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1دورية أكاديمية
المؤلفون: Amanda Ng, Fabian Offensperger, Jose A. Cisneros, Natalie S. Scholes, Monika Malik, Ludovica Villanti, Andrea Rukavina, Evandro Ferrada, J. Thomas Hannich, Anna Koren, Stefan Kubicek, Giulio Superti-Furga, Georg E. Winter
مصطلحات موضوعية: Biophysics, Biochemistry, Cell Biology, Genetics, Molecular Biology, Pharmacology, Biotechnology, Cancer, Inorganic Chemistry, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, morphological profiling assay, morphological changes induced, historically discovered serendipitously, drug response datasets, based drug screens, nonessential protein gspt2, isogenic cell lines, dependent mgd targeting, compound treatment across, workflow would contribute, target spaces restricted, e3 ligase crbn, 14 , nonessential proteome, include cell, compound library, workflow begins, throughput workflow, wider range
الوصف: Molecular glue degraders (MGDs) are small molecules that degrade proteins of interest via the ubiquitin–proteasome system. While MGDs were historically discovered serendipitously, approaches for MGD discovery now include cell-viability-based drug screens or data mining of public transcriptomics and drug response datasets. These approaches, however, have target spaces restricted to the essential proteins. Here we develop a high-throughput workflow for MGD discovery that also reaches the nonessential proteome. This workflow begins with the rapid synthesis of a compound library by sulfur(VI) fluoride exchange chemistry coupled to a morphological profiling assay in isogenic cell lines that vary in levels of the E3 ligase CRBN. By comparing the morphological changes induced by compound treatment across the isogenic cell lines, we were able to identify FL2-14 as a CRBN-dependent MGD targeting the nonessential protein GSPT2. We envision that this workflow would contribute to the discovery and characterization of MGDs that target a wider range of proteins.
الإتاحة: https://doi.org/10.1021/acschembio.3c00598.s001Test
https://figshare.com/articles/journal_contribution/Discovery_of_Molecular_Glue_Degraders_via_Isogenic_Morphological_Profiling/24599386Test -
2دورية أكاديمية
المؤلفون: Alicia Gunning, Sunil Kumar, Cassin Kimmel Williams, Barry M. Berger, Stephen P. Naber, Piyush B. Gupta, Catherine Del Vecchio Fitz, Charlotte Kuperwasser
المصدر: Diagnostics; Volume 13; Issue 4; Pages: 725
مصطلحات موضوعية: NavDx, HPV, oropharyngeal, cancer, papillomavirus, profiling assay, OPSCC
الوصف: The NavDx® blood test analyzes tumor tissue modified viral (TTMV)-HPV DNA to provide a reliable means of detecting and monitoring HPV-driven cancers. The test has been clinically validated in a large number of independent studies and has been integrated into clinical practice by over 1000 healthcare providers at over 400 medical sites in the US. This Clinical Laboratory Improvement Amendments (CLIA), high complexity laboratory developed test, has also been accredited by the College of American Pathologists (CAP) and the New York State Department of Health. Here, we report a detailed analytical validation of the NavDx assay, including sample stability, specificity as measured by limits of blank (LOBs), and sensitivity illustrated via limits of detection and quantitation (LODs and LOQs). LOBs were 0–0.32 copies/μL, LODs were 0–1.10 copies/μL, and LOQs were <1.20–4.11 copies/μL, demonstrating the high sensitivity and specificity of data provided by NavDx. In-depth evaluations including accuracy and intra- and inter-assay precision studies were shown to be well within acceptable ranges. Regression analysis revealed a high degree of correlation between expected and effective concentrations, demonstrating excellent linearity (R2 = 1) across a broad range of analyte concentrations. These results demonstrate that NavDx accurately and reproducibly detects circulating TTMV-HPV DNA, which has been shown to aid in the diagnosis and surveillance of HPV-driven cancers.
وصف الملف: application/pdf
العلاقة: Pathology and Molecular Diagnostics; https://dx.doi.org/10.3390/diagnostics13040725Test
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3رسالة جامعية
المؤلفون: Jingjuan Chen
مصطلحات موضوعية: Cell development, proliferation and death, Cell metabolism, Epigenetics (incl. genome methylation and epigenomics), FAM210A, mitochondria, protein acetylation, TCA cycle, metabolism, proteomics, ribosome, organelle crosstalk, skeletal muscle, muscle stem cells, proteostasis, myofiber, ribosome profiling assay, muscle maintenance
الوصف: Skeletal muscle accounts for 40% of total body weight and the homeostasis of muscle tissue is critical in maintaining proper body function. Skeletal muscle develops during the embryonic stages from the muscle progenitor cells derived from the dermomyotome structure. The myogenic progenitor cells contribute to the primary myogenesis by forming the primary myotubes which are the founding structures that the secondary myogenesis continues to build on. A portion of the myogenic progenitor cells makes up the adult muscle stem cells residing in homeostatic muscle tissue. The adult muscle stem cells contribute substantially for the adult muscle regeneration. Due to the significance of the muscle tissue and the importance of muscle stem cells, dysregulation of the muscle homeostasis or the muscle stem cell homeostasis will result in severe pathological conditions such as myopathy. Mitochondria are cellular organelles that are responsible for generating energy needed for cellular processes, especially for muscle tissue where muscle contraction requires the presence of ATP. On the other hand, mitochondria also serve as signaling molecules and provide macromolecules for the biosynthesis. FAM210A (Family With Sequence Similarity 210 Member A) protein was shown to impact the lean mass of human subjects yet a detailed study on the effect of FAM210A in skeletal muscle was not performed, nor has the molecular mechanisms through which FAM210A function been elucidated. Therefore, I take on the task to unveil the function of FAM210A in muscle development, muscle homeostasis and muscle stem cell behavior by using a combination of mouse models with different myogenic promoters to target Fam210a at different developmental stages. In the first part of the thesis, I investigated the role of FAM210A in post differentiation myofibers. Using the Myl1 Cre driven deletion of Fam210a , I found that Fam210a MKO had normal development before 3 weeks of age, but the growth was stagnant from 4 weeks on, and the mice did not survive past 8 weeks ...
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4
المؤلفون: Kuniko Sunami, Tetsu Hayashida, Kazuto Nishio, Shinji Kohsaka, Ichiro Kinoshita, Hiroyuki Uetake, Kenji Tamura, Koshi Mimori, Hideaki Takahashi, Shinichi Toyooka, Noboru Yamamoto, Hideaki Bando, Masayuki Takeda, Keigo Komine, Katsuya Tsuchihara, Yoichi Naito, Yasushi Yatabe
المصدر: Cancer Science
مصطلحات موضوعية: Oncology, Cancer Research, medicine.medical_specialty, cancer comprehensive genome profiling assay, Guidelines as Topic, Appropriate use, Japan, Report, Neoplasms, Internal medicine, Biomarkers, Tumor, medicine, Humans, Liquid biopsy, plasma, circulating tumor DNA, Blood Specimen Collection, liquid biopsy, Universal health insurance, business.industry, Task force, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Cancer, General Medicine, medicine.disease, Advice (programming), next‐generation sequencer, Circulating tumor DNA, Mutation, Genome profiling, sense organs, Transcriptome, business, Reports
الوصف: Comprehensive genomic profiling (CGP) is being increasingly used for the routine clinical management of solid cancers. In July 2018, the use of tumor tissue‐based CGP assays became available for all solid cancers under the universal health insurance system in Japan. Several restrictions presently exist, such as patient eligibility and limitations on the opportunities to perform such assays. The clinical implementation of CGP based on plasma circulating tumor DNA (ctDNA) is also expected to raise issues regarding the selection and use of tissue DNA and ctDNA CGP. A Joint Task Force for the Promotion of Cancer Genome Medicine comprised of three Japanese cancer‐related societies has formulated a policy proposal for the appropriate use of plasma CGP (in Japanese), available at https://www.jca.gr.jp/researcher/topics/2021/files/20210120.pdfTest, http://www.jsco.or.jp/jpn/user_data/upload/File/20210120.pdfTest, and https://www.jsmo.or.jp/file/dl/newsj/2765.pdfTest. Based on these recommendations, the working group has summarized the respective advantages and cautions regarding the use of tissue DNA CGP and ctDNA CGP with reference to the advice of a multidisciplinary expert panel, the preferred use of plasma specimens over tissue, and multiple ctDNA testing. These recommendations have been prepared to maximize the benefits of performing CGP assays and might be applicable in other countries and regions.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a407ae9edae68c51f00c5b85d878b687Test
https://doi.org/10.1111/cas.15022Test -
5دورية أكاديمية
المؤلفون: PEZONE, ANTONIO, RUSSO, GIUSI, TRAMONTANO, ALFONSO, FLORIO, ERMANNO, SCALA, GIOVANNI, LANDI, ROSARIA, ZUCHEGNA, CANDIDA, ROMANO, ANTONELLA, CHIARIOTTI, LORENZO, Muller, Mark T., Gottesman, Max E., PORCELLINI, ANTONIO, AVVEDIMENTO, VITTORIO ENRICO
المساهمون: Pezone, Antonio, Russo, Giusi, Tramontano, Alfonso, Florio, Ermanno, Scala, Giovanni, Landi, Rosaria, Zuchegna, Candida, Romano, Antonella, Chiariotti, Lorenzo, Muller, Mark T., Gottesman, Max E., Porcellini, Antonio, Avvedimento, VITTORIO ENRICO
مصطلحات موضوعية: DNA methylation profiling assay, epigenetics, DNA methylatio, gene knockdown by shRNA transfection
الوصف: Genome-wide methylation analysis is limited by its low coverage and the inability to detect single variants below 10%. Quantitative analysis provides accurate information on the extent of methylation of single CpG dinucleotide, but it does not measure the actual polymorphism of the methylation profiles of single molecules. To understand the polymorphism of DNA methylation and to decode the methylation signatures before and after DNA damage and repair, we have deep sequenced in bisulfite-treated DNA a reporter gene undergoing site-specific DNA damage and homologous repair. In this paper, we provide information on the data generation, the rationale for the experiments and the type of assays used, such as cytofluorimetry and immunoblot data derived during a previous work published in Scientific Reports, describing the methylation and expression changes of a model gene (GFP) before and after formation of a double-strand break and repair by homologous-recombination or non-homologous-end-joining. These data provide: 1) a reference for the analysis of methylation polymorphism at selected loci in complex cell populations; 2) a platform and the tools to compare transcription and methylation profiles.
العلاقة: info:eu-repo/semantics/altIdentifier/wos/WOS:000400151300002; volume:4; firstpage:170043; numberofpages:10; journal:SCIENTIFIC DATA; https://hdl.handle.net/11588/671271Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85017387085; https://www.nature.com/articles/sdata201743Test
الإتاحة: https://doi.org/10.1038/sdata.2017.43Test
https://hdl.handle.net/11588/671271Test
https://www.nature.com/articles/sdata201743Test -
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المؤلفون: Giovanni Scala, Giusi Russo, Enrico V. Avvedimento, Antonio Pezone, Lorenzo Chiariotti, Candida Zuchegna, Max E. Gottesman, Ermanno Florio, Rosaria Landi, Mark T. Muller, Alfonso Tramontano, Antonella Romano, Antonio Porcellini
المساهمون: Pezone, Antonio, Russo, Giusi, Tramontano, Alfonso, Florio, Ermanno, Scala, Giovanni, Landi, Rosaria, Zuchegna, Candida, Romano, Antonella, Chiariotti, Lorenzo, Muller, Mark T., Gottesman, Max E., Porcellini, Antonio, Avvedimento, VITTORIO ENRICO
المصدر: Scientific Data
مصطلحات موضوعية: 0301 basic medicine, Statistics and Probability, Data Descriptor, DNA Repair, DNA repair, DNA damage, Bioinformatics, Computational biology, Biology, Library and Information Sciences, DNA methylation profiling assay, epigenetics, DNA methylatio, gene knockdown by shRNA transfection, Education, 03 medical and health sciences, Humans, Sulfites, Epigenetics, Post-transcriptional regulation, RNA-Directed DNA Methylation, DNA methylation, Base Sequence, Methylation, Computer Science Applications, Data processing, 030104 developmental biology, Statistics, Probability and Uncertainty, Nucleotide excision repair, Information Systems, DNA Damage
الوصف: Genome-wide methylation analysis is limited by its low coverage and the inability to detect single variants below 10%. Quantitative analysis provides accurate information on the extent of methylation of single CpG dinucleotide, but it does not measure the actual polymorphism of the methylation profiles of single molecules. To understand the polymorphism of DNA methylation and to decode the methylation signatures before and after DNA damage and repair, we have deep sequenced in bisulfite-treated DNA a reporter gene undergoing site-specific DNA damage and homologous repair. In this paper, we provide information on the data generation, the rationale for the experiments and the type of assays used, such as cytofluorimetry and immunoblot data derived during a previous work published in Scientific Reports, describing the methylation and expression changes of a model gene (GFP) before and after formation of a double-strand break and repair by homologous-recombination or non-homologous-end-joining. These data provide: 1) a reference for the analysis of methylation polymorphism at selected loci in complex cell populations; 2) a platform and the tools to compare transcription and methylation profiles.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::187875c0036bd9b7f41b0be7a7d8a399Test
https://pubmed.ncbi.nlm.nih.gov/28398335Test -
7دورية أكاديمية
المؤلفون: Farrell, Jacqueline
المصدر: Graduate Theses and Dissertations
مصطلحات موضوعية: cold acclimation, deacclimation, expression profiling assay, growth chamber assay, ion leakage assay, Lolium perenne, Agronomy and Crop Sciences
الوصف: Studies on climate change have shown an increase in not only the average global surface temperature but also an increase in extreme weather events. One such extreme weather event is the occurrence of winter temperature fluctuations, which can induce loss of cold acclimation. Sudden temperature fluctuations have occurred in the United States in the early spring of 2007 and the late winter of 2009. Both events caused significant freezing damage to plants. However, plants that were able to maintain a portion of their original freezing tolerance, by a process called deacclimation resistance, did not suffer significant damage. Different phenotypic assays were conducted to determine frost tolerance and deacclimation resistance of selected genotypes. Field trial exhibited deacclimation resistance of freezing tolerance loss during a warming trend and sudden freezing in February 2009. Because of this extreme weather event, the number of cultivars in the field trial assay was reduced by 92%. This extreme weather event was simulated in a growth chamber assay. In this assay cultivars from the field trial were exposed to similar temperature fluctuations but under controlled temperature settings. Another assay used to determine plants freezing tolerance during different lengths of deacclimation was the ion leakage assay. This assay indirectly measures freezing tolerance under the premise that ion leakage is negatively correlated with freezing tolerance. However, repeatability of the ion leakage assay was too low, to determine freezing tolerance during deacclimation. By comparing the phenotypic assays (field trial, growth chamber and ion leakage assay) with frost tolerance and deacclimation resistance, the in vivo assay in the growth chamber was best reflecting field conditions. Transcriptome expression profiling was used to find candidate genes for freezing tolerance and/or deacclimation resistance, complementing the phenotypic assays. Expression profiles during cold acclimation, freezing and various lengths of deacclimation ...
وصف الملف: application/pdf
العلاقة: https://lib.dr.iastate.edu/etd/11831Test; https://lib.dr.iastate.edu/cgi/viewcontent.cgi?article=2901&context=etdTest
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8دورية أكاديمية
المؤلفون: William J. Godinez, Vladimir Trifonov, Bin Fang, Guray Kuzu, Luying Pei, W. Armand Guiguemde, Eric J. Martin, Frederick J. King, Jeremy L. Jenkins, Peter Skewes-Cox
مصطلحات موضوعية: Biochemistry, Genetics, Physiology, Pharmacology, Biotechnology, Infectious Diseases, Plant Biology, Virology, Biological Sciences not elsewhere classified, Mathematical Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, Information Systems not elsewhere classified, results thus demonstrate, gene expression data, single profiling assay, malaria inhibition assay, dependent transcriptomic profiles, obtained useful models, computational models based, tat modeling framework, compound activity prediction, seq assay, transcriptomic responses, tat model, target activities, standing challenge, seemingly unrelated, realistic held, phenotypic hits, multiple concentrations
الوصف: Predicting compound activity in assays is a long-standing challenge in drug discovery. Computational models based on compound-induced gene expression signatures from a single profiling assay have shown promise toward predicting compound activity in other, seemingly unrelated, assays. Applications of such models include predicting mechanisms-of-action (MoA) for phenotypic hits, identifying off-target activities, and identifying polypharmacologies. Here, we introduce transcriptomics-to-activity transformer (TAT) models that leverage gene expression profiles observed over compound treatment at multiple concentrations to predict the compound activity in other biochemical or cellular assays. We built TAT models based on gene expression data from a RASL-seq assay to predict the activity of 2692 compounds in 262 dose–response assays. We obtained useful models for 51% of the assays, as determined through a realistic held-out set. Prospectively, we experimentally validated the activity predictions of a TAT model in a malaria inhibition assay. With a 63% hit rate, TAT successfully identified several submicromolar malaria inhibitors. Our results thus demonstrate the potential of transcriptomic responses over compound concentration and the TAT modeling framework as a cost-efficient way to identify the bioactivities of promising compounds across many assays.
الإتاحة: https://doi.org/10.1021/acs.jcim.3c01855.s001Test
https://figshare.com/articles/journal_contribution/Compound_Activity_Prediction_with_Dose-Dependent_Transcriptomic_Profiles_and_Deep_Learning/25117219Test -
9رسالة جامعية
المؤلفون: Jingjuan Chen (18290026)
مصطلحات موضوعية: Cell development, proliferation and death, Cell metabolism, Epigenetics (incl. genome methylation and epigenomics), FAM210A, mitochondria, protein acetylation, TCA cycle, metabolism, proteomics, ribosome, organelle crosstalk, skeletal muscle, muscle stem cells, proteostasis, myofiber, ribosome profiling assay, muscle maintenance
الوصف: Skeletal muscle accounts for 40% of total body weight and the homeostasis of muscle tissue is critical in maintaining proper body function. Skeletal muscle develops during the embryonic stages from the muscle progenitor cells derived from the dermomyotome structure. The myogenic progenitor cells contribute to the primary myogenesis by forming the primary myotubes which are the founding structures that the secondary myogenesis continues to build on. A portion of the myogenic progenitor cells makes up the adult muscle stem cells residing in homeostatic muscle tissue. The adult muscle stem cells contribute substantially for the adult muscle regeneration. Due to the significance of the muscle tissue and the importance of muscle stem cells, dysregulation of the muscle homeostasis or the muscle stem cell homeostasis will result in severe pathological conditions such as myopathy.Mitochondria are cellular organelles that are responsible for generating energy needed for cellular processes, especially for muscle tissue where muscle contraction requires the presence of ATP. On the other hand, mitochondria also serve as signaling molecules and provide macromolecules for the biosynthesis. FAM210A (Family With Sequence Similarity 210 Member A) protein was shown to impact the lean mass of human subjects yet a detailed study on the effect of FAM210A in skeletal muscle was not performed, nor has the molecular mechanisms through which FAM210A function been elucidated. Therefore, I take on the task to unveil the function of FAM210A in muscle development, muscle homeostasis and muscle stem cell behavior by using a combination of mouse models with different myogenic promoters to target Fam210a at different developmental stages.In the first part of the thesis, I investigated the role of FAM210A in post differentiation myofibers. Using the Myl1Cre driven deletion of Fam210a, I found that Fam210aMKO had normal development before 3 weeks of age, but the growth was stagnant from 4 weeks on, and the mice did not survive past 8 weeks of age. I found that the assembly of the ribosomes in the Fam210aMKO was defective, leading to impaired translation which attenuated the muscle atrophy phenotype. I identified through proteomics that the mitochondrial autophagy and proteostatic control pathways were significantly induced yet mitochondrial organization and energetic proteins were downregulated. Metabolomics analysis showed that the signaling metabolite acetyl-CoA was increased in the Fam210aMKO which led to increased protein acetylation, specifically, we showed that the ribosomal proteins were hyperacetylated, and that the acetylation increase was elicited by the Fam210a-null mitochondria.In the second part of the thesis, I investigated the function of FAM210A in muscle progenitor cells. In the FamMKO mice, I found that deletion of Fam210a from embryonic myogenic progenitor cells led to developmental arrest and postnatal death at day 6. In the FamPKO mice, I found that Fam210a is needed for adult muscle stem cell to contribute to regeneration. Loss of Fam210a leads to the regenerative defects when the muscle was exposed to injury cues. We further showed that Fam210a deletion in muscle stem cells resulted in disruption of the proteostatic control over muscle stem cell activation, thereby forbidding the translational increase necessary to facilitate activation and proliferation. Furthermore, I showed that Fam210a deletion leads to excessive OPA1 cleavage, which contributes to the regenerative failure of muscle stem cells as fusion is required for the mitochondrial network remodeling during regeneration. Therefore, Fam210a safeguards the mitochondrial network and proteostasis during regeneration.In summary, my studies characterized the functional contribution of FAM210A during embryonic muscle development, muscle mass maintenance and adult muscle stem cell homeostasis. The regulation of FAM210A in these three processes impinge on the translational regulation. My studies further demonstrated the importance of mitochondrial regulated protein translation in skeletal muscle and muscle stem cells.
