Article
Biology
Harvey Perez, May F. Abdallah, Jose Chavira, Angelina S. Norris, Martin T. Egeland, Karen L. Vo, Callan L. Buechsenschuetz, Valentina Sanghez, Jeannie L. Kim, Molly Pind, Kotoka Nakamura, Geoffrey G. Hicks, Richard A. Gatti, Joaquin Madrenas, Michelina Iacovino, Peter J. McKinnon, Paul J. Mathews
Summary: By introducing null mutations in both the Atm and Aptx genes in mice, researchers have created a novel mouse model that exhibits progressively severe ataxic phenotype and cerebellar molecular layer atrophy. The perturbations significantly alter the biophysical properties of cerebellar Purkinje neurons and their neural activity, correlating with cerebellar atrophy and ataxia over the animal's first year of life. Additionally, the double mutant mice also show a predisposition to cancer and immune abnormalities, resembling symptoms of A-T.
Article
Neurosciences
Simon Deacon, William Dalleywater, Charles Peat, Simon M. L. Paine, Rob A. Dineen
Summary: Cerebellar neurodegeneration is a prominent feature of ataxia telangiectasia (A-T) caused by loss-of-function mutation of the ATM gene. The study found elevated transcription of ATM in the cerebellar cortex compared to other brain regions during neurodevelopment in individuals without A-T, suggesting the importance of intact ATM function in the cerebellum. Gene ontology analysis revealed that ATM expression in the cerebellum is associated with various biological processes, including cellular respiration, mitochondrial function, histone methylation, and cell-cycle regulation, in addition to its canonical role in DNA repair.
Article
Multidisciplinary Sciences
Lauren N. Miterko, Tao Lin, Joy Zhou, Meike E. van der Heijden, Jaclyn Beckinghausen, Joshua J. White, Roy Sillitoe
Summary: Deep brain stimulation (DBS) shows potential in improving motor function in a mouse model of ataxia, with the combination of cerebellar nuclei DBS and physical activity being particularly effective.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Jakub Czarny, Marta Andrzejewska, Olga Zajac-Spychala, Elzbieta Latos-Grazynska, Agata Pastorczak, Kamila Wypyszczak, Aleksandra Szczawinska-Poplonyk, Izabela Niewiadomska-Wojnalowicz, Agnieszka Wziatek, Patrycja Marciniak-Stepak, Michal Dopierala, Jadwiga Maldyk, Katarzyna Jonczyk-Potoczna, Katarzyna Derwich
Summary: Ataxia-telangiectasia (AT) is a rare genetic disorder characterized by DNA repair defect, chromosomal instability, and hypersensitivity to radiation. Successful clinical management of patients with AT is challenging due to poor treatment response, high toxicity, and the need to avoid radiation exposure. This case report describes a 7-year-old female patient with AT and LBCL with IRF4 rearrangement who achieved a favorable outcome through treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Physiology
Rachel Warren, Andrew M. Dylag, Molly Behan, William Domm, Min Yee, Margot Mayer-Proschel, Luis Martinez-Sobrido, Michael A. O'Reilly
Summary: Children and young adults with mutant forms of the ATM gene, which is involved in DNA damage signaling and mitochondrial homeostasis, suffer from respiratory infections, immune deficiencies, and obstructive airways disease associated with disorganized airway epithelium. A study on mice showed that ATM is required for the regeneration of injured airway epithelium after influenza virus infection. Mice lacking ATM exhibited increased airway resistance and reduced lung compliance during infection, and their lungs developed an abnormal proximal airway epithelium containing cells lacking expression of the immunomodulatory protein Scgb1a1. Restoration of Scgb1a1 expression in the airways required ATM and failure to efficiently restore it may contribute to the respiratory diseases seen in individuals with ataxia telangiectasia.
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Divya A. Shiroor, Kuang-Tse Wang, Bhargav D. Sanketi, Justin K. Tapper, Carolyn E. Adler
Summary: Stem cells acquire mutations during division, but can activate the DNA damage response network to repair or induce apoptosis. In planarian flatworms, ATM promotes radiation-induced apoptosis, which is important for long-term animal survival.
Article
Multidisciplinary Sciences
Jun Shen, Yingxi Xu, Shuo Zhang, Shuzhen Lyu, Yingying Huo, Yaoyao Zhu, Kejing Tang, Junli Mou, Xinjie Li, Dixie L. Hoyle, Min Wang, Jianxiang Wang, Xin Li, Zack Z. Wang, Tao Cheng
Summary: This study used single-cell transcriptomic analysis to explore hematopoietic differentiation of human pluripotent stem cells and found that hypoxic conditions during differentiation promoted the generation of functional T cells, which inhibited tumor growth in vitro and in vivo. This represents a significant advancement in guiding the generation of functional T cells for clinical applications.
Article
Genetics & Heredity
Sara Biagiotti, Ambra Barone, Mattia Paolo Aliano, Giulia Federici, Marco Malatesta, Caterina Caputi, Silvia Soddu, Vincenzo Leuzzi, Luciana Chessa, Mauro Magnani
Summary: Most ATM variants associated with Ataxia Telangiectasia are classified as variants with uncertain significance. This study focused on a specific ATM variant found in Lebanese brothers, revealing it to be pathogenic even though it causes an atypical phenotype. Dexamethasone showed therapeutic potential on this and possibly other missense ATM variants.
FRONTIERS IN GENETICS
(2021)
Article
Immunology
Thomas J. Weitering, Janine E. Melsen, Monique M. van Ostaijen-ten Dam, Corry M. R. Weemaes, Marco W. Schilham, Mirjam van der Burg
Summary: Ataxia Telangiectasia (AT) is a rare genetic disorder characterized by immune deficiency, cancer susceptibility, and cerebellar ataxia. Despite reduced naive T cells, AT patients have a fully developed memory T cell compartment, possibly due to the presence of normal numbers of stem cell memory T cells.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Immunology
Ruth Pia Duecker, Lucia Gronau, Patrick C. Baer, Stefan Zielen, Ralf Schubert
Summary: Our study focused on investigating the feasibility of different approaches of hematopoietic stem cell transplantation (HSCT) for Ataxia-telangiectasia (A-T) by using Atm-deficient mice as models. The results showed that haploidentical HSCT could extend the lifespan of Atm-deficient mice and improve T-cell numbers and functionality. Interestingly, HSCT using heterozygous donor cells also led to improved survival and enhanced CD4 cell functionality in Atm-deficient mice, suggesting it as a potential strategy for A-T treatment.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Goutham Narayanan Subramanian, Abrey Jie Yeo, Magtouf Hnaidi Gatei, David John Coman, Martin Francis Lavin
Summary: The ATM protein kinase has diverse functions in the cell, including protecting DNA, maintaining cellular homeostasis, and safeguarding against external and internal damage.
Article
Oncology
Venturina Stagni, Archontia Kaminari, Claudia Contadini, Daniela Barila, Rosario Luigi Sessa, Zili Sideratou, Spiros A. Vlahopoulos, Dimitris Tsiourvas
Summary: Doxorubicin is commonly used in breast cancer treatment but resistance is a problem. Breast cancer stem cells (BCSCs) are particularly resistant. Researchers have developed a polymeric nanocarrier that targets BCSCs and enhances sensitivity to chemotherapy drugs by inhibiting ATM kinase.
Article
Cell & Tissue Engineering
Marina P. Hommersom, Ronald A. M. Buijsen, Willeke M. C. van Roon-Mom, Bart P. C. van de Warrenburg, Hans van Bokhoven
Summary: Recent findings from studies using human induced pluripotent stem cells (hiPSCs) for modeling SCAs are systematically summarized, indicating the potential of these models to provide new mechanistic insights and assist in the development of genetic therapies. However, the use of standardized methods and multiple clones of isogenic lines are essential to increase the validity and reproducibility of the insights gained.
STEM CELL REVIEWS AND REPORTS
(2022)
Article
Biotechnology & Applied Microbiology
Teresa P. Silva, Rui Sousa-Luis, Tiago G. Fernandes, Evguenia P. Bekman, Carlos A. V. Rodrigues, Sandra H. Vaz, Leonilde M. Moreira, Yas Hashimura, Sunghoon Jung, Brian Lee, Maria Carmo-Fonseca, Joaquim M. S. Cabral
Summary: This study demonstrates the reproducible and scalable production of cerebellar organoids using a novel single-use Vertical-Wheel bioreactor system, with faster cerebellar commitment and significant enrichment of extracellular matrix observed. The dynamic differentiation protocol allows for efficient generation of organoids with cerebellar identity, paving the way for large-scale production and potential applications in drug screening and studying pathological pathways related to cerebellar degeneration.
BIOTECHNOLOGY AND BIOENGINEERING
(2021)
Article
Obstetrics & Gynecology
Wei-Jun Gao, Hui-Xia Li, Juan Feng, Xin-Ran Lu, Peng-Luo Yin, Hua Jia, Wen-Zhi Ma
Summary: High temperature inhibits the differentiation of spermatogonial stem cells (SSCs), leading to apoptosis of differentiated spermatogenic cells, oxidative damage to sperm DNA, and changes in morphology and function of Sertoli cells. Heat stress treatment at 37 degrees C significantly inhibited SSC differentiation and down-regulated key genes involved in differentiation. The p53, ribosome, and carbon metabolism signaling pathways were found to be enriched in the inhibition of SSC differentiation by high temperature.
REPRODUCTIVE SCIENCES
(2023)
Article
Genetics & Heredity
Sean B. Wilson, Sara E. Howden, Jessica M. Vanslambrouck, Aude Dorison, Jose Alquicira-Hernandez, Joseph E. Powell, Melissa H. Little
Summary: This study developed an unbiased tool (DevKidCC) for accurately classifying cell identities in kidney organoids and comparing different single-cell datasets. By applying this tool, differences in the relative proportions of cell types between kidney organoids generated using different protocols can be identified, leading to improvements in kidney organoid generation methods.
Article
Multidisciplinary Sciences
Seyhan Yazar, Jose Alquicira-Hernandez, Kristof Wing, Anne Senabouth, M. Grace Gordon, Stacey Andersen, Qinyi Lu, Antonia Rowson, Thomas R. P. Taylor, Linda Clarke, Katia Maccora, Christine Chen, Anthony L. Cook, Chun Jimmie Ye, Kirsten A. Fairfax, Alex W. Hewitt, Joseph E. Powell
Summary: This study utilizes single-cell RNA sequencing to uncover the genetic drivers of interindividual variation in the human immune system. The researchers identify specific loci that have cell type-specific effects on gene expression and demonstrate dynamic allelic effects in B cells. Additionally, they use Mendelian randomization to determine the causal route by which risk loci contribute to autoimmune disease at the cellular level.
Article
Immunology
Nathan W. Zammit, Joseph McDowell, Joanna Warren, Walter Muskovic, Joanne Gamble, Yan-Chuan Shi, Dominik Kaczorowski, Chia-Ling Chan, Joseph Powell, Chris Ormandy, David Brown, Samantha R. Oakes, Shane T. Grey
Summary: Women with autoimmune and inflammatory conditions may experience reduced fertility. A genetic variant in TNFAIP3, a negative regulator of inflammation, has been found to be associated with infertility. This variant decreases the activation threshold of inflammatory response and affects reproductive system, mammary gland development, and insulin resistance. This study highlights the potential link between heightened immunity and reduced fertility.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biochemical Research Methods
Belinda Phipson, Choon Boon Sim, Enzo R. Porrello, Alex W. Hewitt, Joseph Powell, Alicia Oshlack
Summary: Single cell RNA-Sequencing (scRNA-seq) is popular for profiling cell transcriptomes. propeller is a robust method leveraging biological replication to find significant differences in cell type proportions. It performs well in various scenarios.
Article
Medicine, Research & Experimental
SungWoo Choi, Giulia Ferrari, Louise A. Moyle, Kirsty Mackinlay, Naira Naouar, Salma Jalal, Sara Benedetti, Christine Wells, Francesco Muntoni, Francesco Saverio Tedesco
Summary: Muscle satellite stem cells (MuSCs) play a crucial role in muscle growth and regeneration. Researchers have found that DLL4 and PDGF-BB can enhance the migration capacity of myogenic progenitors derived from human induced pluripotent stem cells (hiPSCs), bringing hiPSCs closer to potential applications in muscle gene and cell therapies.
EMBO MOLECULAR MEDICINE
(2022)
Article
Genetics & Heredity
Margaret Brown, Emily Greenwood, Biao Zeng, Joseph E. Powell, Greg Gibson
Summary: Expression quantitative trait locus detection is crucial for understanding the contribution of noncoding variants to disease susceptibility and complex traits. This study compares different methods for fine-mapping and causal variant discovery, finding limitations in each approach and proposing a 5-tier method to narrow down credible sets and prioritize likely causal variants.
Article
Immunology
Zahra Elahi, Paul W. Angel, Suzanne K. Butcher, Nadia Rajab, Jarny Choi, Yidi Deng, Justine D. Mintern, Kristen Radford, Christine A. Wells
Summary: Dendritic cells (DCs) are functionally diverse and play important roles in human tissues. However, limited numbers and short lifespan of DCs in circulation have hindered the understanding of human DC biology. In this study, a transcriptional atlas of human DCs was constructed by combining samples from multiple expression profiling studies. The study revealed significant gene expression variation of DC subset-defining markers across different tissues and upon viral or bacterial stimulation. The study also highlighted the differences between in vitro-derived DC subsets and their in vivo counterparts, and provided evidence that in vitro-differentiated DCs fail to capture the repertoire of primary DC subsets or behaviors. The construction of the reference DC atlas provides a valuable resource for identifying and annotating tissue-specific DC subsets from single-cell datasets, as well as benchmarking new in vitro models of DC biology.
JOURNAL OF IMMUNOLOGY
(2022)
Review
Genetics & Heredity
Anna S. E. Cuomo, Aparna Nathan, Soumya Raychaudhuri, Daniel G. MacArthur, Joseph E. Powell
Summary: In this Review, the authors discuss the field of single-cell genetics, which combines single-cell genomics with human genetics. They highlight the importance of single-cell expression quantitative trait loci studies in linking genetic variation to cellular processes in human biology and disease. The authors also mention the potential implications of this field for disease diagnosis, risk prediction, and therapeutic development, and emphasize the need for advances in data generation and analysis methods to fully utilize single-cell genomic data.
NATURE REVIEWS GENETICS
(2023)
Review
Genetics & Heredity
Jennifer Lim, Venessa Chin, Kirsten Fairfax, Catia Moutinho, Dan Suan, Hanlee Ji, Joseph E. Powell
Summary: Genomics has been widely used in clinical practice, leading to innovations in genetic screening, rare disease diagnosis, and molecularly guided therapy choice. Single-cell technologies have the potential to revolutionize genomic medicine by unveiling the cellular heterogeneity underlying disease pathology and mechanisms. However, challenges in translating single-cell genomics from research to clinical practice need to be addressed.
NATURE REVIEWS GENETICS
(2023)
Article
Biotechnology & Applied Microbiology
Angli Xue, Seyhan Yazar, Drew Neavin, Joseph E. Powell
Summary: Using latent variables in gene expression data can improve eQTL detection and correct confounding factors. PEER and PCA are commonly used methods for bulk RNA-seq analysis, but their performance in single-cell eQTL analysis has not been extensively evaluated. Our study shows that additional quality control and data transformation steps are required for valid latent variables in single-cell eQTL analysis.
Article
Oncology
Rika Tyebally, Angli Xue, Joseph E. Powell
Summary: Complex diseases exhibit heterogeneity in treatment response due to genetic and environmental variations. Integrating GWAS and eQTL analyses can identify cell-type specific candidate genes and pathways relevant to the disease, which can be applied to patient stratification and novel therapeutic target identification.
CLINICAL AND TRANSLATIONAL MEDICINE
(2023)