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Learning the language of antibody hypervariability.
Proc Natl Acad Sci U S A
January 2025
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139.
Protein language models (PLMs) have demonstrated impressive success in modeling proteins. However, general-purpose "foundational" PLMs have limited performance in modeling antibodies due to the latter's hypervariable regions, which do not conform to the evolutionary conservation principles that such models rely on. In this study, we propose a transfer learning framework called Antibody Mutagenesis-Augmented Processing (AbMAP), which fine-tunes foundational models for antibody-sequence inputs by supervising on antibody structure and binding specificity examples.
View Article and Find Full Text PDFEfficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction.
Proc Natl Acad Sci U S A
January 2025
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405.
Dysregulation of GABAergic inhibition is associated with pathological pain. Consequently, enhancement of GABAergic transmission represents a potential analgesic strategy. However, therapeutic potential of current GABA agonists and modulators is limited by unwanted side effects.
View Article and Find Full Text PDFHydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors.
Proc Natl Acad Sci U S A
January 2025
Cancer Biology & Genetics Program, Sloan Kettering Institute, New York, NY 10065.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). These malignancies develop within preexisting benign lesions called plexiform neurofibromas (PNs). PNs are solely driven by biallelic loss eliciting RAS pathway activation, and they respond favorably to MEK inhibitor therapy.
View Article and Find Full Text PDFComputational-aided rational mutation design of pertuzumab to overcome active HER2 mutation S310F through antibody-drug conjugates.
Proc Natl Acad Sci U S A
January 2025
Laboratory of Precision Medicine and Biopharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Recurrent missense mutations in the human epidermal growth factor receptor 2 (HER2) have been identified across various human cancers. Among these mutations, the active S310F mutation in the HER2 extracellular domain stands out as not only oncogenic but also confers resistance to pertuzumab, an antibody drug widely used in clinical cancer therapy, by impeding its binding. In this study, we have successfully employed computational-aided rational design to undertake directed evolution of pertuzumab, resulting in the creation of an evolved pertuzumab variant named Ptz-SA.
View Article and Find Full Text PDFFrom Plant to Pathway: Molecular Mechanisms of Ruscogenin in Preventing Amyloid-Beta Aggregation through Computational and Experimental Approaches.
ACS Chem Neurosci
January 2025
Department of Bioengineering and Biotechnology, Birla Institute of Technology Mesra, Ranchi, Jharkhand 835215, India.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, extracellular amyloid-β (Aβ) plaque accumulation, and intracellular neurofibrillary tangles. Recent efforts to find effective therapies have increased interest in natural compounds with multifaceted effects on AD pathology. This study explores natural compounds for their potential to mitigate AD pathology using molecular docking, ADME screening, and assays, with ruscogenin─a steroidal sapogenin from emerging as a promising candidate.
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