Biophysics reviews最新文献

In the modern world, myocardial infarction is one of the most common cardiovascular diseases, which are responsible for around 18 million deaths every year or almost 32% of all deaths. Due to the detrimental effects of COVID-19 on the cardiovascular system, this rate is expected to increase in the coming years. Although there has been some progress in myocardial infarction treatment, translating pre-clinical findings to the clinic remains a major challenge. One reason for this is the lack of reliable and human representative healthy and fibrotic cardiac tissue models that can be used to understand the fundamentals of ischemic/reperfusion injury caused by myocardial infarction and to test new drugs and therapeutic strategies. In this review, we first present an overview of the anatomy of the heart and the pathophysiology of myocardial infarction, and then discuss the recent developments on pre-clinical infarct models, focusing mainly on the engineered three-dimensional cardiac ischemic/reperfusion injury and fibrosis models developed using different engineering methods such as organoids, microfluidic devices, and bioprinted constructs. We also present the benefits and limitations of emerging and promising regenerative therapy treatments for myocardial infarction such as cell therapies, extracellular vesicles, and cardiac patches. This review aims to overview recent advances in three-dimensional engineered infarct models and current regenerative therapeutic options, which can be used as a guide for developing new models and treatment strategies.

The nanoscale organization of functional (bio)molecules on solid substrates with nanoscale spatial resolution and single-molecule control-in both position and orientation-is of great interest for the development of next-generation (bio)molecular devices and assays. Herein, we report the fabrication of nanoarrays of individual proteins (and dyes) via the selective organization of DNA origami on nanopatterned surfaces and with controlled protein orientation. Nanoapertures in metal-coated glass substrates were patterned using focused ion beam lithography; 88% of the nanoapertures allowed immobilization of functionalized DNA origami structures. Photobleaching experiments of dye-functionalized DNA nanostructures indicated that 85% of the nanoapertures contain a single origami unit, with only 3% exhibiting double occupancy. Using a reprogrammed genetic code to engineer into a protein new chemistry to allow residue-specific linkage to an addressable ssDNA unit, we assembled orientation-controlled proteins functionalized to DNA origami structures; these were then organized in the arrays and exhibited single molecule traces. This strategy is of general applicability for the investigation of biomolecular events with single-molecule resolution in defined nanoarrays configurations and with orientational control of the (bio)molecule of interest.

Digital twins employ mathematical and computational models to virtually represent a physical object (e.g., planes and human organs), predict the behavior of the object, and enable decision-making to optimize the future behavior of the object. While digital twins have been widely used in engineering for decades, their applications to oncology are only just emerging. Due to advances in experimental techniques quantitatively characterizing cancer, as well as advances in the mathematical and computational sciences, the notion of building and applying digital twins to understand tumor dynamics and personalize the care of cancer patients has been increasingly appreciated. In this review, we present the opportunities and challenges of applying digital twins in clinical oncology, with a particular focus on integrating medical imaging with mechanism-based, tissue-scale mathematical modeling. Specifically, we first introduce the general digital twin framework and then illustrate existing applications of image-guided digital twins in healthcare. Next, we detail both the imaging and modeling techniques that provide practical opportunities to build patient-specific digital twins for oncology. We then describe the current challenges and limitations in developing image-guided, mechanism-based digital twins for oncology along with potential solutions. We conclude by outlining five fundamental questions that can serve as a roadmap when designing and building a practical digital twin for oncology and attempt to provide answers for a specific application to brain cancer. We hope that this contribution provides motivation for the imaging science, oncology, and computational communities to develop practical digital twin technologies to improve the care of patients battling cancer.

Tetrazine (Tz) is an emerging bioorthogonal ligand that is expected to have applications (e.g., bioimaging) in chemistry and chemical biology. In this review, we highlight the interactions of reduced tetrazine (rTz) derivatives insoluble in aqueous media with biological membrane constituents or their related lipids, such as dipalmitoyl-phosphatidylcholine, dipalmitoyl-phosphatidylethanolamine, dipalmitoyl-phosphatidylglycerol, palmitoyl-sphingomyelin, and cholesterol in the Langmuir monolayer state at the air-water interface. The two-component interaction was thermodynamically elucidated by measuring the surface pressure (π) and molecular area (A) isotherms. The monolayer miscibility between the two components was analyzed using the excess Gibbs energy of mixing and two-dimensional phase diagram. The phase behavior of the binary monolayers was studied using the Brewster angle, fluorescence, and atomic force microscopy. This study discusses the affinities of the rTz moieties for the hydrophilic groups of the lipids used.

Transport of ions and small molecules across the cell membrane against electrochemical gradients is catalyzed by integral membrane proteins that use a source of free energy to drive the energetically uphill flux of the transported substrate. Secondary active transporters couple the spontaneous influx of a "driving" ion such as Na⁺ or H⁺ to the flux of the substrate. The thermodynamics of such cyclical non-equilibrium systems are well understood, and recent work has focused on the molecular mechanism of secondary active transport. The fact that these transporters change their conformation between an inward-facing and outward-facing conformation in a cyclical fashion, called the alternating access model, is broadly recognized as the molecular framework in which to describe transporter function. However, only with the advent of high resolution crystal structures and detailed computer simulations, it has become possible to recognize common molecular-level principles between disparate transporter families. Inverted repeat symmetry in secondary active transporters has shed light onto how protein structures can encode a bi-stable two-state system. Based on structural data, three broad classes of alternating access transitions have been described as rocker-switch, rocking-bundle, and elevator mechanisms. More detailed analysis indicates that transporters can be understood as gated pores with at least two coupled gates. These gates are not just a convenient cartoon element to illustrate a putative mechanism but map to distinct parts of the transporter protein. Enumerating all distinct gate states naturally includes occluded states in the alternating access picture and also suggests what kind of protein conformations might be observable. By connecting the possible conformational states and ion/substrate bound states in a kinetic model, a unified picture emerges in which the symporter, antiporter, and uniporter functions are extremes in a continuum of functionality. As usual with biological systems, few principles and rules are absolute and exceptions are discussed as well as how biological complexity may be integrated in quantitative kinetic models that may provide a bridge from the structure to function.

The cellular proteome is complex and dynamic, with proteins playing a critical role in cell-level biological processes that contribute to homeostasis, stimuli response, and disease pathology, among others. As such, protein analysis and characterization are of extreme importance in both research and clinical settings. In the last few decades, most proteomics analysis has relied on mass spectrometry, affinity reagents, or some combination thereof. However, these techniques are limited by their requirements for large sample amounts, low resolution, and insufficient dynamic range, making them largely insufficient for the characterization of proteins in low-abundance or single-cell proteomic analysis. Despite unique technical challenges, several single-molecule protein sequencing (SMPS) technologies have been proposed in recent years to address these issues. In this review, we outline several approaches to SMPS technologies and discuss their advantages, limitations, and potential contributions toward an accurate, sensitive, and high-throughput platform.

The ability to manipulate the electrophysiology of electrically active cells and tissues has enabled a deeper understanding of healthy and diseased tissue states. This has primarily been achieved via input/output (I/O) bioelectronics that interface engineered materials with biological entities. Stable long-term application of conventional I/O bioelectronics advances as materials and processing techniques develop. Recent advancements have facilitated the development of graphene-based I/O bioelectronics with a wide variety of functional characteristics. Engineering the structural, physical, and chemical properties of graphene nanostructures and integration with modern microelectronics have enabled breakthrough high-density electrophysiological investigations. Here, we review recent advancements in 2D and 3D graphene-based I/O bioelectronics and highlight electrophysiological studies facilitated by these emerging platforms. Challenges and present potential breakthroughs that can be addressed via graphene bioelectronics are discussed. We emphasize the need for a multidisciplinary approach across materials science, micro-fabrication, and bioengineering to develop the next generation of I/O bioelectronics.

Ventricular arrhythmias are the primary cause of sudden cardiac death and one of the leading causes of mortality worldwide. Whole-heart computational modeling offers a unique approach for studying ventricular arrhythmias, offering vast potential for developing both a mechanistic understanding of ventricular arrhythmias and clinical applications for treatment. In this review, the fundamentals of whole-heart ventricular modeling and current methods of personalizing models using clinical data are presented. From this foundation, the authors summarize recent advances in whole-heart ventricular arrhythmia modeling. Efforts in gaining mechanistic insights into ventricular arrhythmias are discussed, in addition to other applications of models such as the assessment of novel therapeutics. The review emphasizes the unique benefits of computational modeling that allow for insights that are not obtainable by contemporary experimental or clinical means. Additionally, the clinical impact of modeling is explored, demonstrating how patient care is influenced by the information gained from ventricular arrhythmia models. The authors conclude with future perspectives about the direction of whole-heart ventricular arrhythmia modeling, outlining how advances in neural network methodologies hold the potential to reduce computational expense and permit for efficient whole-heart modeling.

Phagocytic immune cells can clear pathogens from the body by engulfing them. Bacterial biofilms are communities of bacteria that are bound together in a matrix that gives biofilms viscoelastic mechanical properties that do not exist for free-swimming bacteria. Since a neutrophil is too small to engulf an entire biofilm, it must be able to detach and engulf a few bacteria at a time if it is to use phagocytosis to clear the infection. We recently found a negative correlation between the target elasticity and phagocytic success. That earlier work used time-consuming, manual analysis of micrographs of neutrophils and fluorescent beads. Here, we introduce and validate flow cytometry as a fast and high-throughput technique that increases the number of neutrophils analyzed per experiment by two orders of magnitude, while also reducing the time required to do so from hours to minutes. We also introduce the use of polyacrylamide gels in our assay for engulfment success. The tunability of polyacrylamide gels expands the mechanical parameter space we can study, and we find that high toughness and yield strain, even with low elasticity, also impact the phagocytic success as well as the timescale thereof. For stiff gels with low-yield strain, and consequent low toughness, phagocytic success is nearly four times greater when neutrophils are incubated with gels for 6 h than after only 1 h of incubation. In contrast, for soft gels with high-yield strain and consequent high toughness, successful engulfment is much less time-sensitive, increasing by less than a factor of two from 1 to 6 h incubation.