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19 pages, 6213 KiB  
Article
Studies upon Fluorescent Modulation of Silver Nanoclusters Formed on Bifunctional DNA Template
by Patrycja Filipczuk, Agnieszka Fedoruk-Wyszomirska, Joanna Nowak-Karnowska, Zuzanna Pietralik-Molińska, Ewa Banachowicz, Maciej Kozak and Anna Dembska
Int. J. Mol. Sci. 2025, 26(10), 4914; https://doi.org/10.3390/ijms26104914 - 20 May 2025
Viewed by 540
Abstract
The use of DNA as a scaffold for nanoclusters is particularly interesting due to its structural versatility and easy integration with aptamers. In their structure, aptamers often contain non-canonical forms of DNA, i.e., G-quadruplexes (GQs). Four-stranded GQs are used to construct nanomachines and [...] Read more.
The use of DNA as a scaffold for nanoclusters is particularly interesting due to its structural versatility and easy integration with aptamers. In their structure, aptamers often contain non-canonical forms of DNA, i.e., G-quadruplexes (GQs). Four-stranded GQs are used to construct nanomachines and biosensors for monitoring changes in the concentration of potassium ions. In the present study, we continue our work related to the synthesis of silver nanoclusters formed on a bifunctional DNA template. By attaching a cytosine-rich domain (C12) to a G-quadruplex-forming sequence—human telomeric (Tel22) or thrombin-binding aptamer (TBA)—we constructed bifunctional templates for fluorescent silver nanoclusters (C12) with the ability to detect potassium ions (GQs). The changing localization of the C12 domain from the 3′ to 5′ end of the oligonucleotide was a successful way to improve the fluorescence properties of the obtained fluorescent probes. The best performance as a probe for potassium ions was exhibited by C12Tel22-AgNCs, with an LOD of 0.68 mM in PBS. The introduction of the fluorescent cytosine analog tC leads to an LOD of 0.68 mM in PBS and 0.46 mM in Tris-acetate. Additionally, we performed AFM, TEM, DLS analysis, and cellular studies to further investigate the structural properties and behavior of the Tel22C12-AgNCs in biological contexts. Full article
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13 pages, 3020 KiB  
Article
The Structural Stability of Enzymatic Proteins in the Gas Phase: A Comparison of Semiempirical Hamiltonians and the GFN-FF
by Jarosław J. Panek
Molecules 2025, 30(10), 2131; https://doi.org/10.3390/molecules30102131 - 12 May 2025
Viewed by 489
Abstract
The study of the gas-phase behavior of proteins has recently gained momentum due to numerous prospective applications in, e.g., the construction of molecular sensors or nano-machines. The study of proteins outside their standard water environment, necessary to arrive at their successful applied use, [...] Read more.
The study of the gas-phase behavior of proteins has recently gained momentum due to numerous prospective applications in, e.g., the construction of molecular sensors or nano-machines. The study of proteins outside their standard water environment, necessary to arrive at their successful applied use, is, however, limited by the loss of the structure and function of the macromolecules in the gas phase. We selected two enzymatic proteins with great potential for applied use, the digestive enzyme trypsin and the cytochrome sterol demethylase, for which to develop gas-phase structural models. The employed levels of theory were semiempirical, density functional tight binding, and polarizable force-field techniques. The convergence of the self-consistent field equations was very slow and in most cases led to oscillatory behavior, encouraging careful tuning of the convergence parameters. The structural optimization and molecular dynamics simulations indicated the parts of the proteins most prone to structural distortion under gas-phase conditions with unscreened electrostatics. This problem was more pronounced for cationic trypsin, for which the stability of the simulation was lower. The fate of the hydrogen bonding network of the catalytic triad in the gas phase was also investigated. Full article
(This article belongs to the Special Issue Hydrogen Bond and Intramolecular Force)
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16 pages, 3497 KiB  
Article
Multicomponent DNA Nanomachines for Amplification-Free Viral RNA Detection
by Valeria V. Solyanikova, Daria A. Gorbenko, Valeriya V. Zryacheva, Anna A. Shtro and Maria S. Rubel
Int. J. Mol. Sci. 2025, 26(8), 3652; https://doi.org/10.3390/ijms26083652 - 12 Apr 2025
Viewed by 556
Abstract
The rapid and accurate detection of viral infections is of paramount importance, given their widespread impact across diverse demographics. Common viruses such as influenza, parainfluenza, rhinovirus, and adenovirus contribute significantly to respiratory illnesses. The pathogenic nature of certain viruses, characterized by rapid mutations [...] Read more.
The rapid and accurate detection of viral infections is of paramount importance, given their widespread impact across diverse demographics. Common viruses such as influenza, parainfluenza, rhinovirus, and adenovirus contribute significantly to respiratory illnesses. The pathogenic nature of certain viruses, characterized by rapid mutations and high transmissibility, underscores the urgent need for dynamic detection methodologies. Quantitative reverse transcription PCR (RT-qPCR) remains the gold-standard diagnostic tool. Its reliance on costly equipment, reagents, and skilled personnel has driven explorations of alternative approaches, such as catalytic DNA nanomachines. Diagnostic platforms using catalytic DNA nanomachines offer amplification-free nucleic acid detection without the need for protein enzymes and demonstrate feasibility and cost-effectiveness for both laboratory and point-of-care diagnostics. This study focuses on the development of multicomponent DNA nanomachines with catalytic proficiency towards a fluorescent substrate, enabling the generation of a fluorescent signal upon the presence of target nucleic acids. Specifically tailored variants are designed for detecting human parainfluenza virus type 3 (HPIV) and respiratory syncytial virus (RSV). The engineered DNA nanomachine features six RNA-binding arms for recognition and unwinding of RNA secondary structures, along with a catalytic core for nucleic acid cleavage, indicating potential utility in real clinical practice with minimal requirements. This research showcases the potential of DNA nanomachines as a reliable and sensitive diagnostic tool for RNA virus identification, offering promising prospects for clinical applications in the realm of infectious disease management. Full article
(This article belongs to the Section Molecular Biology)
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35 pages, 3239 KiB  
Review
A Review on AC-Dielectrophoresis of Nanoparticles
by Tonoy K. Mondal, Aaditya V. B. Bangaru and Stuart J. Williams
Micromachines 2025, 16(4), 453; https://doi.org/10.3390/mi16040453 - 11 Apr 2025
Viewed by 3324
Abstract
Dielectrophoresis at the nanoscale has gained significant attention in recent years as a low-cost, rapid, efficient, and label-free technique. This method holds great promise for various interdisciplinary applications related to micro- and nanoscience, including biosensors, microfluidics, and nanomachines. The innovation and development of [...] Read more.
Dielectrophoresis at the nanoscale has gained significant attention in recent years as a low-cost, rapid, efficient, and label-free technique. This method holds great promise for various interdisciplinary applications related to micro- and nanoscience, including biosensors, microfluidics, and nanomachines. The innovation and development of such devices and platforms could promote wider applications in the field of nanotechnology. This review aims to provide an overview of recent developments and applications of nanoparticle dielectrophoresis, where at least one dimension of the geometry or the particles being manipulated is equal to or less than 100 nm. By offering a theoretical foundation to understand the processes and challenges that occur at the nanoscale—such as the need for high field gradients—this article presents a comprehensive overview of the advancements and applications of nanoparticle dielectrophoresis platforms over the past 15 years. This period has been characterized by significant progress, as well as persistent challenges in the manipulation and separation of nanoscale objects. As a foundation for future research, this review will help researchers explore new avenues and potential applications across various fields. Full article
(This article belongs to the Collection Micro/Nanoscale Electrokinetics)
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12 pages, 974 KiB  
Review
How Does the Archaellum Work?
by Morgan Beeby and Bertram Daum
Biomolecules 2025, 15(4), 465; https://doi.org/10.3390/biom15040465 - 21 Mar 2025
Viewed by 648
Abstract
The archaellum is the simplest known molecular propeller. An analogue of bacterial flagella, archaella are long helical tails found in Archaea that are rotated by cell-envelope-embedded rotary motors to exert thrust for cell motility. Despite their simplicity, however, they are less well studied, [...] Read more.
The archaellum is the simplest known molecular propeller. An analogue of bacterial flagella, archaella are long helical tails found in Archaea that are rotated by cell-envelope-embedded rotary motors to exert thrust for cell motility. Despite their simplicity, however, they are less well studied, and how they work remains only partially understood. Here we describe four key aspects of their function: assembly, the transition from assembly to rotation, the mechanics of rotation, and how rotation generates thrust. We outline future research directions that will enhance our understanding of archaellar function. Full article
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12 pages, 2288 KiB  
Article
Cryo-EM Structure of the Flagellar Motor Complex from Paenibacillus sp. TCA20
by Sakura Onoe, Tatsuro Nishikino, Miki Kinoshita, Norihiro Takekawa, Tohru Minamino, Katsumi Imada, Keiichi Namba, Jun-ichi Kishikawa and Takayuki Kato
Biomolecules 2025, 15(3), 435; https://doi.org/10.3390/biom15030435 - 18 Mar 2025
Viewed by 952
Abstract
The bacterial flagellum, a complex nanomachine composed of numerous proteins, is utilized by bacteria for swimming in various environments and plays a crucial role in their survival and infection. The flagellar motor is composed of a rotor and stator complexes, with each stator [...] Read more.
The bacterial flagellum, a complex nanomachine composed of numerous proteins, is utilized by bacteria for swimming in various environments and plays a crucial role in their survival and infection. The flagellar motor is composed of a rotor and stator complexes, with each stator unit functioning as an ion channel that converts flow from outside of cell membrane into rotational motion. Paenibacillus sp. TCA20 was discovered in a hot spring, and a structural analysis was conducted on the stator complex using cryo-electron microscopy to elucidate its function. Two of the three structures (Classes 1 and 3) were found to have structural properties typical for other stator complexes. In contrast, in Class 2 structures, the pentamer ring of the A subunits forms a C-shape, with lauryl maltose neopentyl glycol (LMNG) bound to the periplasmic side of the interface between the A and B subunits. This interface is conserved in all stator complexes, suggesting that hydrophobic ligands and lipids can bind to this interface, a feature that could potentially be utilized in the development of novel antibiotics aimed at regulating cell motility and infection. Full article
(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)
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10 pages, 5208 KiB  
Communication
A DNA-Based Plasmonic Nano-Ruler
by Aura Cencini, Mary Bortoluzzi, Graziano Rilievo, Federica Tonolo, Fabio Vianello, Massimiliano Magro and Alessandro Cecconello
Int. J. Mol. Sci. 2025, 26(6), 2557; https://doi.org/10.3390/ijms26062557 - 12 Mar 2025
Viewed by 818
Abstract
DNA is an exceptional building block for the fabrication of dynamic supramolecular systems with switchable geometries. Here, a self-assembled, tunable plasmonic–fluorescent nanostructure was developed. A precise sliding motion mechanism was operated through the control of strand displacement reactions, shifting two single-strand DNA (ssDNA) [...] Read more.
DNA is an exceptional building block for the fabrication of dynamic supramolecular systems with switchable geometries. Here, a self-assembled, tunable plasmonic–fluorescent nanostructure was developed. A precise sliding motion mechanism was operated through the control of strand displacement reactions, shifting two single-strand DNA (ssDNA) rails connected by a ssDNA quasi-ring structure. The system was reconfigured as a nano-mechanical structure, generating six discrete configurations, and setting specific distances between a tethered gold nanoparticle (AuNP) and a fluorophore, Sulfo-Cyanine3 (Cy3). Each configuration produced a distinct fluorescence emission intensity via plasmonic quenching/enhancement effects, and therefore the structure behaved as a nano-ruler. To optimize the system, the reversible distance-dependent fluorescence quenching or enhancement phenomena were investigated by testing AuNPs with diameters of 5, 10, and 15 nm, yielding the best performances with 10 nm AuNPs. Furthermore, a geometric model of the system was produced, confirming the observed results. The fluorophore–plasmonic surface positioning, conferred by the DNA ruler, led to a finite state nano-machine with six alternative signal outputs. This mechanism, working as a fluorescent reporter, could find application in a multiple-responsive detection system of single-strand nucleic acids, such as viruses or microRNAs. Full article
(This article belongs to the Section Molecular Biophysics)
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9 pages, 1672 KiB  
Proceeding Paper
Algorithm Design for Multicellular Molecular Communication Simulations
by Shohei Imanaka and Tadashi Nakano
Eng. Proc. 2025, 89(1), 5; https://doi.org/10.3390/engproc2025089005 - 21 Feb 2025
Viewed by 278
Abstract
Computing interactions among cells is computationally complex in multicellular molecular communication simulations, making the design of efficient algorithms crucial. We review simulation algorithms for computing interactions among cells in multicellular molecular communication simulations. The naïve algorithm, the Cell List algorithm, the Barnes–Hut algorithm, [...] Read more.
Computing interactions among cells is computationally complex in multicellular molecular communication simulations, making the design of efficient algorithms crucial. We review simulation algorithms for computing interactions among cells in multicellular molecular communication simulations. The naïve algorithm, the Cell List algorithm, the Barnes–Hut algorithm, and a hybrid of the Cell List and Barnes–Hut algorithms are explored. Full article
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21 pages, 3970 KiB  
Review
It’s a Small World After All: The Remarkable but Overlooked Diversity of Venomous Organisms, with Candidates Among Plants, Fungi, Protists, Bacteria, and Viruses
by William K. Hayes, Eric C. K. Gren, David R. Nelsen, Aaron G. Corbit, Allen M. Cooper, Gerad A. Fox and M. Benjamin Streit
Toxins 2025, 17(3), 99; https://doi.org/10.3390/toxins17030099 - 20 Feb 2025
Cited by 2 | Viewed by 4008
Abstract
Numerous organisms, including animals, plants, fungi, protists, and bacteria, rely on toxins to meet their needs. Biological toxins have been classified into three groups: poisons transferred passively without a delivery mechanism; toxungens delivered to the body surface without an accompanying wound; and venoms [...] Read more.
Numerous organisms, including animals, plants, fungi, protists, and bacteria, rely on toxins to meet their needs. Biological toxins have been classified into three groups: poisons transferred passively without a delivery mechanism; toxungens delivered to the body surface without an accompanying wound; and venoms conveyed to internal tissues via the creation of a wound. The distinctions highlight the evolutionary pathways by which toxins acquire specialized functions. Heretofore, the term venom has been largely restricted to animals. However, careful consideration reveals a surprising diversity of organisms that deploy toxic secretions via strategies remarkably analogous to those of venomous animals. Numerous plants inject toxins and pathogenic microorganisms into animals through stinging trichomes, thorns, spines, prickles, raphides, and silica needles. Some plants protect themselves via ants as venomous symbionts. Certain fungi deliver toxins via hyphae into infected hosts for nutritional and/or defensive purposes. Fungi can possess penetration structures, sometimes independent of the hyphae, that create a wound to facilitate toxin delivery. Some protists discharge harpoon-like extrusomes (toxicysts and nematocysts) that penetrate their prey and deliver toxins. Many bacteria possess secretion systems or contractile injection systems that can introduce toxins into targets via wounds. Viruses, though not “true” organisms according to many, include a group (the bacteriophages) which can inject nucleic acids and virion proteins into host cells that inflict damage rivaling that of conventional venoms. Collectively, these examples suggest that venom delivery systems—and even toxungen delivery systems, which we briefly address—are much more widespread than previously recognized. Thus, our understanding of venom as an evolutionary novelty has focused on only a small proportion of venomous organisms. With regard to this widespread form of toxin deployment, the words of the Sherman Brothers in Disney’s iconic tune, It’s a Small World, could hardly be more apt: “There’s so much that we share, that it’s time we’re aware, it’s a small world after all”. Full article
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17 pages, 5184 KiB  
Article
Ultrashort Pulse Laser Fabrication and Evaluation of Innovative Resorbable Barbed Sutures
by Karuna Nambi Gowri, Walid Al Asad, Shubha Majumder, Xin Zhao and Martin William King
Polymers 2025, 17(4), 544; https://doi.org/10.3390/polym17040544 - 19 Feb 2025
Viewed by 689
Abstract
Laser micro-machining is a rapidly growing technique to create, manufacture and fabricate microstructures on different materials ranging from metals and ceramics to polymers. Micro- and nano-machining on different materials has been helpful and useful for various biomedical applications. This study focuses on the [...] Read more.
Laser micro-machining is a rapidly growing technique to create, manufacture and fabricate microstructures on different materials ranging from metals and ceramics to polymers. Micro- and nano-machining on different materials has been helpful and useful for various biomedical applications. This study focuses on the micro-machining of innovative barbed sutures using an ultrashort pulse laser, specifically a femtosecond (fs) laser system. Two bioresorbable polymeric materials, namely, catgut and poly (4-hydroxybutyrate) (P4HB), were studied and micro-machined using the femtosecond (fs) laser system. The optimized laser parameter was used to fabricate two different barb geometries, namely, straight and curved barbs. The mechanical properties were evaluated via tensile testing, and the anchoring performance was studied by means of a suture–tissue pull-out protocol using porcine dermis tissue which was harvested from the medial dorsal site. Along with the evaluation of the mechanical and anchoring properties, the thermal characteristics and degradation profiles were assessed and compared against mechanically cut barbed sutures using a flat blade. The mechanical properties of laser-fabricated barbed sutures were significantly improved when compared to the mechanical properties of the traditionally/mechanically cut barbed sutures, while there was not any significant difference in the anchoring properties of the barbed sutures fabricated through either of the fabrication techniques. Based on the differential scanning calorimetry (DSC) results for thermal transitions, there was no major impact on the inherent material properties due to the laser treatment. This was also observed in the degradation results, where both the mechanically cut and laser-fabricated barbed sutures exhibited similar profiles throughout the evaluation time period. It was concluded that switching the fabrication technique from mechanical cutting to laser fabrication would be beneficial in producing a more reproducible and consistent barb geometry with more precision and accuracy. Full article
(This article belongs to the Topic Advanced Biomaterials: Processing and Applications)
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23 pages, 3730 KiB  
Review
SERS-Active Micro/Nanomachines for Biosensing
by Chenbing Li, Wenqing Zhang, Kai Zheng and Jianhe Guo
Biosensors 2025, 15(2), 115; https://doi.org/10.3390/bios15020115 - 16 Feb 2025
Cited by 2 | Viewed by 1726
Abstract
Surface-enhanced Raman spectroscopy (SERS) has emerged as a powerful noninvasive analytical technique with widespread applications in biochemical analysis and biomedical diagnostics. The need for highly sensitive, reproducible, and efficient detection of biomolecules in complex biological environments has driven significant advancements in SERS-based biosensing [...] Read more.
Surface-enhanced Raman spectroscopy (SERS) has emerged as a powerful noninvasive analytical technique with widespread applications in biochemical analysis and biomedical diagnostics. The need for highly sensitive, reproducible, and efficient detection of biomolecules in complex biological environments has driven significant advancements in SERS-based biosensing platforms. In this context, micro/nanomachines (MNMs) have garnered attention as versatile SERS-active substrates due to their unique structural and motional characteristics at the micro- and nanoscale. This review explores the advantages of integrating MNMs with SERS for biosensing, discussing recent technological advances, various propulsion strategies, and their potential in a range of analytical applications. Full article
(This article belongs to the Special Issue The Emerging Techniques in Biosensors and Bioelectronics)
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10 pages, 1118 KiB  
Review
The Bacterial Type III Secretion System as a Broadly Applied Protein Delivery Tool in Biological Sciences
by Liyu Jia and Lihua Zhu
Microorganisms 2025, 13(1), 75; https://doi.org/10.3390/microorganisms13010075 - 3 Jan 2025
Viewed by 2390
Abstract
The type III secretion system (T3SS) is a nano-machine that allows Gram-negative bacteria to alter eukaryotic host biology by directly delivering effector proteins from the bacterial cytoplasm. Protein delivery based on the bacterial T3SS has been widely used in research in biology. This [...] Read more.
The type III secretion system (T3SS) is a nano-machine that allows Gram-negative bacteria to alter eukaryotic host biology by directly delivering effector proteins from the bacterial cytoplasm. Protein delivery based on the bacterial T3SS has been widely used in research in biology. This review explores recent advancements in the structure and function of the T3SS. We explore the molecular underpinnings of the T3SS apparatus, which spans bacterial and host cell membranes, and discuss the intricate transport mechanisms of effector proteins. Furthermore, this review emphasizes the innovative applications of the T3SS in crop biology, where it has been leveraged to study plant–pathogen interactions. By summarizing the current knowledge and recent progress, we underscore the potential of the T3SS as a powerful tool in biological sciences and their implications for future research in plant pathology and agricultural biotechnology. Full article
(This article belongs to the Section Molecular Microbiology and Immunology)
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31 pages, 5629 KiB  
Review
CAR T Cell Nanosymbionts: Revealing the Boundless Potential of a New Dyad
by Juan C. Baena, Lucy M. Pérez, Alejandro Toro-Pedroza, Toshio Kitawaki and Alexandre Loukanov
Int. J. Mol. Sci. 2024, 25(23), 13157; https://doi.org/10.3390/ijms252313157 - 7 Dec 2024
Cited by 2 | Viewed by 2580
Abstract
Cancer treatment has traditionally focused on eliminating tumor cells but faces challenges such as resistance and toxicity. A promising direction involves targeting the tumor microenvironment using CAR T cell immunotherapy, which has shown potential for treating relapsed and refractory cancers but is limited [...] Read more.
Cancer treatment has traditionally focused on eliminating tumor cells but faces challenges such as resistance and toxicity. A promising direction involves targeting the tumor microenvironment using CAR T cell immunotherapy, which has shown potential for treating relapsed and refractory cancers but is limited by high costs, resistance, and toxicity, especially in solid tumors. The integration of nanotechnology into ICAM cell therapy, a concept we have named “CAR T nanosymbiosis”, offers new opportunities to overcome these challenges. Nanomaterials can enhance CAR T cell delivery, manufacturing, activity modulation, and targeting of the tumor microenvironment, providing better control and precision. This approach aims to improve the efficacy of CAR T cells against solid tumors, reduce associated toxicities, and ultimately enhance patient outcomes. Several studies have shown promising results, and developing this therapy further is essential for increasing its accessibility and effectiveness. Our “addition by subtraction model” synthesizes these multifaceted elements into a unified strategy to advance cancer treatment paradigms. Full article
(This article belongs to the Topic New Nanomaterials for Biomedical Applications)
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12 pages, 5223 KiB  
Article
Dynamics of Nanomotors Propelled by Enzyme Cascade Reactions
by Jia-Qi Hu, Rui Zhao, Ru-Fei Cui, Jian-Long Kou and Jiang-Xing Chen
Int. J. Mol. Sci. 2024, 25(23), 12586; https://doi.org/10.3390/ijms252312586 - 23 Nov 2024
Cited by 1 | Viewed by 1266 | Correction
Abstract
Enzyme-powered nanomotors have attracted significant attention in materials science and biomedicine for their biocompatibility, versatility, and the use of biofuels in biological environments. Here, we employ a hybrid mesoscale method combining molecular dynamics and multi-particle collision dynamics (MD–MPC) to study the dynamics of [...] Read more.
Enzyme-powered nanomotors have attracted significant attention in materials science and biomedicine for their biocompatibility, versatility, and the use of biofuels in biological environments. Here, we employ a hybrid mesoscale method combining molecular dynamics and multi-particle collision dynamics (MD–MPC) to study the dynamics of nanomotors powered by enzyme reactions. Two cascade enzymes are constructed to be layered on the same surface of a Janus colloid, providing a confined space that greatly enhances reaction efficiency. Simulations indicate that such a configuration significantly improves the utilization of intermediate products and, consequently, increases the self-propulsion of the Janus motor. By presenting the gradient fields of substrates and products, as well as the hydrodynamics surrounding the motor, we explore the underlying mechanism behind the enhanced autonomous velocity. Additionally, we discuss the improvements in environmental safety of the modified motor, which may shed light on the fabrication of biocatalytic nano-machines in experiments. Full article
(This article belongs to the Section Physical Chemistry and Chemical Physics)
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14 pages, 2284 KiB  
Article
Preamble-Based Noncoherent Synchronization in Molecular Communication: A Machine Learning Approach
by Seok-Hwan Moon, Pankaj Singh and Sung-Yoon Jung
Appl. Sci. 2024, 14(23), 10779; https://doi.org/10.3390/app142310779 - 21 Nov 2024
Viewed by 836
Abstract
In the field of wireless communication, there is growing interest in molecular communication (MC), which integrates nano-, bio-, and communication technologies. Inspired by nature, MC uses molecules to transmit data, especially in environments where EM waves struggle to penetrate. In MC, signals can [...] Read more.
In the field of wireless communication, there is growing interest in molecular communication (MC), which integrates nano-, bio-, and communication technologies. Inspired by nature, MC uses molecules to transmit data, especially in environments where EM waves struggle to penetrate. In MC, signals can be distinguished based on molecular concentration, known as concentrated-encoded molecular communication (CEMC). These molecules diffuse through an MC channel and are received via ligand–receptor binding mechanisms. Synchronization in CEMC is critical for minimizing errors and enhancing communication performance. This study introduces a novel preamble-based noncoherent synchronization method, specifically designed for resource-constrained environments like nanonetworks. The method’s simple, low-complexity structure makes it suitable for nanomachines, while machine learning (ML) techniques are used to improve synchronization accuracy by adapting to the nonlinear characteristics of the channel. The proposed approach leverages ML to achieve robust performance. Simulation results demonstrate a synchronization probability of 0.8 for a transmitter-receiver distance of 1 cm, given a molecular collection time duration four times the pulse duration. These results confirm the significant benefits of integrating ML, showcasing improved synchronization probability and reduced mean square error. The findings contribute to the advancement of efficient and practical MC systems, offering insights into synchronization and error reduction in complex environments. Full article
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