Physical biology最新文献_第2页

Comparative thermodynamic and kinetic properties governing the nucleic acid interactions of CRISPR-Cas9 and Cas12a. 控制CRISPR-Cas9和Cas12a核酸相互作用的比较热力学和动力学性质。

IF 1.6 4区生物学

Physical biology Pub Date : 2026-03-10 DOI: 10.1088/1478-3975/ae4b7f

Camila E Molina, Alexa L Knight, George P Lisi

{"title":"Comparative thermodynamic and kinetic properties governing the nucleic acid interactions of CRISPR-Cas9 and Cas12a.","authors":"Camila E Molina, Alexa L Knight, George P Lisi","doi":"10.1088/1478-3975/ae4b7f","DOIUrl":"10.1088/1478-3975/ae4b7f","url":null,"abstract":"Clustered regularly interspaced short palindromic repeat-associated proteins (CRISPR-Cas) biochemistry has been leveraged for genome editing applications in biochemical research and therapeutics. CRISPR-Cas9 and CRISPR-Cas12a are the two most widely used RNA-guided endonucleases and while Cas9 and Cas12a have a shared function, both have unique biophysical properties that alter their specificity and efficiency. The thermodynamic and kinetic properties governing their molecular interactions, recognition and binding of target DNA, and R-loop formation can differ. In some cases, these critical biophysical metrics have not been resolved. Distinctions between Cas9 and Cas12a enzymes are also prevalent in RNA:DNA hybrid binding affinities, DNA localization relative to the preferred PAM site and the DNA cleavage mechanism. In this review, we examine the thermodynamic and kinetic properties of both endonucleases, focused on the nucleic acid interactions that confer specificity and function. Complementing this biophysical overview, we discuss case studies in disparate model organisms that compare the genome editing and fidelity of Cas9 and Cas12a.","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147318056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanistic modeling predicts efficacy of CISH knockout in tumor-infiltrating lymphocytes with synergistic gene editing. 机制建模预测协同基因编辑在肿瘤浸润淋巴细胞中CISH敲除的功效。

IF 1.6 4区生物学

Physical biology Pub Date : 2026-03-09 DOI: 10.1088/1478-3975/ae4705

Nikolaos Memmos, Kamran Kaveh, Beau R Webber, Branden S Moriarity, David J Odde

{"title":"Mechanistic modeling predicts efficacy of CISH knockout in tumor-infiltrating lymphocytes with synergistic gene editing.","authors":"Nikolaos Memmos, Kamran Kaveh, Beau R Webber, Branden S Moriarity, David J Odde","doi":"10.1088/1478-3975/ae4705","DOIUrl":"10.1088/1478-3975/ae4705","url":null,"abstract":"Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cell therapy, where the lymphocytes of a cancer patient's tumor are harvested, expandedin vitrousing IL-2 stimulation, and then infused back into the patient Rosenberg and Restifo (2015Science34862-68), Bonini and Mondino (2015Eur. J. Immunol.452457-69). However, even with the use of TIL therapy, cancer cells can survive for various reasons, such as poor lymphocyte infiltration into tumors, chronic activation of the T cell receptor and the immunosuppressive tumor microenvironment Morganet al(1976Science1931007-8). Cytokine-inducible SH2-containing (CISH) protein is a negative regulator of T cell activation, and in a recent clinical trial was knocked out in TILs to improve TIL therapy efficacy Rosenberget al(1985J. Exp. Med.1611169-88). A mechanistic signaling pathway model was developed to theoretically evaluate the efficacy ofCISHknockout (CISHKO) in T cell activation and examine potential alternative target genes that can theoretically be targeted using multiplex gene-editing or drugs to further improve T cell activation and function Donohueet al(1984J. Immunol.1322123-8). Based on the results,CISHknockout increases the transcription of activation biomarkers IL-2 and TNF-α, but also inhibitory biomarkers such as PD1 and FasL. Using global sensitivity analysis, we also found thatGSK3B, which is responsible for the deactivation of NFAT, is also predicted to further increase T cell activation when knocked out. In addition, it was predicted thatPDCD1, FASandCTLA4can be knocked out in combination withCISHto further enhance T cell activation and prevent exhaustion and apoptosis.","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146213877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rapid and interpretable protein contact map prediction using a pattern-matching strategy. 使用模式匹配策略的快速和可解释的蛋白质接触图预测。

IF 1.6 4区生物学

Physical biology Pub Date : 2026-02-20 DOI: 10.1088/1478-3975/ae443c

Aysima Hacisuleyman, Dirk Fasshauer

{"title":"Rapid and interpretable protein contact map prediction using a pattern-matching strategy.","authors":"Aysima Hacisuleyman, Dirk Fasshauer","doi":"10.1088/1478-3975/ae443c","DOIUrl":"10.1088/1478-3975/ae443c","url":null,"abstract":"Protein sequence determines structure, function, and dynamics, yet the gap between sequenced proteins and experimentally determined structures continues to widen. While machine learning approaches like AlphaFold2 have transformed structural biology, they require substantial computational resources. Coevolution-based methods such as mutual information (MI) and direct coupling analysis (DCA), such as GREMLIN, offer alternatives but depend on extensive multiple sequence alignments with thousands of homologs. Here, we present a template-based pattern-matching approach that predicts protein contact maps by identifying conserved structural motifs from homologous experimental structures. Our method encodes spatial arrangements of up to five residues within 8.0 Å distance as sequence patterns, then aligns these patterns to query sequences to predict residue-residue contacts. Critically, our approach requires only a modest number of structural templates (typically 50-500) and runs on standard hardware without graphics processing units or high-performance computing clusters, processing proteins in 12-16 min regardless of length. We validated our method on 25 well-characterized protein domains, achieving correlations of 0.735-0.942 with experimental contact maps. Comparative analysis against MI and GREMLIN demonstrated that our method achieved better contact coverage while maintaining comparable accuracy. To demonstrate broader applicability, we tested on 7599 poorly annotated sequences using high-confidence AlphaFold structures as reference, achieving meanF1-score of 0.609 ± 0.095 and accuracy of 0.954 ± 0.036. Our pattern matching approach provides a computationally efficient, interpretable alternative to both deep learning and coevolution-based methods, particularly valuable for proteins with limited sequence homologs or when rapid predictions are needed.","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Thermodynamic uncertainty relation constrains information transmission through cell signaling systems. 热力学不确定性关系约束了细胞信号系统的信息传递。

IF 1.6 4区生物学

Physical biology Pub Date : 2026-02-19 DOI: 10.1088/1478-3975/ae4086

Shreyansh Verma, Vishva Saravanan R, Bhaswar Ghosh

{"title":"Thermodynamic uncertainty relation constrains information transmission through cell signaling systems.","authors":"Shreyansh Verma, Vishva Saravanan R, Bhaswar Ghosh","doi":"10.1088/1478-3975/ae4086","DOIUrl":"10.1088/1478-3975/ae4086","url":null,"abstract":"Biological systems in general operate out of equilibrium, which brings the requirement for a constant supply of energy due to non-equilibrium entropy production. The thermodynamic uncertainty relation (TUR) essentially imposes a bound on the minimum current fluctuation the system can have given an entropy production rate. The fluctuation eventually impacts the signal-to-noise ratio, imposing an upper bound on the information transmission accuracy. In this study, we explore the role of the TUR on the information transmission capacity of a set of cellular signaling systems using coupled mathematical and machine learning approaches on experimental data in yeast under several stress conditions. Cell signaling systems are involved in sensing changes in the environment by activating a set of transcription factors (TFs), which typically diffuse inside the nucleus to trigger transcription of the required genes. However, the inherent stochasticity of the biochemical pathways severely limits the accuracy of estimating the environmental input by the TFs. The application of TUR reveals a general picture of the working principle of the TFs. We find that the activation followed by biased diffusion of TFs toward the nucleus triggers entropy production, which amplifies the magnitude of the overall TF currents toward the nucleus as well as reducing the fluctuations. These outcomes significantly improve the accuracy of information transmission carried out by the TFs following the bound imposed by TUR, leading to a correlation between accuracy and entropy production. However, TUR only imposes an upper bound on accuracy, and the correlation emerges due to the pathway being operated in the linear response regime. Thus, experimental observations coupled with TUR-based theoretical models demonstrate the role of thermodynamic fluctuation and entropy production on cellular information processing.","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Gaussian network model as a framework for allosteric analysis: dynamic distance, edge centrality, and entropy sensitivity in KRAS. 高斯网络模型作为变构分析的框架：KRAS中的动态距离、边缘中心性和熵敏感性。

IF 1.6 4区生物学

Physical biology Pub Date : 2026-02-05 DOI: 10.1088/1478-3975/ae3e49

Burak Erman

{"title":"The Gaussian network model as a framework for allosteric analysis: dynamic distance, edge centrality, and entropy sensitivity in KRAS.","authors":"Burak Erman","doi":"10.1088/1478-3975/ae3e49","DOIUrl":"10.1088/1478-3975/ae3e49","url":null,"abstract":"Allosteric communication in proteins relies on network connectivity patterns that channel conformational signals between distant sites. We introduce a unified mathematical framework based on three complementary measures of network organization derived from a single quantity. The first, the dynamic distanceRij, quantifies the mean-squared relative fluctuation between residue pairs. From this foundation, we derive two further metrics: the edge centrality, which identifies contacts critical for global connectivity by measuring their recurrence across all possible communication pathways, and the entropy sensitivity, which quantifies how perturbations to specific interactions alter system-wide flexibility. The mathematical structure shows that both topological centrality and thermodynamic sensitivity are linear functions of the dynamic distance. This derived unification demonstrates that residue pairs with high dynamic dissimilarity simultaneously function as flexible bottlenecks essential for allosteric communication. Applied to the oncoprotein KRAS, all three measures converge to identify the same residue pairs, corresponding to experimentally known allosteric sites. This convergence provides a unified graph-theoretical explanation for their functional importance. Analysis of the G12D and Q61H mutations and adagrasib binding shows how local perturbations rewire global communication pathways, highlighting specific residue pairs that gain or lose importance as network bottlenecks.","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146066201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular modeling of the orphan SLC6A16 transporter revealed an unusual composition of the substrate transport pathway. 孤儿SLC6A16转运体的分子模型揭示了底物运输途径的不寻常组成。

IF 1.6 4区生物学

Physical biology Pub Date : 2026-02-03 DOI: 10.1088/1478-3975/ae3af9

Tolith Gidaga, Jędrzej Kukułowicz, Martyna Ogos, Marek Bajda

引用次数: 0

Identifying the sources of noise synergy and redundancy in the gene expression of feed-forward loop motif. 识别前馈环基序基因表达中的噪声协同和冗余来源。

IF 1.6 4区生物学

Physical biology Pub Date : 2026-01-30 DOI: 10.1088/1478-3975/ae3a2e

Mintu Nandi, Sudip Chattopadhyay, Suman K Banik

{"title":"Identifying the sources of noise synergy and redundancy in the gene expression of feed-forward loop motif.","authors":"Mintu Nandi, Sudip Chattopadhyay, Suman K Banik","doi":"10.1088/1478-3975/ae3a2e","DOIUrl":"10.1088/1478-3975/ae3a2e","url":null,"abstract":"The propagation of noise through parallel pathways is a characteristic feature of feed-forward loops (FFLs) in genetic networks. Although the contributions of the direct and indirect pathways to output variability have been well characterized, the impact of their joint action arising from their shared input and output remains poorly understood. Here, we identify a cross-interaction noise emerging specifically from this pathway convergence. Using inter-gene correlations, we reveal the regulatory basis of the cross-interaction noise and interpret it as synergy or redundancy in noise propagation. Positive values of cross-interaction noise reflect synergy (noise amplification), while negative values reflect redundancy (noise suppression); a zero value indicates that the parallel pathways act independently. Synergy typically arises in coherent FFLs, whereas redundancy is common in incoherent ones. To quantify this effect, we introduce relative synergy noise, a dimensionless quantity, which captures the magnitude and sign of synergy and redundant noise relative to other noise sources. Further, by systematically tuning intrinsic noise strengths through effective gene expression burst, we find that when the intermediate node exhibits the highest intrinsic noise, it results in a relative synergy noise value approaching zero, indicating pathway independence. In contrast, when intrinsic noises follow a hierarchy in which the input is the most noisy, the intermediate is the least noisy, and the output is in between them, FFLs exhibit the strongest synergy in coherent motifs and the strongest redundancy in incoherent motifs. Furthermore, by relating these synergies and redundancies to dynamical properties such as sign-sensitive delay or response acceleration, the framework offers a statistical lens to interpret the functional roles in cellular decision-making. Our framework, thus, advances the mechanistic understanding of noise propagation in FFLs by quantifying pathway coupling as a measurable and biologically interpretable quantity.","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Physical and chemical considerations for successfulin vitroculture of rust fungi: challenges, insights and novel strategies. 锈菌体外培养成功的物理和化学因素：挑战，见解和新策略。

IF 1.6 4区生物学

Physical biology Pub Date : 2026-01-20 DOI: 10.1088/1478-3975/ae35bd

Sarah Sale, Volker Nock, Ashley Garrill

引用次数: 0

CW ESR spectroscopy and protein spin labeling in membrane biology. 膜生物学中的连续波ESR光谱和蛋白质自旋标记。

IF 1.6 4区生物学

Physical biology Pub Date : 2025-12-30 DOI: 10.1088/1478-3975/ae2db1

Olamide Ishola, Adeyemi Ogunbowale, Emma Abdul-Rahman, Katie Starr, Pengyu Zhu, Peter P Borbat, Elka R Georgieva

{"title":"CW ESR spectroscopy and protein spin labeling in membrane biology.","authors":"Olamide Ishola, Adeyemi Ogunbowale, Emma Abdul-Rahman, Katie Starr, Pengyu Zhu, Peter P Borbat, Elka R Georgieva","doi":"10.1088/1478-3975/ae2db1","DOIUrl":"10.1088/1478-3975/ae2db1","url":null,"abstract":"Biological membranes define cellular and organelle boundaries, and perform vital functions, providing transport, recognition, signaling, and interaction with other cells. These membranes are majorly composed of lipid bilayers and membrane proteins. Membrane proteins perform most membrane functions. Based on their localization, they are classified as integral and peripheral proteins. In this overview, we provide basic information about membrane proteins structure, conformational dynamics, and functions, and outline the methodologies used to produce highly-pure functional membrane proteins forin vitrobiophysical characterizations based on selected examples. To this end, expression of membrane proteins in a host, their extraction, purification and reconstitution in model lipid bilayers are described. Further, biophysical approaches play key role in elucidation of the structure and function of membrane proteins. Our focus here is on the technique of continuous wave electron paramagnetic/spin resonance (CW ESR) spectroscopy applied to spin-labeled membrane proteins. We describe the basic principles of membrane proteins labeling with nitroxide spin labels (paramagnetic tags) and how the CW ESR can be successfully used in elucidating the conformational dynamics of such proteins. We describe the basic principles of the CW ESR technique. The capability of this technique to characterize physiologically relevant conformational dynamics of proteins is demonstrated using two examples of CW ESR studies on spin-labeled human Tau and influenza A M2 proteins. The method is highly suitable to study physiological structure-function relationships of a broad range of proteins, and to explain the malfunctional states of proteins linked to diseases. This review is directed to the broader biophysical community with interest in molecular biophysics of biological membranes.","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The interaction between dynamic ligand signaling and epigenetics in Notch-induced cancer metastasis. notch诱导的肿瘤转移中动态配体信号与表观遗传学的相互作用。

IF 1.6 4区生物学

Physical biology Pub Date : 2025-12-30 DOI: 10.1088/1478-3975/ae2c34

Tianchi Chen, M Ali Al-Radhawi, Herbert Levine, Eduardo D Sontag

{"title":"The interaction between dynamic ligand signaling and epigenetics in Notch-induced cancer metastasis.","authors":"Tianchi Chen, M Ali Al-Radhawi, Herbert Levine, Eduardo D Sontag","doi":"10.1088/1478-3975/ae2c34","DOIUrl":"10.1088/1478-3975/ae2c34","url":null,"abstract":"Metastatic melanoma presents a formidable challenge in oncology due to its high invasiveness and resistance to current treatments. Central to its ability to metastasize is the Notch signaling pathway, which, when activated through direct cell-cell interactions, propels cells into a metastatic state through mechanisms akin to the epithelial-mesenchymal transition (EMT). While the upregulation of miR-222 has been identified as a critical step in this metastatic progression, the mechanism through which this upregulation persists in the absence of active Notch signaling remains unclear. Here we introduce a dynamical system model that integrates miR-222 gene regulation with histone feedback mechanisms. Through computational analysis spanning both sustained and pulsatile ligand inputs, we delineate the non-linear decision boundaries that govern melanoma cell fate transitions, taking into account the dynamics of Notch signaling and the role of epigenetic modifications. Dimensional analysis reduces the 11-parameter system to three critical control groups governing chromatin modification rates and feedback strengths, providing a theoretical framework for parameter selection in the absence of complete kinetic measurements. Global sensitivity analysis identifies PRC2-mediated methylation and KDM5A-mediated demethylation as the dominant control parameters, while stochastic simulations show population heterogeneity consistent with the variable EMT responses observed in cancer cell populations. Our analysis examines the interplay between Notch signaling pathways and epigenetic regulation in dictating melanoma cell fate.","PeriodicalId":20207,"journal":{"name":"Physical biology","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0