Article
Multidisciplinary Sciences
Jesus Garcia-Castillo, Francisca Alcaraz-Perez, Elena Martinez-Balsalobre, Diana Garcia-Moreno, Marlies P. Rossmann, Miriam Fernandez-Lajarin, Manuel Bernabe-Garcia, Ana B. Perez-Oliva, Virginia C. Rodriguez-Cortez, Clara Bueno, Isaac Adatto, Suneet Agarwal, Pablo Menendez, Leonard Zon, Victoriano Mulero, Maria L. Cayuela
Summary: Dyskeratosis congenita (DC) is a rare genetic syndrome caused by mutations in telomerase or telomeric proteins. Research shows that zebrafish terc plays a crucial role in regulating the expression of master myeloid genes, while mutations found in DC patients affect this process.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Jian Qin, Alexandre Garus, Chantal Autexier
Summary: This study reveals that mutations in the C-terminal extension (CTE) of dyskerin impair its interaction with hTR, leading to X-linked dyskeratosis congenita (X-DC) and related telomere syndromes. These mutations result in reduced binding to SHQ1 and defective binding to hTR. Furthermore, deletion of the CTE further reduces binding to hTR and disrupts the localization and interaction of dyskerin with other molecules.
HUMAN MOLECULAR GENETICS
(2023)
Article
Cell Biology
Julij Selb, Katarina Osolnik, Izidor Kern, Peter Korosec, Matija Rijavec
Summary: Recent studies have shown that approximately 10% of individuals with IPF have causative variants in TCG genes. We conducted a sequencing study on a cohort of well-characterized IPF patients to validate these findings and assess the clinical utility. Our results, based on individual patient-level analysis in routine clinical practice, confirmed a prevalence of 11.1% of pathogenic TCG variants in the cohort, consistent with previous studies.
Article
Hematology
Christopher R. Reilly, Mikko Myllymaki, Robert Redd, Shilpa Padmanaban, Druha Karunakaran, Valerie Tesmer, Frederick D. Tsai, Christopher J. Gibson, Huma Q. Rana, Liang Zhong, Wael Saber, Stephen R. Spellman, Zhen-Huan Hu, Esther H. Orr, Maxine M. Chen, Immaculata De Vivo, Daniel J. DeAngelo, Corey Cutler, Joseph H. Antin, Donna Neuberg, Judy E. Garber, Jayakrishnan Nandakumar, Suneet Agarwal, R. Coleman Lindsley
Summary: Research indicates that rare TERT variants are associated with an increased risk of developing MDS and nonrelapse mortality, with 90% of the variants showing impairment in telomere elongation function. Routine screening for TERT rare variants in MDS patients may enhance transplant outcomes.
Article
Biology
Rafael Jesus Fernandez, Zachary J. G. Gardner, Katherine J. Slovik, Derek C. Liberti, Katrina N. Estep, Wenli Yang, Qijun Chen, Garrett T. Santini, Javier Perez, Sarah Root, Ranvir Bhatia, John W. Tobias, Apoorva Babu, Michael P. Morley, David B. Frank, Edward E. Morrisey, Christopher J. Lengner, F. Brad Johnson
Summary: DC is a rare genetic disorder that causes short telomeres and early onset of age-related diseases. Using iAT2 cells to model, it is shown that shortened telomeres lead to cell senescence and Wnt signaling defects. The study suggests that Wnt agonists may be potential therapies for DC-related pathologies.
Review
Medicine, General & Internal
Claudio Tirelli, Chiara Pesenti, Monica Miozzo, Michele Mondoni, Laura Fontana, Stefano Centanni
Summary: Idiopathic pulmonary fibrosis (IPF) is a rare lung disease with unknown etiology and poor prognosis. Familial pulmonary fibrosis (FPF) has been linked to specific genetic mutations, while evidence of genetics in sporadic IPF is limited. Research focuses on genetic and epigenetic mechanisms in the pathogenesis and prognosis of IPF and FPF.
Review
Respiratory System
Ping Wang, Zuojun Xu
Summary: DC-associated PF commonly occurs later in life without significant hematological manifestations. Mutations in genes encoding different components of the telomere maintenance pathway are associated with clinical phenotypes and prognosis. Clinicians should consider PF caused by DC in the differential diagnosis of patients with unexplained PF and should exclude it before diagnostic surgical lung biopsy or empirical immunosuppression therapy.
BMC PULMONARY MEDICINE
(2021)
Review
Medicine, General & Internal
Dongyan Ding, Rong Gao, Qianfei Xue, Rumei Luan, Junling Yang
Summary: This article systematically summarizes the genetic mechanisms of familial idiopathic pulmonary fibrosis (f-IPF), revealing the genetic variations and susceptibility related to the disease. It contributes to a better understanding of IPF pathogenesis and facilitates early detection.
INTERNATIONAL JOURNAL OF MEDICAL SCIENCES
(2023)
Article
Critical Care Medicine
Yosafe Wakwaya, Deepa Ramdurai, Jeffrey J. Swigris
Summary: Chronic cough in patients with IPF may involve multiple mechanisms, including comorbid conditions and IPF itself. Diagnostic and management approaches need to be multi-faceted, but may lack robust data support.
Article
Oncology
Szymon Janczar, Martin Kirschner, Fabian Beier, Tim H. Bruemmendorf, Marek Ussowicz, Katarzyna Babol-Pokora, Aleksandra Oszer, Ayami Yoshimi, Krzysztof Kalwak, Wojciech Mlynarski
Summary: Dyskeratosis congenita is a bone marrow failure syndrome with telomere biology abnormalities. A boy with a rare TERT gene variant presented with juvenile myelomonocytic leukemia.
PEDIATRIC BLOOD & CANCER
(2022)
Article
Multidisciplinary Sciences
Chiara Pederiva, Davide M. Trevisan, Dimitra Peirasmaki, Shan Chen, Sharon A. Savage, Ola Larsson, Jernej Ule, Laura Baranello, Federico Agostini, Marianne Farnebo
Summary: Posttranscriptional modifications of mRNA, including pseudouridylation, play a crucial role in gene expression regulation. In this study, dyskerin, a pseudouridine synthase, was found to bind to RNA polymerase II and be responsible for pseudouridylation of thousands of mRNAs. Dyskerin-mediated pseudouridylation was shown to interfere with translation and reduction of the modification led to enhanced protein synthesis. Furthermore, dyskeratosis congenita patients with mutations in the dyskerin-encoding gene showed severe reduction in mRNA pseudouridylation.
Article
Biochemistry & Molecular Biology
Ji Hoon Han, Gavin Ryan, Alyson Guy, Lu Liu, Mathieu Quinodoz, Ingrid Helbling, Joey E. Lai-Cheong, Julian Barwell, Marc Folcher, John A. McGrath, Celia Moss, Carlo Rivolta
Summary: The study identified LIPHAK as a previously unrecognized ribosomopathy, where variants in the LTV1 gene result in abnormal splicing and premature termination of the protein it encodes.
HUMAN MOLECULAR GENETICS
(2022)
Review
Biochemistry & Molecular Biology
Roxana-Elena Cirjaliu, Mariana Deacu, Ioana Gherghisan, Angela Stefania Marghescu, Manuela Enciu, Gabriela Izabela Baltatescu, Antonela Anca Nicolau, Doina-Ecaterina Tofolean, Oana Cristina Arghir, Ariadna-Petronela Fildan
Summary: This review provides a comprehensive analysis of the risk factors, clinical, radiologic, and histological features of both post-COVID-19 pulmonary fibrosis (PCPF) and idiopathic pulmonary fibrosis (IPF). It highlights the similarities and differences between these two diseases by gathering relevant articles published in English up until October 2022 using multiple databases. This review aims to assist clinicians, pathologists, and researchers in making accurate diagnoses and selecting patients for anti-fibrotic therapies and future therapeutic perspectives.
Review
Medicine, General & Internal
Alba Mulet, Jaime Signes-Costa
Summary: Idiopathic pulmonary fibrosis is a lung disease with unknown causes, which has a poor prognosis. Telomeric shortening may play an important role in its pathogenesis, but mutations in telomere-related genes are not always present. Telomere shortening can serve as a biomarker for disease prognosis independently of other clinical factors.
JOURNAL OF CLINICAL MEDICINE
(2022)
Article
Immunology
Benjamin Rolles, Andres Caballero-Oteyza, Michele Proietti, Sigune Goldacker, Klaus Warnatz, Nadezhda Camacho-Ordonez, Seraina Prader, Jana Pachlopnik Schmid, Margherita Vieri, Susanne Isfort, Robert Meyer, Martin Kirschner, Tim H. Bruemmendorf, Fabian Beier, Bodo Grimbacher
Summary: Telomere biology disorders (TBD) are genetic diseases caused by pathogenic variants in genes related to telomere maintenance. TBD can manifest in adulthood and have variable symptoms, making diagnosis complicated. Common variable immunodeficiency (CVID) is an antibody deficiency syndrome caused by dysfunctional B lymphocytes. In our study, we found that approximately 22% of CVID patients carried rare candidate variants in telomere-associated genes. We recommend including all TBD-associated genes in the genetic screening of patients with antibody deficiencies.
CLINICAL IMMUNOLOGY
(2023)
Article
Multidisciplinary Sciences
Charlotte Hodson, Jason K. K. Low, Sylvie van Twest, Samuel E. Jones, Paolo Swuec, Vincent Murphy, Kaima Tsukada, Matthew Fawkes, Rohan Bythell-Douglas, Adelina Davies, Jessica K. Holien, Julienne J. O'Rourke, Benjamin L. Parker, Astrid Glaser, Michael W. Parker, Joel P. Mackay, Andrew N. Blackford, Alessandro Costa, Andrew J. Deans
Summary: The RecQ-like helicase BLM cooperates with topoisomerase IIIa to dissolve double Holliday junctions in homologous recombination. Mutations in the Bloom syndrome complex can cause genome instability and cancer susceptibility, including breast cancer.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biophysics
Stefan J. Hermans, Tracy L. Nero, Craig J. Morton, Jonathan H. Gooi, Gabriela A. N. Crespi, Nancy C. Hancock, Chen Gao, Kenta Ishii, Jasmina Markulic, Michael W. Parker
Summary: Alzheimer's disease is an age-related disease with no effective treatments. Cell surface receptors and immune system-related genes have been found to be associated with the disease risk. Structural biology has provided important insights into the functioning of these receptors.
BIOPHYSICAL REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Ashley J. Ovens, Yi Sing Gee, Naomi X. Y. Ling, Dingyi Yu, Justin P. Hardee, Jin D. Chung, Kevin R. W. Ngoei, Nicholas J. Waters, Nolan J. Hoffman, John W. Scott, Kim Loh, Katrin Spengler, Regine Heller, Michael W. Parker, Gordon S. Lynch, Fei Huang, Sandra Galic, Bruce E. Kemp, Jonathan B. Baell, Jonathan S. Oakhill, Christopher G. Langendorf
Summary: AMPK is a cellular energy sensor and regulator of energy homeostasis. Activating AMPK shows potential for treating type 2 diabetes and insulin resistance. Recent studies suggest that the ??202??1 isoform combination is primarily responsible for these effects. Structure/function analysis of SC4 activator led to the discovery of MSG010 and MSG011, which show greater potency in activating ??202??1 AMPK compared to MK-8722. These findings guide the development of selective AMPK activators.
BIOCHEMICAL JOURNAL
(2022)
Article
Multidisciplinary Sciences
Stanley C. Xie, Riley D. Metcalfe, Elyse Dunn, Craig J. Morton, Shih-Chung Huang, Tanya Puhalovich, Yawei Du, Sergio Wittlin, Shuai Nie, Madeline R. Luth, Liting Ma, Mi-Sook Kim, Charisse Flerida A. Pasaje, Krittikorn Kumpornsin, Carlo Giannangelo, Fiona J. Houghton, Alisje Churchyard, Mufuliat T. Famodimu, Daniel C. Barry, David L. Gillett, Sumanta Dey, Clara C. Kosasih, William Newman, Jacquin C. Niles, Marcus C. S. Lee, Jake Baum, Sabine Ottilie, Elizabeth A. Winzeler, Darren J. Creek, Nicholas Williamson, Michael W. Parker, Stephen Brand, Steven P. Langston, Lawrence R. Dick, Michael D. W. Griffin, Alexandra E. Gould, Leann Tilley
Summary: This study identifies aminoacyl transfer RNA synthetases as potential drug targets and presents a novel compound that can inhibit these enzymes, effectively killing the malaria parasite.
Article
Hematology
Aram Niaz, Jia Truong, Annabel Manoleras, Lucy C. Fox, Piers Blombery, Raja S. Vasireddy, Hilda A. Pickett, Julie A. Curtin, Pasquale M. Barbaro, Jonathan Rodgers, John Roy, Lisa G. Riley, Jessica K. Holien, Scott B. Cohen, Tracy M. Bryan
Summary: Telomere biology disorders (TBDs) are inherited disorders characterized by bone marrow failure. This study investigated a patient with compound heterozygous variants in the TERT gene and found functional interaction between the proteins encoded by the two alleles.
Article
Biochemistry & Molecular Biology
Vivian Cody, Jia Q. Truong, Bruce A. Holdsworth, Jessica K. Holien, Samantha J. Richardson, David K. Chalmers, David J. Craik
Summary: Human transthyretin (hTTR) amyloid deposits can disrupt cellular function, but the molecule VCP-6 can bind to and stabilize hTTR, reducing amyloid formation.
Review
Oncology
Yali Deng, Doan T. M. Ngo, Jessica K. Holien, Jarmon G. Lees, Shiang Y. Lim
Summary: Drp1 inhibition holds great potential as a targeted mitochondrial therapy for doxorubicin-induced cardiotoxicity, which is a significant challenge in clinical practice.
CURRENT ONCOLOGY REPORTS
(2022)
Article
Medicine, Research & Experimental
Johannes Zeller, Karen S. Cheung Tung Shing, Tracy L. Nero, James D. McFadyen, Guy Krippner, Balazs Bogner, Sheena Kreuzaler, Jurij Kiefer, Verena K. Horner, David Braig, Habiba Danish, Sara Baratchi, Mark Fricke, Xiaowei Wang, Michel G. Kather, Bernd Kammerer, Kevin J. Woollard, Prerna Sharma, Craig J. Morton, Geoffrey Pietersz, Michael W. Parker, Karlheinz Peter, Steffen U. Eisenhardt
Summary: C-reactive protein (CRP) is highly upregulated during inflammatory reactions and exhibits pro-inflammatory effects. We discovered a mechanism in which CRP undergoes conformational changes, resulting in highly inflammatory forms. By designing a low molecular weight CRP inhibitor that mimics phosphocholine, we demonstrated its ability to inhibit CRP-driven inflammation while preserving its pathogen-defense functions. This represents a promising and potentially broad-spectrum anti-inflammatory therapy.
EMBO MOLECULAR MEDICINE
(2023)
Review
Allergy
Harshita Pant, Timothy R. Hercus, Damon J. Tumes, Kwok Ho Yip, Michael W. Parker, Catherine M. Owczarek, Angel F. Lopez, David P. Huston
Summary: The family of cytokines IL-3, IL-5, and GM-CSF, which was discovered over 30 years ago, continues to expand in its biological activities and impact on clinical medicine. These cytokines have been identified as bone marrow growth factors and are also recognized as key mediators of inflammation and immunologic diseases. The understanding of their functions has led to increased interest in modulating them for clinical management.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Jessica K. Holien, Lachlan Coff, Andrew J. Guy, Jennifer C. Boer
Summary: During the COVID-19 lockdowns, online learning activities were developed for undergraduate and master's students. An integrative, industry-based research assignment was designed to guide students through a drug discovery project. This assignment allowed students to apply diverse bioinformatic principles to analyze biological and chemical data and make meaningful predictions. It served as the final assessment of the students' knowledge.
JOURNAL OF CHEMICAL EDUCATION
(2023)
Editorial Material
Genetics & Heredity
Tracy M. Bryan
Summary: Telomere length is a crucial factor affecting cellular aging and disease susceptibility, but the underlying genetics of telomere length regulation in humans remains poorly understood. A recent genome-wide CRISPR screen has identified the central involvement of thymidine nucleotide metabolism in telomere length regulation, highlighting its potential implications for disease diagnosis and treatment.
Article
Oncology
Hassina Massudi, Jie-Si Luo, Jessica K. Holien, Satyanarayana Gadde, Sukriti Krishan, Mika Herath, Jessica Koach, Brendan W. Stevenson, Michael A. Gorman, Pooja Venkat, Chelsea Mayoh, Xue-Qun Luo, Michael W. Parker, Belamy B. Cheung, Glenn M. Marshall
Summary: Neuroblastoma, the most common solid tumor in early childhood, has a poor survival rate among children with advanced disease. This study identified a protein called PA2G4 as a cofactor for the MYCN oncogene and developed a compound called WS6 and its analogues to inhibit PA2G4 and MYCN protein levels and reduce tumor cell growth. The novel WS6 analogues showed promise as inhibitors of MYCN and PA2G4 oncogenic functions and may have implications for other MYCN-driven cancers.
Article
Chemistry, Multidisciplinary
Catherine G. Fitzgerald Dickmann, Alexander F. F. McDonald, Nhi Huynh, Angela Rigopoulos, Zhanqi Liu, Nancy Guo, Laura D. D. Osellame, Michael A. A. Gorman, Michael W. W. Parker, Hui K. K. Gan, Andrew M. M. Scott, Uwe Ackermann, Ingrid J. G. Burvenich, Jonathan M. M. White
Summary: A novel molecule, [F-18]BiPET-2, radiolabelled with positron emitting fluorine-18, has been developed and evaluated in vitro and preclinically in glioblastoma models.
CHEMICAL COMMUNICATIONS
(2023)
Review
Genetics & Heredity
Niles Nelson, Simone Feurstein, Aram Niaz, Jia Truong, Jessica K. Holien, Sionne Lucas, Kirsten Fairfax, Joanne Dickinson, Tracy M. Bryan
Summary: The purpose of this study is to improve the genomic diagnosis of patients with underlying telomere biology disorders (TBD) by reducing variants of uncertain significance through the application of functional genomic evidence. The findings suggest a need for further assay standardization and assessment of benign variants to optimize the use of the PS3/BS3 criterion for TBD gene variant classification.
GENETICS IN MEDICINE
(2023)
Article
Biochemical Research Methods
Nathan P. Williams, Carlos H. M. Rodrigues, Jia Truong, David B. Ascher, Jessica K. Holien
Summary: In this study, a efficient Siamese graph-based neural network method called DockNet is proposed for predicting contact residues between two interacting proteins. Unlike other methods, DockNet incorporates the entire protein structure and does not limit protein flexibility during the interaction. Using diverse input node features such as residue type, surface accessibility, residue depth, secondary structure, pharmacophore, and torsional angles, predictions are made at the residue level. DockNet achieves comparable performance to current state-of-the-art methods, with an area under the curve (AUC) value of up to 0.84 on an independent test set (DB5), and can be applied to various protein structures even when accurate unbound protein structures cannot be obtained.