Cell Reports Physical Science最新文献

{"title":"Nucleation dynamics in amyloid-beta dimerization revealed by single-molecule fingerprinting.","authors":"A K M Kafi, Mathias Bogetoft Danielsen, Shixi Song, Deepak Karna, Sajan Shakya, Jiahao Ji, Yitong Hao, Pelayo Alvarez Penanes, Frank Kjeldsen, Hanbin Mao, Chenguang Lou","doi":"10.1016/j.xcrp.2025.102930","DOIUrl":"10.1016/j.xcrp.2025.102930","url":null,"abstract":"<p><p>The aggregation of amyloid-beta <math><mo>(</mo> <mtext>A</mtext> <mi>β</mi> <mo>)</mo></math> peptides ( <math><mtext>A</mtext> <msub><mrow><mi>β</mi></mrow> <mrow><mn>1</mn> <mo>-</mo> <mn>40</mn></mrow> </msub> </math> or <math><mtext>A</mtext> <msub><mrow><mi>β</mi></mrow> <mrow><mn>1</mn> <mo>-</mo> <mn>42</mn></mrow> </msub> </math> ) is closely related to the pathology of Alzheimer's disease (AD). Soluble oligomers that appear during <math><mtext>A</mtext> <mi>β</mi></math> aggregation are primary neurotoxic species; however, their misfolding kinetics have yet to be determined. Here, we report a bottom-up construction of parallel and antiparallel <math><mtext>A</mtext> <msub><mrow><mi>β</mi></mrow> <mrow><mn>1</mn> <mo>-</mo> <mn>40</mn></mrow> </msub> </math> dimers, the first oligomers formed during <math><mtext>A</mtext> <mi>β</mi></math> aggregation. We apply single-molecule mechanical unfolding in optical tweezers to investigate the dynamic structural evolution of these dimers at the single-amino-acid resolution. We observe three intermediates during the association and dissociation of individual <math><mtext>A</mtext> <msub><mrow><mi>β</mi></mrow> <mrow><mn>1</mn> <mo>-</mo> <mn>40</mn></mrow> </msub> </math> dimers, with the diphenylalanine <math> <mfenced><mrow><mtext>A</mtext> <msub><mrow><mi>β</mi></mrow> <mrow><mn>19</mn> <mo>-</mo> <mn>20</mn></mrow> </msub> </mrow> </mfenced> </math> dimer having the highest formation probability. Our single-molecule fingerprinting method reveals that a known <math><mtext>A</mtext> <mi>β</mi></math> aggregation inhibitor, rosmarinic acid, can reduce <math><mtext>A</mtext> <msub><mrow><mi>β</mi></mrow> <mrow><mn>1</mn> <mo>-</mo> <mn>40</mn></mrow> </msub> </math> dimerization by binding to the <math><mtext>A</mtext> <msub><mrow><mi>β</mi></mrow> <mrow><mn>19</mn> <mo>-</mo> <mn>20</mn></mrow> </msub> </math> site. We anticipate that the molecular tool innovated in our study is extensible to investigating other amyloid aggregations responsible for a myriad of neurodegenerative diseases.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 11","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12949408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324865","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":"Erratum: Non-local Schrödinger diffusion model reveals mechanisms of critical brain dynamics.","authors":"Gustavo Deco, Yonatan Sanz Perl, Morten L Kringelbach","doi":"10.1016/j.xcrp.2025.102936","DOIUrl":"https://doi.org/10.1016/j.xcrp.2025.102936","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1016/j.xcrp.2025.102663.].</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 11","pages":"102936"},"PeriodicalIF":7.3,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12630072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145586248","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":"Upscaling of gaseous alkanes into large-volume commodity chemicals via photocatalytic acylation.","authors":"Akshay M Nair, Sergio Barbeira-Arán, Jose M Malga, Martín Fañanás-Mastral","doi":"10.1016/j.xcrp.2025.102912","DOIUrl":"10.1016/j.xcrp.2025.102912","url":null,"abstract":"<p><p>From a circular economy point of view, the valorization of gaseous alkanes into large-volume commodity chemicals is of the utmost importance. Such protocols would help reduce the current reliance on a petroleum-based economy and contribute to the challenge of reducing greenhouse gas emissions. In this regard, we hereby report a methodology based on dual photoredox/nickel catalysis that enables the direct coupling of gaseous alkanes with a range of acid chlorides. The protocol is operationally simple, proceeds under mild reaction conditions, and features high chemo- and regioselectivity and good functional group tolerance. Of note, this method serves as an efficient tool for the upscaling of feedstock gaseous alkanes into industrially relevant ketones, such as propiophenone, acetophenone, or isobutyrophenone derivatives.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 11","pages":"102912"},"PeriodicalIF":7.3,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12630074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145586203","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":"Conformation-gated binding underlies kinetic asymmetry and negative cooperativity in ATP:cob(I)alamin adenosyltransferase.","authors":"Guangjie Yan, Manhua Pan, Aaron M Keller, Ace George Santiago, Michael Lofgren, Ruma Banerjee, Peng Chen, Tai-Yen Chen","doi":"10.1016/j.xcrp.2025.102768","DOIUrl":"10.1016/j.xcrp.2025.102768","url":null,"abstract":"<p><p>Vitamin B₁₂ (cobalamin) is a high-value yet scarce cofactor critical for metabolic homeostasis, necessitating efficient handling mechanisms. ATP:cob(I)alamin adenosyltransferase (MMAB) plays a central role in synthesizing, delivering, and repairing 5'-deoxyadenosylcobalamin (AdoCbl), but the kinetic mechanisms regulating this process, including negative cooperativity, remain unclear. Using single-molecule relative fluorescence spectroscopy, we reveal that conformation-gated binding mechanism, involving a required structural rearrangement prior to the first cofactor association, dictates MMAB's interaction kinetics. This mechanism slows the association of a second AdoCbl, resulting in strong negative cooperativity, favoring the singly bound state, and optimizing AdoCbl handling. This gating mechanism, supported by direct observation of a kinetic intermediate, also contributes to MMAB's preferential handling of AdoCbl over hydroxocobalamin, highlighting MMAB's effective cofactor utilization, supporting bacterial survival in nutrient-limited environments. Furthermore, our approach offers a platform to study cofactor interactions, including cobalamin sensing and gene regulation, shedding light on bacterial adaptation to nutrient fluctuations.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 8","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12431680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063663","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":"Revealing the catalytic mechanism of the Fe(II)/2-oxoglutarate-dependent human epigenetic modifying enzyme ALKBH5.","authors":"Fathima Hameed Cherilakkudy, Midhun George Thomas, Ann Varghese, Sodiq O Waheed, Anandhu Krishnan, Vincenzo Venditti, Christopher J Schofield, Deyu Li, Christo Z Christov, Tatyana G Karabencheva-Christova","doi":"10.1016/j.xcrp.2025.102779","DOIUrl":"10.1016/j.xcrp.2025.102779","url":null,"abstract":"<p><p>ALKBH5 is one of only two known human non-heme Fe(II)/2-oxoglutarate-dependent oxygenases that catalyze the demethylation of N⁶-methyladenine (m⁶A) in single-stranded mRNA, underscoring its role in diverse cancers. Unlike its homolog, the fat mass and obesity-associated protein (FTO), which oxidizes m⁶A to a stable N⁶-hydroxymethyladenine (hm⁶A) intermediate, ALKBH5 demethylates m⁶A, yielding adenine and formaldehyde as products. Here, we integrate molecular dynamics simulations and quantum mechanics/molecular mechanics methods to elucidate ALKBH5's complete catalytic mechanism. Two post-hydroxylation pathways were evaluated: a proton transfer pathway and a Schiff base formation pathway, with the former emerging as the favored mechanism. We identify second-sphere residues Lys132 and Tyr139 as essential contributors to catalysis and demonstrate how Val191 and Tyr133 modulate activity. Dynamic analyses reveal that correlated motions of structural elements such as nucleotide recognition lids NRL1 and NRL2 and increased flexibility of the NRL2 loop in the hm⁶A intermediate may be critical for efficient demethylation.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 8","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079679","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":"A zirconium-89-labeled antibody-drug conjugate PET probe for noninvasive monitoring of Nectin4 expression in breast cancer and lung cancer.","authors":"Wenpeng Huang, Tianyao Wang, Yutong Liang, Fangfang Chao, Qi Yang, Todd E Barnhart, Jonathan W Engle, Liming Li, Lei Kang, Weibo Cai","doi":"10.1016/j.xcrp.2025.102723","DOIUrl":"10.1016/j.xcrp.2025.102723","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) are aggressive solid tumors with limited treatment options. Nectin cell adhesion molecule 4 (Nectin4) is a tumor-associated antigen frequently overexpressed in these cancers, making it a promising therapeutic and imaging target. Here, we report the development and evaluation of [⁸⁹Zr]Zr-desferrioxamine (DFO)-Padcev, a radiolabeled antibody-drug conjugate targeting Nectin4, for immuno-positron emission tomography (ImmunoPET) imaging. [⁸⁹Zr]Zr-DFO-Padcev is synthesized with a radiochemical yield of 88.87% ± 2.59% and a radiochemical purity above 99%. ImmunoPET imaging successfully visualizes Nectin4-positive tumors in TNBC (MDA-MB-468) and NSCLC (H1975) models as early as 6 h post-injection, with uptake progressively increasing and peaking at 48 h (14.57 ± 1.94 and 9.50 ± 0.76 %ID/g, respectively). Minimal tumor uptake is observed in blocking and Nectin4-negative controls, confirming specificity. Complementary fluorescence imaging further reveals the <i>in vivo</i> distribution of Padcev, providing valuable insights into optimal therapeutic time windows.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 8","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12806174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997354","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":"A percolating path to green iron.","authors":"Subhechchha Paul, Brinthan Kanesalingam, Yan Ma, Julie Villanova, Guillermo Requena, Stanley Chidubem Akpu, Dierk Raabe, Ilenia Battiato, Leora Dresselhaus-Marais","doi":"10.1016/j.xcrp.2025.102729","DOIUrl":"https://doi.org/10.1016/j.xcrp.2025.102729","url":null,"abstract":"<p><p>About 1.9 gigatons of steel is produced every year, emitting 8% (3.6 gigatons) of global CO₂ in the process. More than 50% of the CO₂ emissions come from a single step of steel production, known as ironmaking. Hydrogen-based direct reduction (HyDR) of iron oxide to iron has emerged as an emission-free ironmaking alternative. However, multiple physical and chemical phenomena ranging from nanometers to meters inside HyDR reactors alter the microstructure and pore networks in iron oxide pellets, in ways that resist gaseous transport of H₂/H₂O, slow reaction rates, and disrupt continuous reactor operation. Using synchrotron nano X-ray computed tomography and percolation theory, we quantify the evolution of pores in iron oxide pellets and demonstrate how nanoscale pore connectivity influences micro- and macroscale flow properties such as permeability, diffusivity, and tortuosity. Our modeling framework connects disparate scales and offers opportunities to accelerate HyDR.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 8","pages":"102729"},"PeriodicalIF":7.3,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944480","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":"The Sabatier principle governs the performance of self-sufficient heterogeneous biocatalysts for redox biotransformations.","authors":"Eleftheria Diamanti, Ainhoa Oliden-Sánchez, Daniel Grajales-Hernández, Daniel Andrés-Sanz, Rut Fernández-Marín, Daniel Padro, Jesús Ruíz-Cabello, Ronen Zangi, Fernando López-Gallego","doi":"10.1016/j.xcrp.2025.102694","DOIUrl":"10.1016/j.xcrp.2025.102694","url":null,"abstract":"<p><p>Self-sufficient heterogeneous biocatalysts (ssHBs), in which enzymes and cofactors are coimmobilized on the same support, provide <i>in situ</i> cofactor regeneration and reduce operating costs. However, the underlying mechanisms remain poorly understood. Here, we present a theoretical model for ssHBs consisting of NAD(P)H-dependent dehydrogenases immobilized on porous agarose-based materials with cofactors coimmobilized through electrostatic interactions via a cationic polymer coating. This model links enzyme activity to cofactor-polymer binding thermodynamics and demonstrates that ssHBs obey the Sabatier principle, where maximum catalytic efficiency is achieved at an intermediate binding strength. Adjustment of pH and ionic strength modulates this interaction, and the resulting activity exhibits the predicted volcano plot. Depending on the reaction conditions, electrostatic complexation is influenced, resulting in the formation of a dense, liquid-like phase inside the particles. Our study directly confirms the Sabatier principle in ssHBs and highlights the crucial role of cofactor binding thermodynamics in optimizing biocatalysis for chemical applications.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 7","pages":"102694"},"PeriodicalIF":7.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12267118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673935","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":"The dimerization domain of SARS-CoV-2 nucleocapsid protein is partially disordered and forms a dynamic high-affinity dimer.","authors":"Jasmine Cubuk, J Jeremías Incicco, Kathleen B Hall, Alex S Holehouse, Melissa D Stuchell-Brereton, Andrea Soranno","doi":"10.1016/j.xcrp.2025.102695","DOIUrl":"10.1016/j.xcrp.2025.102695","url":null,"abstract":"<p><p>The SARS-CoV-2 nucleocapsid (N) drives the compaction and packaging of the viral genome. Here, we focused on quantifying the mechanisms that control dimer formation utilizing single-molecule Förster resonance energy transfer to investigate the conformations and energetics of the dimerization domain in the context of the full-length protein. Under monomeric conditions, we observed significantly expanded configurations of the dimerization domain (compared to the folded dimer structure), which is consistent with a dynamic conformational ensemble. The addition of unlabeled protein stabilizes a folded dimer configuration with a high mean transfer efficiency, which is in agreement with predictions based on known structures. Dimerization is characterized by a dissociation constant of ~12 nM at 23°C and is driven by strong enthalpic interactions between the two protein subunits, which originate from the coupled folding and binding. We propose that the retained flexibility of the dimer can affect its interaction with RNA and phase separation propensity.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 7","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12385586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944392","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":"Excitation and polarization of isolated neurons by high-frequency sine waves for temporal interference stimulation.","authors":"Iurii Semenov, Vitalii Kim, Giedre Silkuniene, Andrei G Pakhomov","doi":"10.1016/j.xcrp.2025.102660","DOIUrl":"10.1016/j.xcrp.2025.102660","url":null,"abstract":"<p><p>The capacity of temporal interference (TI) stimulation to target deep brain regions without affecting nearby surface electrodes remains uncertain. Using artifact-free optical recording, we compare excitation patterns and thresholds in hippocampal neurons stimulated by \"pure\" and amplitude-modulated sine waves, representing TI waveforms near electrodes and at the target, respectively. We show that pure 2- and 20-kHz sine waves induce repetitive firing at rates that increase up to 60-90 Hz with stronger electric fields. Beyond this limit, action potentials merge into sustained depolarization, resulting in an excitation block. Modulating the sine waves at 20 Hz aligns firing with amplitude \"beats\" and prevents the excitation block but does not lower excitation thresholds. Thus, off-target TI effects appear unavoidable, though the patterns of neuronal excitation and downstream effects may differ from those at the target. We further analyze membrane charging and relaxation kinetics at nanoscale resolution and confirm an excitation mechanism independent of envelope extraction.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 7","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783605","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}