- by Kamanzi, A., Tuckmantel Bido, A., Zhang, Y., Olsen, E., stibbards-lyle, M., Jasinski, M., Gu, Y., Wang, B., Venier-Karzis, M., Berti, R., Jeliazkova, M., Shaheen, C., Leung, J., Cheng, M. H. Y., Cullis, P., Leslie, S.Deciphering the heterogeneity of mRNA-containing lipid nanoparticles (LNPs) is essential for understanding the relationship between their microscopic properties and therapeutic function. Here, by combining alternating laser excitation (ALEX) with Convex Lens-induced Confinement (CLiC) microscopy, we simultaneously measure size, multi-color fluorescence, mRNA payload, and Forster resonance energy transfer (FRET) of individual suspended LNPs containing labeled lipid and mRNA molecules. By varying formulation parameters, including ionizable lipids, formulation buffers, and molecular ratios, we investigated and correlated key microscopic properties for relevant vaccine […]
- by Petalcorin, M. I. R.Life is sustained by the dynamic flow of energy through adenosine triphosphate (ATP), redox carriers such as NADH, and reactive oxygen species (ROS). These molecules not only fuel biochemical reactions but also encode information that regulates gene expression, DNA repair, and replication. Despite decades of biochemical study, the mathematical principles linking cellular energetics to genetic regulation remain unknown. Here we present a hybrid neural-symbolic framework that discovers the governing equations of energy-dependent genetic processes. Using simulated time-series data capturing oscillations […]
- by Ray, S., Roy, T., Acharjee, S., Ghosh, G., Prasad, M., Das, D.Collective cell migration underpins development and disease progression, yet the influence of heterogeneous microenvironments on intercellular forces and migration dynamics remains elusive. Focusing on the chemotactic migration of border cell clusters in Drosophila egg chambers, we present a computational framework that integrates intercellular force dynamics and cell shape changes during large-scale migration, validated with live imaging data. Our model replicates in vivo observations, such as rotations of the cell cluster and its tendency to follow a central path in the […]
- by Aknine, N., Holban, P., Ragaller, F., Carravilla, P., Gurdap, C. O., Cetinkaya, A., Sezgin, E., Klymchenko, A. S.Solvatochromic probes provide microscopic, structural and functional information on their targeted cellular compartments. In this field, the challenge lies in designing probes that are both sufficiently sensitive to environment, and specific in their subcellular localization. Here, we design Prodan-based polarity probes targeting the following organelles: mitochondria, endoplasmic reticulum, Golgi apparatus, lysosomes and lipid droplets. The new probes provide robust organelle targeting, except for the mitochondrial probe, whose targeting ability is cell type dependent. Due to operating range of Prodan fluorophore […]
- by Blazhynska, M., Ansari, N., Lagardere, L., Piquemal, J.-P.Water molecules play a critical role in mediating protein-ligand interactions by forming bridging hydrogen bonds and contributing to ligand solvation. However, their intricate behavior, such as frequent exchange with bulk solvent or persistent stabilization in the binding site, makes the accurate binding free-energy estimation via molecular dynamics-based approaches challenging. Particularly, inadequate sampling of water reorganization might not only bias computed affinities but also obscure key interactions, making adequate rehydration of the binding site violated upon calculations. To address this, we […]
- by Janowska, M. K., Racigh, V., Woods, C. N., Fornasari, M. S., Klevit, R. E.Zinc is an essential metal that supports diverse cellular functions. Zinc exerts its biological activity through protein binding, serving as catalytic cofactors and structural stabilizers of many enzymes, transcription factors, and ubiquitin E3 ligases, among others. Despite total cellular zinc concentrations reaching hundreds of micromolar, free zinc levels are tightly buffered. Elevated free zinc promotes mismetalation and protein aggregation. While zinc is redox-inert, its cysteine-based protein ligands are readily oxidized. Oxidative modification of cysteines leads to zinc dissociation and a […]
- by Marin, M. d. C., Konno, M., Rozenberg, A., Beja, O., Inoue, L.Microbial rhodopsins represent a diverse superfamily of light-sensitive seven-transmembrane proteins with expanding phylogenetic diversity driven by advances in metagenomics. Among these, schizorhodopsins constitute a divergent family originally identified as inward proton pumps from Promethearchaeota (Asgard archaea). Here, we report that in addition to archaeal schizorhodopsins, many members of the family originate from bacteria and detail a comprehensive biophysical characterization of novel schizorhodopsins from Antarctic Minisyncoccota (Patescibacteria) and cyanobacteria, designated as paSzR and psSzR, respectively. Both proteins function as light-driven inward […]
- by Chen, L., Yang, Y.Background: Ca2+-induced Ca2+ release (CICR) has been the prevailing model in cardiomyocytes for over 50 years. However, whether Na+ influx plays a direct role in triggering Ca2+ release has remained unclear. We previously discovered that action potential (AP) phase 0 triggered Ca2+ release while phase 2 regulated the decay phase during the Ca2+ transient (CT). We hypothesized that CICR might only exist under experimental conditions, not during physiological AP cycles. Methods: Simultaneous recordings of ion currents and CT from the […]
- by Kodikara, S. G., Sprunt, S., Balci, H.Liquid crystalline (LC) phases formed by gapped DNA (GDNA) constructs, where two rigid duplexes are connected with a flexible single stranded linker, offer a versatile platform to investigate interactions between DNA molecules. Base pairs containing a locked nucleic acid (LNA-DNA or LNA-LNA pairs) are generally more stable compared to DNA-DNA pairs due to enhanced hydrogen bonding and/or attractive base stacking interactions. In concentrated solutions of GDNA constructs, the stability of terminal base pairs and the base stacking interactions between neighboring […]
- by Wojnowska, M., Flores, V., Yelland, T., Fisher, S. R., Bogucka, A., Stott, K., Walker, D.TonB-dependent uptake systems of Gram-negative bacterial pathogens constitute prominent virulence factors, allowing nutrient acquisition, primarily siderophore-bound iron, to cross the highly impermeable outer membrane (OM). Remarkably, the ferredoxin uptake system (Fus) of Pectobacteriaceae, a group of soft rot-inducing plant pathogens, imports an entire folded host protein into the periplasm and extracts its bound iron for growth. The inner membrane protein FusB, a TonB homologue, plays two roles in facilitating ferredoxin import. First, like other TonBs, it remodels the globular plug […]
- by Xue, W., Wu, J., Bidone, T., Voth, G. A.Microtubules (MTs) are dynamic cytoskeletal filaments composed of – and {beta}-tubulin protein dimers. They are crucial for maintaining cell structure, facilitating intracellular transport, and ensuring proper chromosome segregation among other things. These biological functions are influenced by the dynamic instability of the MT plus-end tip. Recent work has challenged traditional models in which GTP (guanosine-5'-triphosphate) hydrolysis directly regulates microtubule lattice stability. To explore these notions further, in this work, we have constructed, from bottom up, a relatively high resolution coarse-grained […]
- by Weber, K. C., Lu, C., Alvarez, R. V., Pascal, B. D., Glasgow, A.MotivationHydrogen-deuterium exchange/mass spectrometry (HX/MS) is a rapidly expanding technique used to investigate protein conformational ensembles. The growing popularity and utility of HX/MS has driven the development of diverse instrumentation and software, resulting in inconsistent, non-standardized data analysis and representation. Most HX/MS data formats also employ only centroid-level representations of the data rather than full isotopic mass spectra, reducing the information content of the data and limiting downstream quantitative analysis. ResultsInspired by reliable protein structure and genomics data formats, we present […]
- by Lyu, S., Tong, Y., Lin, Q., Ye, Y., Geng, X., Chen, C., Lu, X., Sun, G., Chen, L.N-Acetylglucosamine exists in various forms and linkage patterns within organisms, playing a crucial role in numerous vital biological processes. However, research focusing on {beta}-1,2-linked N-acetylglucosamine within complex biantennary N-glycans on the cell surface remain largely unexplored. Currently, there is a lack of efficient tools and methods capable of directly modifying terminal N-acetylglucosamine on living cells. In this study, we identified a novel {beta}-N-acetylhexosaminidase from Elizabethkingia meningoseptica, which demonstrated favorable enzymatic stability within a pH range of 5-8 and at temperatures […]
- by Kyriazis, V., Gadhe, L., Konstantoulea, K., Louros, N. N., Schymkowitz, J., Rousseau, F.Amyloid fibrils underpin both functional and pathological protein assemblies and exhibit extensive structural polymorphism. More than 600 high-resolution fibril structures are now available across over 50 protein sequences, yet comparative analysis has been hindered by fragmented resources and inconsistent annotation. Here we present Amyloid Explorer, an open-access platform that integrates the complete fibril archive into a standardized, quality-controlled, and thermodynamically annotated framework. Each entry includes residue- and segment-level stability maps, structural quality metrics, and interactive visualization tools. Global analysis across […]
- by Visona, A., Soulan, S., Dieny, B., Morel, R., Nicolas, A.External mechanical stresses acting on cellular compartments critically regulate cell behaviour and can induce cell death. Magnetically actuated particles present a promising strategy to apply such forces in a controlled manner, with potential applications in cancer therapy. In this study, we investigate the effects of actuating vortex magnetic microdiscs on a glioblastoma cell line cultured on soft, biomimetic substrates that mimic in vivo stiffness. Using a Halbach array, we applied either static mechanical compression or a combination of compressive and […]
- by Shi, W., Nguyen, D. T. L., Goh, W. J., Ong, H. T., Tan, R. B., Fu, C., Bershadsky, A., Mogilner, A., Tee, Y. H.The mechanisms underlying both the establishment of mirror symmetry and deviations from it in development of bilateral multicellular organisms remain insufficiently understood. Actin cytoskeletons of individual cells exhibit intrinsic chirality, and a strong correlation exists between single-cell actin fibres chiral organisation and the collective alignment of cells confined to rectangular adhesive islands (2D-microtissues). Here, we demonstrate how multicellular chiral patterns can be inferred from the chiral behaviour of actin fibres in individual cells. By analysing chiral actin systems in cells […]
- by Demir, O., Barros, E. P., Amaro, R. E.p53 is the most important tumor suppressor in humans as well as the most frequently mutated gene found in human cancers with [~]50% of all human tumors bearing p53 missense mutations that leave p53 inactive. Restoring the p53 activity proved to lead to tumor regression even in advanced tumors in mouse models– and thus, is among the most attractive potential strategies for novel cancer therapy. Full-length p53 (fl-p53) consists of 393 residues and multiple domains; some folded and some disordered. […]
- by VERMA, S., Aggarwal, D., ASHAR, M., PANDEY, A. K., SUTRADHAR, A., PANDEY, S., SIRCAR, D., SINGLA, J., KUMAR, P.Enzymatic polyethylene terephthalate (PET) plastic degradation is a promising approach to combat the exploding plastic pollution. EstS1, a pH-tolerant, thermostable esterase, has been previously recognized for its degradation potential against phthalate diester plasticizers. The present study elucidates the exceptional potential of this enzyme to degrade crystalline PET plastic and its primary intermediate, bis(2-hydroxyethyl)terephthalate (BHET), into terephthalate. Kinetic analyses revealed that EstS1 degrades 75% of BHET in 1h, liberating mono(2-hydroxyethyl) terephthalate (MHET) and terephthalate as end products. The co-crystal structure of […]
- by Yang, L., Yu, W., Zeng, X., Dai, Y.The capacity of biomolecular condensates to establish and modulate electrochemical equilibria is emerging as an important functioning mechanism in cellular biochemistry. However, the physical chemistry basis of the electric potentials arising from biomacromolecular phase transitions remains unclear. Here, we show that asymmetry in hydrophobicity, which is a generalizable feature in condensate system, can directly encode an electric potential gradient between the dilute and the dense phases. We demonstrate that using a non-charged intrinsically disordered protein, ion-dependent kosmotropic effect can encode […]
- by Ruppel, A., Woerthmueller, D., Balland, m., Fagotto, F.Cellular force generation and transmission are fundamental processes driving cell migration, division, tissue morphogenesis, and disease progression. Traction Force Microscopy (TFM) and Monolayer Stress Microscopy (MSM) have emerged as essential techniques for quantifying these mechanical processes, but current software solutions are fragmented across multiple platforms with varying degrees of usability and accessibility. Here, we present napariTFM, a comprehensive open-source plugin for the napari image viewer that integrates state-of-the-art algorithms for both TFM and MSM analysis within an intuitive graphical user […]
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