R Taranath Jayanth, Rebecca Duquette, Shanmukh Kutagulla, Sabrina Pietrosemoli Salazar, Emmanuel Okogbue, Jingyuan Zhou, Patrick Carmichael, Yeonwoong Jung, Xiangfeng Duan, Dmitry Kireev, Stephanie K Seidlits, Deji Akinwande
{"title":"Biocompatibility of large-area two-dimensional electronic materials with neural stem cells.","authors":"R Taranath Jayanth, Rebecca Duquette, Shanmukh Kutagulla, Sabrina Pietrosemoli Salazar, Emmanuel Okogbue, Jingyuan Zhou, Patrick Carmichael, Yeonwoong Jung, Xiangfeng Duan, Dmitry Kireev, Stephanie K Seidlits, Deji Akinwande","doi":"10.1016/j.xcrp.2025.103094","DOIUrl":"10.1016/j.xcrp.2025.103094","url":null,"abstract":"<p><p>Two-dimensional (2D) electronic materials are emerging candidates for flexible neural interfaces, yet their biocompatibility remains unclear because most studies use exfoliated flakes or suspensions. Here, we report a systematic <i>in vitro</i> comparison of large-area, electronics-grade, chemical-vapor-deposited graphene, MoS<sub>2</sub>, PtSe<sub>2</sub>, and PtTe<sub>2</sub>, together with flaky MoS<sub>2</sub> and thin-film metals, as substrates for mouse neural stem cells. All large-area 2D materials support neural stem cell viability and show live-dead and metabolic readouts comparable to laminin-coated glass. Each material also supports robust neuronal differentiation, with extensive βIII-tubulin expression. Flaky MoS<sub>2</sub> uniquely promotes strong neuronal maturation, yielding substantially higher fractions of NeuN-positive neurons, whereas PtSe<sub>2</sub> biases differentiation toward glial lineages, including oligodendrocyte- and astrocyte-like cells. These findings establish large-area 2D materials as biocompatible, tunable platforms for neural interfacing and highlight material format as a key design variable for future bioelectronic devices.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"7 2","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13004282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Computational approaches for RNA structure prediction and design.","authors":"Yuki Kagaya, Boyuan Liu, Daisuke Kihara","doi":"10.1016/j.xcrp.2026.103097","DOIUrl":"10.1016/j.xcrp.2026.103097","url":null,"abstract":"<p><p>Determining the three-dimensional (3D) structure of RNA is crucial for understanding its diverse biological functions. The field of computational RNA structure prediction has recently been transformed by deep learning, which has dramatically improved accuracy beyond that of conventional homology- and <i>de novo</i> modeling approaches. This article overviews these advancements. We first summarize the principles of foundational conventional approaches before detailing the current state-of-the-art deep-learning-based approaches. Deep-learning-based approaches are categorized into strategies that leverage multiple sequence alignments (MSAs), recent MSA-free methods that rely on single sequences, and emerging generalist models that can predict entire heterogenic biomolecular complexes. Furthermore, we discuss how these predictive breakthroughs are accelerating the field of RNA design. Finally, we outline the current challenges and future directions for computational RNA structural biology.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"7 2","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12948162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Raquel González-Novo, Héctor Zamora-Carreras, Marina Armesto, Ana de Lope-Planelles, Horacio López-Menéndez, Pedro Roda-Navarro, Francisco Monroy, Lin Wang, Christopher P Toseland, Javier Redondo-Muñoz
{"title":"3D environment favors persistent changes in cell functions and altered morphology, wrinkling, and biomechanical signature of the nucleus.","authors":"Raquel González-Novo, Héctor Zamora-Carreras, Marina Armesto, Ana de Lope-Planelles, Horacio López-Menéndez, Pedro Roda-Navarro, Francisco Monroy, Lin Wang, Christopher P Toseland, Javier Redondo-Muñoz","doi":"10.1016/j.xcrp.2026.103116","DOIUrl":"https://doi.org/10.1016/j.xcrp.2026.103116","url":null,"abstract":"<p><p>The interplay between cells and their surrounding microenvironment drives multiple cellular functions, including migration, proliferation, and cell fate transitions. The nucleus is a mechanosensitive organelle; however, the morphological and functional changes of the nucleus induced by a three-dimensional (3D) extracellular environment remain unclear. Here, we report that leukemia Jurkat cells selected after 3D growth conditions retain persistent nuclear changes even after being released from confinement. These altered cells showed aberrant nuclear wrinkling, visualized by the lamin B1 distribution and mediated by disrupted actin dynamics and protein kinase C (PKC)β signaling. Moreover, these cells presented changes in chromatin compaction, transcription, apoptosis, and <i>in vivo</i> dissemination. By combining biomechanical techniques and single-nucleus analysis, we have determined that these cells exhibit a distinct nuclear mechanical behavior and biophysical signature compared with control cells. Together, these findings demonstrate that 3D microenvironments alter leukemia cell biology by promoting persistent changes in chromatin organization, morphology, and mechanical response of the nucleus.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"7 2","pages":"103116"},"PeriodicalIF":7.3,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13125699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Robert A Shepherd, Manasa Ramachandra, Austin R Hopiavuori, Melanie C Jones, Conrad A Fihn, Alex J Tabag, Ananya Manjunath, Limar Y Gad, Chloe R Whipple, Shaun M K McKinnie, Laura M Sanchez
{"title":"A high-throughput biocatalytic platform for screening isomeric kainoid natural products.","authors":"Robert A Shepherd, Manasa Ramachandra, Austin R Hopiavuori, Melanie C Jones, Conrad A Fihn, Alex J Tabag, Ananya Manjunath, Limar Y Gad, Chloe R Whipple, Shaun M K McKinnie, Laura M Sanchez","doi":"10.1016/j.xcrp.2025.103092","DOIUrl":"10.1016/j.xcrp.2025.103092","url":null,"abstract":"<p><p>The growing field of biocatalysis relies on the generation of large, genetically diverse libraries for downstream colorimetric, fluorogenic, or chromatographic screening. However, challenges remain when assessing enzyme variants in a high-throughput manner whose transformations yield isomeric low-molecular-weight products. The kainoid synthase subfamily of Fe/αKG-dependent dioxygenases produces the isomeric neurochemicals kainic acid (KA) and KA lactone (KAL) in a range of yields and ratios. To enable an improved throughput screening of engineered kainoid synthases, we developed a matrix-assisted laser desorption/ionization-trapped ion mobility spectrometry-mass spectrometry (MALDI-TIMS-MS) platform to directly detect regioisomeric products with near-baseline resolution from bacterial colonies. Screening of 1,054 genetically diversified KabC variants identified seven with improved KAL formation, while retaining favorable expression profiles and improved <i>in vitro</i> stabilities. This workflow establishes MALDI-TIMS-MS as a promising platform for high-throughput isomeric product screening and provides unique enzyme constructs to probe structure-function relationships and for further biocatalytic development.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"7 2","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12995366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Angana De, Vikas Kumar, W Mark Saltzman, Frank J Slack, Ajit Vikram, Anisha Gupta, Raman Bahal
{"title":"Advances in peptide nucleic acid for targeting RNA and genomic DNA.","authors":"Angana De, Vikas Kumar, W Mark Saltzman, Frank J Slack, Ajit Vikram, Anisha Gupta, Raman Bahal","doi":"10.1016/j.xcrp.2025.103061","DOIUrl":"10.1016/j.xcrp.2025.103061","url":null,"abstract":"<p><p>Peptide nucleic acid (PNA) is a synthetic mimic of DNA where the deoxyribose-phosphodiester backbone is replaced with N-(2-aminoethyl) glycine units. The lack of deoxyribose-phosphodiester bonds enhances enzymatic stability and improves binding affinity of PNA with complementary DNA and RNA strands. To enhance target binding, conformational stability, and pharmacological activity, several chemical modifications have been introduced into PNA. Modified PNAs have demonstrated promising preclinical potential as antisense and anti-gene agents, supporting their use in diverse biomedical applications. The limited <i>in vivo</i> biodistribution and cellular uptake of PNA have significantly hindered its clinical development. Enhancing PNA biodistribution using nanoformulations and bioconjugate-based delivery strategies has resulted in substantial <i>in vivo</i> pharmacological effects. Further, with advancements in chemistry and delivery techniques, PNA holds promise in treating genetic diseases, metabolic disorders, cancers, and infectious diseases. This review summarizes PNA's pharmacological mechanisms, chemical modifications, delivery strategies, and therapeutic applications while addressing limitations for clinical translation.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12916000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kamal Bhandari, Yunxiang Sun, Huayuan Tang, Pu Chu Ke, Feng Ding
{"title":"A global thermodynamic-kinetic model capturing the hallmarks of liquid-liquid phase separation and amyloid aggregation.","authors":"Kamal Bhandari, Yunxiang Sun, Huayuan Tang, Pu Chu Ke, Feng Ding","doi":"10.1016/j.xcrp.2025.103031","DOIUrl":"10.1016/j.xcrp.2025.103031","url":null,"abstract":"<p><p>Amyloid aggregation is associated with numerous neurodegenerative, systemic, and metabolic diseases. Amyloidogenic proteins often undergo liquid-liquid phase separation (LLPS), but the effects of LLPS on amyloid aggregation remain unclear, as contrasting fibrillization promotion and inhibition and even biphasic effects have been reported. Here, we adopt the phase-transition theory and integrate LLPS-induced heterogeneity of protein concentrations into a thermodynamic-kinetic model of aggregation. Oligomerization and fibrillization can occur both in the protein-rich condensates and the protein-poor solution. This model allows us to derive the time evolution of different states-monomers, condensates, oligomers, and fibrils-spanning a wide concentration range, and to determine how parameters governing LLPS, fibrillization, and oligomerization influence fibrillization kinetics, thereby capturing the contrasting features of LLPS driven by either monomers or oligomers. In sum, this global model reconciles the seemingly contradictory effects of LLPS on fibrillization and advances our understanding, modulation, and potential mitigation of pathological aggregation in amyloid diseases.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12927656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sheenagh G Aiken, Daniele Fiorito, Matthew Harper, Grzegorz Pikus, Juno Underhill, Jacob Murray, Joshua Rawlinson, AnnMarie C O'Donoghue, Cecilia Gotti, Sarah C R Lummis, Teresa Minguez Viñas, Franco Viscarra, Isabel Bermudez, Timothy Gallagher, A Sofia F Oliveira
{"title":"Understanding varenicline function via key receptor and ligand interactions.","authors":"Sheenagh G Aiken, Daniele Fiorito, Matthew Harper, Grzegorz Pikus, Juno Underhill, Jacob Murray, Joshua Rawlinson, AnnMarie C O'Donoghue, Cecilia Gotti, Sarah C R Lummis, Teresa Minguez Viñas, Franco Viscarra, Isabel Bermudez, Timothy Gallagher, A Sofia F Oliveira","doi":"10.1016/j.xcrp.2025.102992","DOIUrl":"10.1016/j.xcrp.2025.102992","url":null,"abstract":"<p><p>Approved by the US Food and Drug Administration in 2006, varenicline was the first nicotinic-based therapy for smoking cessation, targeting the α4β2 nicotinic acetylcholine receptor (nAChR). While inspired by cytisine, varenicline has distinct effects at both target and off-target receptors; however, despite being widely used clinically, the precise molecular interactions underpinning varenicline's mode of action remain unclear. Using a multidisciplinary approach, the interactions that set varenicline apart from related compounds such as nicotine and cytisine have been identified. In particular, the binding-site residues α4T139, α4T183, and especially β2S133 were shown to be key modulators for varenicline's function. Substituting β2S133 with valine significantly reduced efficacy, pinpointing it as a crucial determinant. Additionally, a set of novel varenicline variants showed that the positioning of the quinoxaline moiety in varenicline is essential for receptor activation. These insights reveal a unique interaction network at α4β2 that underlies varenicline's function, offering a deeper understanding of the ligand's working mechanism.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 12","pages":"102992"},"PeriodicalIF":7.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12711630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aaron M Love, Christopher G Toomey, Abhishek Kumar, Sukesh Narayan Kashyap, Dhinesh Kumar Santhamoorthy, Likith Muthuraj, Hannah L Lynch, Parayil Kumaran Ajikumar, Kumar R Pravin, Nikhil U Nair, Christine N S Santos
{"title":"Reversal of the Leloir pathway to promote galactose and tagatose synthesis from glucose.","authors":"Aaron M Love, Christopher G Toomey, Abhishek Kumar, Sukesh Narayan Kashyap, Dhinesh Kumar Santhamoorthy, Likith Muthuraj, Hannah L Lynch, Parayil Kumaran Ajikumar, Kumar R Pravin, Nikhil U Nair, Christine N S Santos","doi":"10.1016/j.xcrp.2025.102993","DOIUrl":"10.1016/j.xcrp.2025.102993","url":null,"abstract":"<p><p>D-Tagatose is a low-calorie rare sugar with health benefits as a low-glycemic sweetener. Current production methods are limited, often relying on galactose isomerization, and remain inefficient and costly. Here, we report a whole-cell process in <i>Escherichia coli</i> that converts glucose directly to tagatose by reversing the Leloir pathway. Central to this approach is a galactose-1-phosphate-specific phosphatase that drives equilibrium toward galactose. Computational analyses reveal hydrogen-bond networks that underlie stringent substrate selectivity. By co-expressing this phosphatase with an L-arabinose isomerase in a metabolically engineered strain, we demonstrate direct glucose-to-tagatose conversion. Cultures produced ~10.5 g/L galactose from 30 g/L glucose (35% yield) and >1 g/L tagatose. While this is a proof-of-principle demonstration and further optimization is required to improve tagatose production, this strategy eliminates dependence on lactose-derived galactose and provides a framework for scalable, glucose-based biosynthesis of tagatose and other galactose-derived molecules, supporting sustainable rare-sugar production.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 12","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12875667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}