposition during virus-specific CD8+ T cell differentiation. By comparing the location and level of deposition of a combination of H3K4me1, H3K4me2, H3K4me3, H3K27me3, H3K27Ac, chromatin accessibility and binding of the histone acetyltransferase, p300, we could map both known and putative enhancer elements that are differentially regulated between naive, effector and memory virus-specific CD8+ T cells. Using this epigenetic blueprint, we identified putative transcriptional enhancers located upstream of the Ccl5 gene, a key CD8+ T cell effector gene. We demonstrate that acquisition of Ccl5 transcription upon T cell activation is regulated via temporal and transcription factor (TF) dependent chromatin remodelling. Using chromatin conformation capture (3C) to measure enhancer-promoter interactions, we show that that TF dependent looping of these enhancer elements onto the Ccl5 promoter correlated with transcriptional activation and potential. These studies form a platform for more in depth analysis of key non-coding regulatory elements that regulate acquisition of virus-specific T cell gene expression and maintenance into memory.
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Capaci, Valeria, Feras Kharrat, Andrea Conti, Emanuela Salviati, Manuela Giovanna Basilicata, Pietro Campiglia, Nour Balasan et al. „The Deep Proteomics Approach Identified Extracellular Vesicular Proteins Correlated to Extracellular Matrix in Type One and Two Endometrial Cancer“. International Journal of Molecular Sciences 25, Nr. 9 (24.04.2024): 4650. http://dx.doi.org/10.3390/ijms25094650.
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Among gynecological cancers, endometrial cancer is the most common in developed countries. Extracellular vesicles (EVs) are cell-derived membrane-surrounded vesicles that contain proteins involved in immune response and apoptosis. A deep proteomic approach can help to identify dysregulated extracellular matrix (ECM) proteins in EVs correlated to key pathways for tumor development. In this study, we used a proteomics approach correlating the two acquisitions—data-dependent acquisition (DDA) and data-independent acquisition (DIA)—on EVs from the conditioned medium of four cell lines identifying 428 ECM proteins. After protein quantification and statistical analysis, we found significant changes in the abundance (p < 0.05) of 67 proteins. Our bioinformatic analysis identified 26 pathways associated with the ECM. Western blotting analysis on 13 patients with type 1 and type 2 EC and 13 endometrial samples confirmed an altered abundance of MMP2. Our proteomics analysis identified the dysregulated ECM proteins involved in cancer growth. Our data can open the path to other studies for understanding the interaction among cancer cells and the rearrangement of the ECM.
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Maddela, Joanna Joyce, Maria Castaneda, Petra den Hollander, Nick Kuburich und Sendurai Mani. „Abstract LB225: Regulation of breast cancer stem cell identity by PLK1 and FOXC2“. Cancer Research 84, Nr. 7_Supplement (05.04.2024): LB225. http://dx.doi.org/10.1158/1538-7445.am2024-lb225.
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Abstract One of the main drivers for the drastic reduction in survival rates caused by metastatic breast cancer is attributed to Epithelial-to-Mesenchymal Transition (EMT). During embryonic development and wound healing, EMT plays a vital role and during cancer pathogenesis, cancer cells reactivate this program to gain plasticity, migration, and invasion promoting metastasis. In addition, EMT also plays a crucial role in generating a subpopulation of highly resilient tumor cells known as cancer stem cells (CSCs). Moreover, following conventional treatment, residual tumor cells that remain after treatment tend to exhibit CSC properties. EMT-induced cancer stem cells exhibit heightened plasticity and stemness, significantly fueling the metastatic spread of cancer and enhancing the endurance and adaptability throughout the process of metastasis. Thus, understanding the molecular intricacies governing stem cell properties holds immense potential for developing targeted therapies to target metastasis and the development of resistance to treatments. To further elucidate EMT-induced cancer stem cell generation, our lab has demonstrated that the Polo-like kinase 1 (PLK1), an important G2/M regulator, plays an important role in the generation of CSCs through Forkhead box protein C2 (FOXC2). Most importantly, we have shown that the FOXC2 transcription factor, known to be crucial in embryonic development, now has emerging roles in metastatic cancer progression. FOXC2 is positioned at the center of the complex network of signal transduction pathways and functions downstream of most EMT-inducing transcription factors. FOXC2 is necessary for the acquisition and maintenance of stem cell property. In addition, we found that phosphorylation of FOXC2 by PLK1 stabilizes, and inhibition of PLK1 causes a decrease in FOXC2 and stemness in cancer cells. This led us to hypothesize that EMT-induced CSC generation is driven by the PLK1-FOXC2 axis. By expressing phosphomimetic and non-phosphorylatable FOXC2 mutants in breast cancer cell lines, we show that PLK1 phosphorylation is necessary for gaining stemness and an increase in symmetric self-renewal type of stem cell division. Evidence will be presented as to how we are targeting the PLK1-FOXC2 axis to make tumors sensitive to standard-of-care treatments. Citation Format: Joanna Joyce Maddela, Maria Castaneda, Petra den Hollander, Nick Kuburich, Sendurai Mani. Regulation of breast cancer stem cell identity by PLK1 and FOXC2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB225.
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Pierre-Jerome, Edith, Colleen Drapek und Philip N. Benfey. „Regulation of Division and Differentiation of Plant Stem Cells“. Annual Review of Cell and Developmental Biology 34, Nr. 1 (06.10.2018): 289–310. http://dx.doi.org/10.1146/annurev-cellbio-100617-062459.
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A major challenge in developmental biology is unraveling the precise regulation of plant stem cell maintenance and the transition to a fully differentiated cell. In this review, we highlight major themes coordinating the acquisition of cell identity and subsequent differentiation in plants. Plant cells are immobile and establish position-dependent cell lineages that rely heavily on external cues. Central players are the hormones auxin and cytokinin, which balance cell division and differentiation during organogenesis. Transcription factors and miRNAs, many of which are mobile in plants, establish gene regulatory networks that communicate cell position and fate. Small peptide signaling also provides positional cues as new cell types emerge from stem cell division and progress through differentiation. These pathways recruit similar players for patterning different organs, emphasizing the modular nature of gene regulatory networks. Finally, we speculate on the outstanding questions in the field and discuss how they may be addressed by emerging technologies.
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Ho, Patrick, Jeffrey A. Bluestone und Qizhi Tang. „Elucidating Inflammation-induced Cell Fate Decisions in Primary Human Tregs“. Journal of Immunology 210, Nr. 1_Supplement (01.05.2023): 238.01. http://dx.doi.org/10.4049/jimmunol.210.supp.238.01.
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Abstract Adoptive regulatory T-cell (Treg) therapy is an emerging therapeutic paradigm for promoting immune tolerance in transplant and autoimmune disease settings. Prior investigations demonstrate that murine Tregs can undergo epigenetic reprogramming within chronically inflamed tissue environments, resulting in acquisition of proinflammatory functions and the capacity to exacerbate tissue damage. Despite the ramifications of Treg lineage decommitment for cell therapy applications, inflammation-induced human Treg cell fate decisions remain poorly understood. Here, we present a robust in vitromodel of IL6, IL1β, and IL23-driven Treg instability characterized by progressive FOXP3 and HELIOS downregulation, FOXP3conserved non-coding sequence (CNS)2 enhancer re-methylation, diminished in vitrosuppressive function, and elevated proinflammatory cytokine expression. To gain insight into the gene regulatory networks enabling the loss of Treg identity, we generated single-cell transcriptomic and chromatin accessibility profiles of primary human Tregs maintained in the presence or absence of IL6, IL1β, and IL23. Unsupervised clustering revealed a dysfunctional Treg population with an epigenetic signature consistent with murine Treg to “exTreg” conversion, including altered chromatin accessibility at the IFNγ, IL17A, and FOXP3CNS2 loci. Inference of transcription factor (TF)-associated changes in chromatin accessibility indicated a key role for E26 transformation-specific (ETS) family members. Ongoing experiments aim to identify specific TF modules that can be targeted to better safeguard the function and stability of Treg therapeutics.
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Coradini, Danila, Patrizia Boracchi, Federico Ambrogi, Elia Biganzoli und Saro Oriana. „Cell Polarity, Epithelial-Mesenchymal Transition, and Cell-Fate Decision Gene Expression in Ductal Carcinoma In Situ“. International Journal of Surgical Oncology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/984346.
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Loss of epithelial cell identity and acquisition of mesenchymal features are early events in the neoplastic transformation of mammary cells. We investigated the pattern of expression of a selected panel of genes associated with cell polarity and apical junction complex or involved in TGF-β-mediated epithelial-mesenchymal transition and cell-fate decision in a series of DCIS and corresponding patient-matched normal tissue. Additionally, we compared DCIS gene profile with that of atypical ductal hyperplasia (ADH) from the same patient. Statistical analysis identified a “core” of genes differentially expressed in both precursors with respect to the corresponding normal tissue mainly associated with a terminally differentiated luminal estrogen-dependent phenotype, in agreement with the model according to which ER-positive invasive breast cancer derives from ER-positive progenitor cells, and with an autocrine production of estrogens through androgens conversion. Although preliminary, present findings provide transcriptomic confirmation that, at least for the panel of genes considered in present study, ADH and DCIS are part of a tumorigenic multistep process and strongly arise the necessity for the regulation, maybe using aromatase inhibitors, of the intratumoral and/or circulating concentration of biologically active androgens in DCIS patients to timely hamper abnormal estrogens production and block estrogen-induced cell proliferation.
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Braunstein, Marsela, und Michele K. Anderson. „HEB in the Spotlight: Transcriptional Regulation of T-Cell Specification, Commitment, and Developmental Plasticity“. Clinical and Developmental Immunology 2012 (2012): 1–15. http://dx.doi.org/10.1155/2012/678705.
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The development of T cells from multipotent progenitors in the thymus occurs by cascades of interactions between signaling molecules and transcription factors, resulting in the loss of alternative lineage potential and the acquisition of the T-cell functional identity. These processes require Notch signaling and the activity of GATA3, TCF1, Bcl11b, and the E-proteins HEB and E2A. We have shown that HEB factors are required to inhibit the thymic NK cell fate and that HEBAlt allows the passage of T-cell precursors from the DN to DP stage but is insufficient for suppression of the NK cell lineage choice. HEB factors are also required to enforce the death of cells that have not rearranged their TCR genes. The synergistic interactions between Notch1, HEBAlt, HEBCan, GATA3, and TCF1 are presented in a gene network model, and the influence of thymic stromal architecture on lineage choice in the thymus is discussed.
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Chung, Whasun O., Yoonsuk Park, Richard J. Lamont, Rod McNab, Bruno Barbieri und Donald R. Demuth. „Signaling System in Porphyromonas gingivalis Based on a LuxS Protein“. Journal of Bacteriology 183, Nr. 13 (01.07.2001): 3903–9. http://dx.doi.org/10.1128/jb.183.13.3903-3909.2001.
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ABSTRACT The luxS gene of quorum-sensing Vibrio harveyi is required for type 2 autoinducer production. We identified a Porphyromonas gingivalis open reading frame encoding a predicted peptide of 161 aa that shares 29% identity with the amino acid sequence of the LuxS protein of V. harveyi. Conditioned medium from a late-log-phase P. gingivalis culture induced the luciferase operon of V. harveyi, but that from a luxS insertional mutant did not. In P. gingivalis, the expression ofluxS mRNA was environmentally controlled and varied according to the cell density and the osmolarity of the culture medium. In addition, differential display PCR showed that the inactivation ofP. gingivalis luxS resulted in up-regulation of a hemin acquisition protein and an arginine-specific protease and reduced expression of a hemin-regulated protein, a TonB homologue, and an excinuclease. The data suggest that the luxS gene inP. gingivalis may function to control the expression of genes involved in the acquisition of hemin.
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Guo, Jing, Teng Zhang, Yueshuai Guo, Tao Sun, Hui Li, Xiaoyun Zhang, Hong Yin et al. „Oocyte stage-specific effects of MTOR determine granulosa cell fate and oocyte quality in mice“. Proceedings of the National Academy of Sciences 115, Nr. 23 (21.05.2018): E5326—E5333. http://dx.doi.org/10.1073/pnas.1800352115.
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MTOR (mechanistic target of rapamycin) is a widely recognized integrator of signals and pathways key for cellular metabolism, proliferation, and differentiation. Here we show that conditional knockout (cKO) of Mtor in either primordial or growing oocytes caused infertility but differentially affected oocyte quality, granulosa cell fate, and follicular development. cKO of Mtor in nongrowing primordial oocytes caused defective follicular development leading to progressive degeneration of oocytes and loss of granulosa cell identity coincident with the acquisition of immature Sertoli cell-like characteristics. Although Mtor was deleted at the primordial oocyte stage, DNA damage accumulated in oocytes during their later growth, and there was a marked alteration of the transcriptome in the few oocytes that achieved the fully grown stage. Although oocyte quality and fertility were also compromised when Mtor was deleted after oocytes had begun to grow, these occurred without overtly affecting folliculogenesis or the oocyte transcriptome. Nevertheless, there was a significant change in a cohort of proteins in mature oocytes. In particular, down-regulation of PRC1 (protein regulator of cytokinesis 1) impaired completion of the first meiotic division. Therefore, MTOR-dependent pathways in primordial or growing oocytes differentially affected downstream processes including follicular development, sex-specific identity of early granulosa cells, maintenance of oocyte genome integrity, oocyte gene expression, meiosis, and preimplantation developmental competence.
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Hwang, Young Sun, Yasunari Seita, M. Andrés Blanco und Kotaro Sasaki. „CRISPR loss of function screening to identify genes involved in human primordial germ cell-like cell development“. PLOS Genetics 19, Nr. 12 (13.12.2023): e1011080. http://dx.doi.org/10.1371/journal.pgen.1011080.
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Despite our increasing knowledge of molecular mechanisms guiding various aspects of human reproduction, those underlying human primordial germ cell (PGC) development remain largely unknown. Here, we conducted custom CRISPR screening in an in vitro system of hPGC-like cells (hPGCLCs) to identify genes required for acquisition and maintenance of PGC fate in humans. Amongst our candidates, we identified TCL1A, an AKT coactivator. Functional assessment in our in vitro hPGCLCs system revealed that TCL1A played a critical role in later stages of hPGCLC development. Moreover, we found that TCL1A loss reduced AKT-mTOR signaling, downregulated expression of genes related to translational control, and subsequently led to a reduction in global protein synthesis and proliferation. Together, our study highlights the utility of CRISPR screening for human in vitro-derived germ cells and identifies novel translational regulators critical for hPGCLC development.
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Huang, Mengting, Yixuan Yang, Xingzhao Wen, Weiqiang Xu, Na Lu, Xiao Sun, Jing Tu und Zuhong Lu. „Inferring single cell expression profiles from overlapped pooling sequencing data with compressed sensing strategy“. Nucleic Acids Research 49, Nr. 14 (09.07.2021): 7995–8006. http://dx.doi.org/10.1093/nar/gkab581.
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Abstract Though single cell RNA sequencing (scRNA-seq) technologies have been well developed, the acquisition of large-scale single cell expression data may still lead to high costs. Single cell expression profile has its inherent sparse properties, which makes it compressible, thus providing opportunities for solutions. Here, by computational simulation as well as experiment of 54 single cells, we propose that expression profiles can be compressed from the dimension of samples by overlapped assigning each cell into plenty of pools. And we prove that expression profiles can be inferred from these pool expression data with overlapped pooling design and compressed sensing strategy. We also show that by combining this approach with plate-based scRNA-seq measurement, it can maintain its superiorities in gene detection sensitivity and individual identity and recover the expression profile with high precision, while saving about half of the library cost. This method can inspire novel conceptions on the measurement, storage or computation improvements for other compressible signals in many biological areas.
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Gonçalves, A. Pedro, Jens Heller, Adriana M. Rico-Ramírez, Asen Daskalov, Gabriel Rosenfield und N. Louise Glass. „Conflict, Competition, and Cooperation Regulate Social Interactions in Filamentous Fungi“. Annual Review of Microbiology 74, Nr. 1 (08.09.2020): 693–712. http://dx.doi.org/10.1146/annurev-micro-012420-080905.
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Social cooperation impacts the development and survival of species. In higher taxa, kin recognition occurs via visual, chemical, or tactile cues that dictate cooperative versus competitive interactions. In microbes, the outcome of cooperative versus competitive interactions is conferred by identity at allorecognition loci, so-called kind recognition. In syncytial filamentous fungi, the acquisition of multicellularity is associated with somatic cell fusion within and between colonies. However, such intraspecific cooperation entails risks, as fusion can transmit deleterious genotypes or infectious components that reduce fitness, or give rise to cheaters that can exploit communal goods without contributing to their production. Allorecognition mechanisms in syncytial fungi regulate somatic cell fusion by operating precontact during chemotropic interactions, during cell adherence, and postfusion by triggering programmed cell death reactions. Alleles at fungal allorecognition loci are highly polymorphic, fall into distinct haplogroups, and show evolutionary signatures of balancing selection, similar to allorecognition loci across the tree of life.
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Incitti, Tania, Andrea Messina, Yuri Bozzi und Simona Casarosa. „Sorting of Sox1-GFP Mouse Embryonic Stem Cells Enhances Neuronal Identity Acquisition upon Factor-Free Monolayer Differentiation“. BioResearch Open Access 3, Nr. 3 (Juni 2014): 127–35. http://dx.doi.org/10.1089/biores.2014.0009.
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Garel, S., F. Marin, R. Grosschedl und P. Charnay. „Ebf1 controls early cell differentiation in the embryonic striatum“. Development 126, Nr. 23 (01.12.1999): 5285–94. http://dx.doi.org/10.1242/dev.126.23.5285.
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Ebf1/Olf-1 belongs to a small multigene family encoding closely related helix-loop-helix transcription factors, which have been proposed to play a role in neuronal differentiation. Here we show that Ebf1 controls cell differentiation in the murine embryonic striatum, where it is the only gene of the family to be expressed. Ebf1 targeted disruption affects postmitotic cells that leave the subventricular zone (SVZ) en route to the mantle: they appear to be unable to downregulate genes normally restricted to the SVZ or to activate some mantle-specific genes. These downstream genes encode a variety of regulatory proteins including transcription factors and proteins involved in retinoid signalling as well as adhesion/guidance molecules. These early defects in the SVZ/mantle transition are followed by an increase in cell death, a dramatic reduction in size of the postnatal striatum and defects in navigation and fasciculation of thalamocortical fibres travelling through the striatum. Our data therefore show that Ebf1 plays an essential role in the acquisition of mantle cell molecular identity in the developing striatum and provide information on the genetic hierarchies that govern neuronal differentiation in the ventral telencephalon.
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Caye, Aurélie, Kevin Rouault-Pierre, Marion Strullu, Elodie Lainey, Ander Abarrategi, Odile Fenneteau, Chloé Arfeuille et al. „Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment“. Leukemia 34, Nr. 6 (27.11.2019): 1658–68. http://dx.doi.org/10.1038/s41375-019-0662-y.
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AbstractJuvenile myelomonocytic leukemia (JMML) is a rare aggressive myelodysplastic/myeloproliferative neoplasm of early childhood, initiated by RAS-activating mutations. Genomic analyses have recently described JMML mutational landscape; however, the nature of JMML-propagating cells (JMML-PCs) and the clonal architecture of the disease remained until now elusive. Combining genomic (exome, RNA-seq), Colony forming assay and xenograft studies, we detect the presence of JMML-PCs that faithfully reproduce JMML features including the complex/nonlinear organization of dominant/minor clones, both at diagnosis and relapse. Further integrated analysis also reveals that although the mutations are acquired in hematopoietic stem cells, JMML-PCs are not always restricted to this compartment, highlighting the heterogeneity of the disease during the initiation steps. We show that the hematopoietic stem/progenitor cell phenotype is globally maintained in JMML despite overexpression of CD90/THY-1 in a subset of patients. This study shed new lights into the ontogeny of JMML, and the identity of JMML-PCs, and provides robust models to monitor the disease and test novel therapeutic approaches.
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Yuan, Xiaofei, Yanqing Song, Yizhi Song, Jiabao Xu, Yinhu Wu, Andrew Glidle, Maggie Cusack et al. „Effect of Laser Irradiation on Cell Function and Its Implications in Raman Spectroscopy“. Applied and Environmental Microbiology 84, Nr. 8 (02.02.2018): e02508-17. http://dx.doi.org/10.1128/aem.02508-17.
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ABSTRACTLasers are instrumental in advanced bioimaging and Raman spectroscopy. However, they are also well known for their destructive effects on living organisms, leading to concerns about the adverse effects of laser technologies. To implement Raman spectroscopy for cell analysis and manipulation, such as Raman-activated cell sorting, it is crucial to identify nondestructive conditions for living cells. Here, we evaluated quantitatively the effect of 532-nm laser irradiation on bacterial cell fate and growth at the single-cell level. Using a purpose-built microfluidic platform, we were able to quantify the growth characteristics, i.e., specific growth rates and lag times of individual cells, as well as the survival rate of a population in conjunction with Raman spectroscopy. Representative Gram-negative and Gram-positive species show similar trends in response to a laser irradiation dose. Laser irradiation could compromise the physiological function of cells, and the degree of destruction is both dose and strain dependent, ranging from reduced cell growth to a complete loss of cell metabolic activity and finally to physical disintegration. Gram-positive bacterial cells are more susceptible than Gram-negative bacterial strains to irradiation-induced damage. By directly correlating Raman acquisition with single-cell growth characteristics, we provide evidence of nondestructive characteristics of Raman spectroscopy on individual bacterial cells. However, while strong Raman signals can be obtained without causing cell death, the variety of responses from different strains and from individual cells justifies careful evaluation of Raman acquisition conditions if cell viability is critical.IMPORTANCEIn Raman spectroscopy, the use of powerful monochromatic light in laser-based systems facilitates the detection of inherently weak signals. This allows environmentally and clinically relevant microorganisms to be measured at the single-cell level. The significance of being able to perform Raman measurement is that, unlike label-based fluorescence techniques, it provides a “fingerprint” that is specific to the identity and state of any (unlabeled) sample. Thus, it has emerged as a powerful method for studying living cells under physiological and environmental conditions. However, the laser's high power also has the potential to kill bacteria, which leads to concerns. The research presented here is a quantitative evaluation that provides a generic platform and methodology to evaluate the effects of laser irradiation on individual bacterial cells. Furthermore, it illustrates this by determining the conditions required to nondestructively measure the spectra of representative bacteria from several different groups.
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Swaims, Alison, Richard Haaland, Davis Lupo, Tammy Evans-Strickfaden, Jacob Kohlmeier, Lisa Haddad und Clyde Hart. „Intra-epithelial T lymphocytes from the cervical-vaginal mucosa of healthy women contain a majority population of CD4+ cells and express high levels of the HIV-1 co-receptor CCR5. (P3341)“. Journal of Immunology 190, Nr. 1_Supplement (01.05.2013): 210.2. http://dx.doi.org/10.4049/jimmunol.190.supp.210.2.
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Abstract Current HIV sexual acquisition models for women posit that cell-free virus is carried into genital tissues by antigen presenting cells in the mucosa and that virus also penetrates the mucosa through microabrasions. The potential for genital mucosal intra-epithelial lymphocytes (IELs) to act as primary targets for HIV acquisition in women has not been well-characterized due to the difficulty of isolating and characterizing these cells free of blood contamination. We developed a method to enhance recovery of IELs from the lower genital tract mucosa of women using an atraumatic cervical-vaginal lavage procedure. This procedure was effective for collecting IELs with a T cell resident memory (T¬RM) phenotype from 10 healthy women without the blood contamination that often occurs using cytobrush or vaginal biopsy methods. We detected a high frequency of mucosal CD103+ expression on the CD8+ TRM cells, confirming their identity as IEL cells. Conversely, little to no CD103 expression was detected on CD4+ TRM cells. Moreover, CD4+ cells comprised up to 80% of the T cell population collected from CVL compared to CD8+ T cells (10-20%), with greater CCR5 expression compared to T cells in the peripheral blood. These results show that our atraumatic isolation method is effective for characterizing IELs in the female genital mucosa and that the abundance of CD4+ CCR5hi TRM cells in this population may likely be a highly vulnerable target for HIV-1 sexual transmission.
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Simic, Milos S., Erica A. Moehle, Robert T. Schinzel, Franziska K. Lorbeer, Jonathan J. Halloran, Kartoosh Heydari, Melissa Sanchez, Damien Jullié, Dirk Hockemeyer und Andrew Dillin. „Transient activation of the UPRER is an essential step in the acquisition of pluripotency during reprogramming“. Science Advances 5, Nr. 4 (April 2019): eaaw0025. http://dx.doi.org/10.1126/sciadv.aaw0025.
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Somatic cells can be reprogrammed into pluripotent stem cells using the Yamanaka transcription factors. Reprogramming requires both epigenetic landscape reshaping and global remodeling of cell identity, structure, basic metabolic processes, and organelle form and function. We hypothesize that variable regulation of the proteostasis network and its influence upon the protein-folding environment within cells and their organelles is responsible for the low efficiency and stochasticity of reprogramming. We find that the unfolded protein response of the endoplasmic reticulum (UPRER), the mitochondrial UPR, and the heat shock response, which ensure proteome quality during stress, are activated during reprogramming. The UPRER is particularly crucial, and its ectopic, transient activation, genetically or pharmacologically, enhances reprogramming. Last, stochastic activation of the UPRER predicts reprogramming efficiency in naïve cells. Thus, the low efficiency and stochasticity of cellular reprogramming are due partly to the inability to properly initiate the UPRER to remodel the ER and its proteome.
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Felix, Ricardo, Carmen J. Serrano, Claudio L. Treviño, Carlos Muñoz-Garay, Alejandra Bravo, América Navarro, Judith Pacheco, Victor Tsutsumi und Alberto Darszon. „Identification of distinct K+ channels in mouse spermatogenic cells and sperm“. Zygote 10, Nr. 2 (Mai 2002): 183–88. http://dx.doi.org/10.1017/s0967199402002241.
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Potassium (K+) channels are believed to regulate mammalian sperm acquisition of fertilising capacity. However, the molecular identity of these proteins in sperm has not been elucidated. In this report, using immunoconfocal and electron microscopy we show that a minimum of four different classes of K+ channels (Kv1.1, Kv1.2, Kv3.1 and GIRK1) are present and regionally distributed over the surface of mouse epididymal sperm. In addition, the use of reverse transcription polymerase chain reaction on RNA from mouse spermatogenic cells allowed the amplification of multiple transcripts corresponding to the channels identified by immunocytochemistry. Consistent with this, whole-cell patch-clamp recordings showed the expression of at least two different outwardly rectifying K+ currents in spermatogenic cells.
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Worth, Charli, Provas Das, Kelsey Johnson und Joseph Taube. „Abstract B015: KDM6A, lysine demethylase, loss affects epithelial-to-mesenchymal related gene expression and breast cancer growth“. Cancer Research 84, Nr. 3_Supplement_1 (01.02.2024): B015. http://dx.doi.org/10.1158/1538-7445.advbc23-b015.
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Abstract Epithelial-to-mesenchymal transition (EMT) or its reversal mesenchymal-to-epithelial transition (MET) are of critical importance throughout development and is implicated in wound healing, fibrotic disorders, and cancer metastasis. The ability of a cell to undergo EMT and MET, cellular plasticity, underlies tumor progression through multi-step metastasis and acquisition of chemotherapy resistance as alterations in the cellular and molecular level confer changes in motility, stemness properties, gene expression, and cellular dynamics. These changes facilitate invasion and dissemination of cancer cells. Epigenetic modifications leading to cancer cell plasticity are partially driven by histone modifying proteins including lysine (K)-specific demethylase 6A (KDM6A). KDM6A is a member of the COMPASS-like protein complex, and catalyzes the removal of methyl groups from H3K27me3, facilitating gene expression. KDM6A regulation of H3K27me3 has been associated with bivalent programs in gene expression, associates with oncogenic pathways, and contributes to low survival prognoses in breast cancer. There is critical need to elucidate the mechanisms of KDM6A suppression to understand its control on cellular plasticity. Previously we have shown that KDM6A is suppressed upon EMT. In this study, we sought to identify the regulatory mechanisms of KDM6A expression and how its activity is required to maintain epithelial cellular identity. To investigate the role of KDM6A in the context of EMT, KDM6A expression was compromised using CRISPR-Cas9 to determine the impact on H3K27me3, gene expression and cellular identity. Breast cancer cell lines were transduced with CRISPR-Cas9 and GFP via lentiviral transduction. KDM6A KO and control cell lines were generated via a CRISPR KO. We observed that the KDM6A suppression or inhibition profoundly impacts cellular identity, leading to gain of mesenchymal and stemness properties. Moreover, KDM6A was determined to be regulated through sub-cellular localization leading to partial sequestration of COMPASS-like protein complex outside the nucleus. These findings were validated via Western blot analysis of subcellular protein fractions of breast cancer cell lines and KDM6A KO cell lines and well as immunofluorescence and enzyme activity analysis. We conclude that KDM6A functions as a master regulator of epithelial cellular identity which is controlled by multi-factorial mechanisms including transcriptional suppression and altered protein localization. Citation Format: Charli Worth, Provas Das, Kelsey Johnson, Joseph Taube. KDM6A, lysine demethylase, loss affects epithelial-to-mesenchymal related gene expression and breast cancer growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B015.
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Zoghlami, Aya, Yassin Refahi, Christine Terryn und Gabriel Paës. „Three-Dimensional Imaging of Plant Cell Wall Deconstruction Using Fluorescence Confocal Microscopy“. Sustainable Chemistry 1, Nr. 2 (30.07.2020): 75–85. http://dx.doi.org/10.3390/suschem1020007.
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Lignocellulosic biomass (LB) is recalcitrant to enzymatic hydrolysis due to its compact and complex cell wall structure. To identify the parameters behind LB recalcitrance, experimental data over hydrolysis time must be collected. Here, we describe a novel method to collect time-lapse images during cell wall deconstruction by enzymatic hydrolysis. The protocol includes instructions for sample preparation, layout of a custom designed incubation chamber and instructions for confocal time lapse acquisition. The protocol sets out a detailed plan where cross-sections of untreated and pretreated poplar samples are mounted in a sealed frame containing a buffer and an enzymatic cocktail. The sealed frame is then placed into an incubator to maintain the sample at a constant temperature of 50 °C, which is optimal for enzymatic reaction while avoiding enzymatic cocktail evaporation. Using lignin natural autofluorescence, confocal z-stacks of untreated and pretreated samples were acquired at regular time intervals during enzymatic hydrolysis for 24 h. Acquisition parameters were optimized to compromise between image resolution and reduced photo-bleaching. The acquired image might then be processed by further development of algorithms to extract precise quantitative information on cell wall deconstruction. This protocol is an important first step towards elucidating the underlying parameters of LB recalcitrance by allowing the acquisition of high-quality images of LB hydrolysis for extracting quantitative data on LB deconstruction.
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Trindade, Inês B., Bruno M. Fonseca, Pedro M. Matias, Ricardo O. Louro und Elin Moe. „A putative siderophore-interacting protein from the marine bacteriumShewanella frigidimarinaNCIMB 400: cloning, expression, purification, crystallization and X-ray diffraction analysis“. Acta Crystallographica Section F Structural Biology Communications 72, Nr. 9 (09.08.2016): 667–71. http://dx.doi.org/10.1107/s2053230x16011419.
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Siderophore-binding proteins (SIPs) perform a key role in iron acquisition in multiple organisms. In the genome of the marine bacteriumShewanella frigidimarinaNCIMB 400, the gene tagged as SFRI_RS12295 encodes a protein from this family. Here, the cloning, expression, purification and crystallization of this protein are reported, together with its preliminary X-ray crystallographic analysis to 1.35 Å resolution. The SIP crystals belonged to the monoclinic space groupP21, with unit-cell parametersa= 48.04,b= 78.31,c= 67.71 Å, α = 90, β = 99.94, γ = 90°, and are predicted to contain two molecules per asymmetric unit. Structure determination by molecular replacement and the use of previously determined ∼2 Å resolution SIP structures with ∼30% sequence identity as templates are ongoing.
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Struski, Stéphanie, Martine Doco‐Fenzy, Michael Koehler, Ilse Chudoba, Francis Levy, Linda Masson, Nicole Michel et al. „Cytogenetic Evolution of Human Ovarian Cell Lines Associated with Chemoresistance and Loss of Tumorigenicity“. Analytical Cellular Pathology 25, Nr. 3 (2003): 115–22. http://dx.doi.org/10.1155/2003/151042.
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In order to identify genomic changes associated with a resistant phenotype acquisition, we used comparative genomic hybridization (CGH) to compare a human ovarian cell line, Igrov1, and four derived subcell lines, resistant to vincristine and presenting a reversion of malignant properties. Multicolor FISH (Multiplex‐FISH and Spectral Karyotype) and conventional FISH are also used to elucidate the karyotype of parental cell line. The drug‐resistant subcell lines displayed many chromosomal abnormalities suggesting the implication of different pathways leading to a multidrug resistance phenotype. However, these cell lines shared two common rearrangements: an unbalanced translocation der(8)t(8;13)(p22;q?) and a deletion of the 11p. These chromosomal imbalances could reflected the acquisition of the chemoresistance (der(8)) or the loss of tumorigenicity properties (del(11p)). Colour figure can be viewed onhttp://www.esacp.org/acp/2003/25‐3/struski.htm.
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Rampias, Theodoros, Christos K. Kontos, Alexandros Polyzos, Aris Giotakis, Evangelos Giotakis, Andreas Scorilas, Euthymios Kirodimos, Periklis Foukas und Amanda Psyrri. „Translating transcriptome to immunophenotype in head and neck squamous cell carcinoma (HNSCC) to identify pathways promoting T-cell infiltration.“ Journal of Clinical Oncology 37, Nr. 15_suppl (20.05.2019): e17542-e17542. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e17542.
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e17542 Background: We sought to analyze the transcriptional landscape of HNSCC in an attempt to identify tumor-intrinsic oncogenic pathways that appear to mediate T-cell infiltration of tumor tissue. In this direction, we employ a methodology that integrates histopathology data of the tumor microenvironment with its corresponding transcriptome. Methods: 32 frozen HNSCCs were subjected to RNA-seq and corresponding FFPE were scored for plasma cells, tertiary lymphoid structures and CD8a+ TILs (center, invasive margin). RNA-seq data were analyzed to identify differentially expressed genes (DEGs) between tumors scored by immunohistochemistry (IHC) as CD8a high and CD8a low. Gene ontology analysis (GO) was performed based on DEGs > 1.5 fold expression change between CD8a high and CD8a low groups. Candidate genes were investigated by hierarchical clustering in TCGA RNA-seq data and further validated by IHC and quantitative RT-PCR in our cohort. Results: 32 HNSCCs were either scored as CD8a high or CD8a low based on IHC detection of CD8a+ cells in invasive margin of tumors. Comparative analysis of mRNA expression data between CD8a high and CD8a low groups in our cohort revealed that Muc1/16 overexpression and glycosylation was highly enriched in T cell infiltrated group of tumors. This finding was further validated using antibodies that detect glycosylated epitopes for both mucins. Analysis of TCGA RNA-seq data indicated that Muc1/16 overexpressing tumors share signatures of early keratinocyte differentiation and stem cell identity and co-express high levels of enzymes that promote Muc1/16 glycosylation. Interestingly, loss of CDH1 and acquisition of epithelial mesenchymal transition (EMT) markers in the cluster of Muc1/16 overexpressing tumors is strongly correlated with elevated CD8a, IDO1, CD274 and CXCL10 mRNA levels (P < 0.0001). Conclusions: Muc1/16 overexpressing tumors represent a very immunogenic HNSCC cluster. Previous studies have shown that mucins 1 and 16 in cancer cells expose glycosylated-specific epitopes that are recognized by T cells as cancer antigens. To this end, MUC1/16 expression may serve as predictive biomarkers for response to immunotherapy and MUC-targeted immunotherapy may function as an attractive partner to checkpoint inhibitors in HNSCC.
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Yang, Feng Wei, Lea Tomášová, Zeno v. Guttenberg, Ke Chen und Anotida Madzvamuse. „Investigating Optimal Time Step Intervals of Imaging for Data Quality through a Novel Fully-Automated Cell Tracking Approach“. Journal of Imaging 6, Nr. 7 (07.07.2020): 66. http://dx.doi.org/10.3390/jimaging6070066.
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Computer-based fully-automated cell tracking is becoming increasingly important in cell biology, since it provides unrivalled capacity and efficiency for the analysis of large datasets. However, automatic cell tracking’s lack of superior pattern recognition and error-handling capability compared to its human manual tracking counterpart inspired decades-long research. Enormous efforts have been made in developing advanced cell tracking packages and software algorithms. Typical research in this field focuses on dealing with existing data and finding a best solution. Here, we investigate a novel approach where the quality of data acquisition could help improve the accuracy of cell tracking algorithms and vice-versa. Generally speaking, when tracking cell movement, the more frequent the images are taken, the more accurate cells are tracked and, yet, issues such as damage to cells due to light intensity, overheating in equipment, as well as the size of the data prevent a constant data streaming. Hence, a trade-off between the frequency at which data images are collected and the accuracy of the cell tracking algorithms needs to be studied. In this paper, we look at the effects of different choices of the time step interval (i.e., the frequency of data acquisition) within the microscope to our existing cell tracking algorithms. We generate several experimental data sets where the true outcomes are known (i.e., the direction of cell migration) by either using an effective chemoattractant or employing no-chemoattractant. We specify a relatively short time step interval (i.e., 30 s) between pictures that are taken at the data generational stage, so that, later on, we may choose some portion of the images to produce datasets with different time step intervals, such as 1 min, 2 min, and so on. We evaluate the accuracy of our cell tracking algorithms to illustrate the effects of these different time step intervals. We establish that there exist certain relationships between the tracking accuracy and the time step interval associated with experimental microscope data acquisition. We perform fully-automatic adaptive cell tracking on multiple datasets, to identify optimal time step intervals for data acquisition, while at the same time demonstrating the performance of the computer cell tracking algorithms.
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Hass, Ralf, Juliane von der Ohe und Hendrik Ungefroren. „The Intimate Relationship among EMT, MET and TME: A T(ransdifferentiation) E(nhancing) M(ix) to Be Exploited for Therapeutic Purposes“. Cancers 12, Nr. 12 (07.12.2020): 3674. http://dx.doi.org/10.3390/cancers12123674.
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Intratumoral heterogeneity is considered the major cause of drug unresponsiveness in cancer and accumulating evidence implicates non-mutational resistance mechanisms rather than genetic mutations in its development. These non-mutational processes are largely driven by phenotypic plasticity, which is defined as the ability of a cell to reprogram and change its identity (phenotype switching). Tumor cell plasticity is characterized by the reactivation of developmental programs that are closely correlated with the acquisition of cancer stem cell properties and an enhanced potential for retrodifferentiation or transdifferentiation. A well-studied mechanism of phenotypic plasticity is the epithelial-mesenchymal transition (EMT). Current evidence suggests a complex interplay between EMT, genetic and epigenetic alterations, and clues from the tumor microenvironment in cell reprogramming. A deeper understanding of the connections between stem cell, epithelial–mesenchymal, and tumor-associated reprogramming events is crucial to develop novel therapies that mitigate cell plasticity and minimize the evolution of tumor heterogeneity, and hence drug resistance. Alternatively, vulnerabilities exposed by tumor cells when residing in a plastic or stem-like state may be exploited therapeutically, i.e., by converting them into less aggressive or even postmitotic cells. Tumor cell plasticity thus presents a new paradigm for understanding a cancer’s resistance to therapy and deciphering its underlying mechanisms.
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Banarjee, Reema, Amit Dey, Thedoe Nyunt, Jordan Gregg, Dimitrios Tsitsipatis, Allison Herman, Myriam Gorospe und Nathan Basisty. „THE CELL “SURFACEOME”: A STRATEGY TO TARGET SENESCENT CELLS IN VIVO“. Innovation in Aging 7, Supplement_1 (01.12.2023): 592. http://dx.doi.org/10.1093/geroni/igad104.1939.
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Abstract Senescent cell accumulation drives aging and related pathologies including metabolic disorders and neurodegeneration, and their selective elimination is a promising therapeutic approach to treat multiple diseases of aging in humans. However, developing drugs to eliminate senescent cells requires specific biomarkers to selectively identify and target these cells in vivo. In this study, we have performed a comprehensive and quantitative proteomic profiling of surface proteomes (surfaceomes) of senescent cells to identify potential senescence biomarker candidates in human tissues. We induced senescence using ionizing radiation in a variety of cell types including lung fibroblasts, monocytes, vascular smooth muscle cells, aortic endothelial cells and preadipocytes. Senescence was validated using a panel of canonical markers including reduced proliferation, increased senescence-associated β-galactosidase activity, and increased expression of p21, p16, IL6, and others. The cell surface proteome was enriched using an optimized surface biotinylation approach (Glyco-cell surface capture) followed by data-independent acquisition (DIA) LC-MS/MS analysis on a Q-Exactive HF Orbitrap mass spectrometer. Our analysis revealed novel cell surface targets that were further validated by flow cytometry and immunohistochemistry. These results provide clinically useful information for establishing biomarkers and therapeutic targets to aid in the translation of senescence-targeted therapies to treat age-associated diseases.
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Jones, Devin M., Kaitlin A. Read, Srijana Pokhrel, Emily Hales, Caprice Eisele, Robert T. Warren, Patrick Collins, Aharon Freud und Kenneth J. Oestreich. „Aiolos restrains the acquisition of cytotoxic features by CD4+ T cells“. Journal of Immunology 208, Nr. 1_Supplement (01.05.2022): 166.03. http://dx.doi.org/10.4049/jimmunol.208.supp.166.03.
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Abstract Classically, CD4+ T cells have been defined as “helper” type cells, providing aid to other immune cell populations via the secretion of cytokines and direct cell-cell interactions. More recently, a subset of CD4+ T cells with cytotoxic capabilities, termed CD4+ cytotoxic T lymphocytes (CD4-CTLs), have been observed in both mice and humans, performing protective functions in the settings of infection and cancer while conversely contributing to the pathogenesis of autoimmunity. Despite their well-documented importance in several disease contexts, the complete mechanisms that underlie their differentiation and function remain unknown. Here, we identify the Ikaros family member, Aiolos, as a novel regulator of CD4+ CTL differentiation and function. We find that Aiolos deficiency results in increased expression of key CD4+ CTL transcription factors and effector molecules both in vitro and in an in vivo murine model of influenza infection. Mechanistically, we find that Aiolos deficiency results in increased IL-2/STAT5 signaling, supporting a repressive role for Aiolos in CD4+ CTL differentiation via negative regulation of the IL-2/STAT5 pathway. Collectively, this work identifies Aiolos as a novel negative regulator of CD4+ cytotoxic gene programming, and thus may represent a therapeutic target for the treatment of autoimmune diseases and enhanced anti-tumor immunity. Sponsored by a grant from NIAID (NIH-RO1 AI134972) and funds through The Ohio State University College of Medicine