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Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion.
PLoS Biol
January 2025
RNA Virus Replication Laboratory, The Francis Crick Institute, London, United Kingdom.
Coronaviruses express their structural and accessory genes via a set of subgenomic RNAs, whose synthesis is directed by transcription regulatory sequences (TRSs) in the 5' genomic leader and upstream of each body open reading frame. In SARS-CoV-2, the TRS has the consensus AAACGAAC; upon searching for emergence of this motif in the global SARS-CoV-2 sequences, we find that it evolves frequently, especially in the 3' end of the genome. We show well-supported examples upstream of the Spike gene-within the nsp16 coding region of ORF1b-which is expressed during human infection, and upstream of the canonical Envelope gene TRS, both of which have evolved convergently in multiple lineages.
View Article and Find Full Text PDFGranulocyte and Monocyte Adsorption Therapy in Patients With Sepsis: A Feasibility Study.
Artif Organs
January 2025
Laboratory for Immune Response and Regulatory Medicine, Fujita Health University School of Medicine, Toyoake, Japan.
Background: The pathogenesis of sepsis is thought to be linked to a dysregulated immune response, particularly that involving neutrophils. We have developed a granulocyte adsorption column as a "decoy organ," which relocates the massive inflammation in organs in the body to a blood purification column. This study was conducted to assess the safety and experimental effectiveness of granulocyte monocyte adsorption apheresis-direct hemoperfusion (G1-DHP) in the treatment of patients with sepsis, using a prospective, multicenter design.
View Article and Find Full Text PDFA PERTURBATION CELL ATLAS OF HUMAN INDUCED PLURIPOTENT STEM CELLS.
bioRxiv
November 2024
Department of Bioengineering, University of California San Diego, CA, USA.
Towards comprehensively investigating the genotype-phenotype relationships governing the human pluripotent stem cell state, we generated an expressed genome-scale CRISPRi Perturbation Cell Atlas in KOLF2.1J human induced pluripotent stem cells (hiPSCs) mapping transcriptional and fitness phenotypes associated with 11,739 targeted genes. Using the transcriptional phenotypes, we created a minimum distortion embedding map of the pluripotent state, demonstrating rich recapitulation of protein complexes, such as strong co-clustering of MRPL, BAF, SAGA, and Ragulator family members.
View Article and Find Full Text PDFZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer.
Cell Rep
December 2024
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Ludwig Center at Harvard, Boston, MA 02115, USA. Electronic address:
Article Synopsis
- The study identifies KDM5A as an important oncogene in basal breast cancer, showing that its amplification and overexpression can be targeted to suppress cancer cell growth.
- CRISPR knockout screens reveal that deleting the ZBTB7A transcription factor makes cells more sensitive to KDM5 inhibition, while the deletion of RHO-GTPases provides resistance.
- The research highlights the role of ZBTB7A and KDM5A/B in regulating gene expression, particularly regarding NF-κB targets, and links high ZBTB7A levels to poorer treatment responses in triple-negative breast cancer.
Soluble antigen arrays provide increased efficacy and safety over free peptides for tolerogenic immunotherapy.
Front Immunol
June 2024
Columbia Center for Translational Immunology, Department of Medicine and Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY, United States.
Autoantigen-specific immunotherapy using peptides offers a more targeted approach to treat autoimmune diseases, but clinical implementation has been challenging. We previously showed that multivalent delivery of peptides as soluble antigen arrays (SAgAs) efficiently protects against spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse model. Here, we compared the efficacy, safety, and mechanisms of action of SAgAs versus free peptides.
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