Amyloid-beta (Aβ) peptide accumulation on blood vessels in the brain is a hallmark of neurodegeneration. While Aβ peptides constrict cerebral arteries and arterioles, their impact on capillaries is less understood. Aβ was recently shown to constrict brain capillaries through pericyte contraction, but whether-and if so how-Aβ affects endothelial cells (ECs) remains unknown. ECs represent the predominant

Intrinsically disordered proteins (IDPs) show structural changes stimulated by changes in external conditions. This study aims to reveal the temperature dependence of the structure and dynamics of the intrinsically disordered region of Hef, one of the typical IDPs, using an integrative approach. Small-angle X-ray scattering (SAXS) and circular dichroism (CD) studies revealed that the radius of gyration

In the circulatory system, the microenvironment surrounding cancer cells is complex and involves multiple coupled factors. We selected two core physical factors, shear stress and hydraulic resistance, and constructed a microfluidic device with dual negative inputs to study the trade-off movement behavior of cancer cells when facing coupled factors. We detected significant shear stress escape phenomena

Cholesterol-enriched plasma membrane domains are known to serve as signaling platforms in a diverse array of cellular processes. However, the link between cholesterol homeostasis and mutant APC-KRas-associated colorectal tumorigenesis remains to be established. Thus, we investigated the impact of Apc-Kras on (i) colonocyte plasma membrane cholesterol homeostasis, order, and receptor nanoclustering

Despite their large functional diversity and poor sequence similarity, tetrameric and pseudo-tetrameric potassium, sodium, calcium and cyclic-nucleotide gated channels, as well as two-pore channels, transient receptor potential channels and ionotropic glutamate receptors share a common folding pattern of the transmembrane (TM) helices in the pore-forming domain. In each subunit or repeat, the pore

The HIV-1 capsid is an irregularly shaped protein complex containing the viral genome and several proteins needed for integration into the host cell genome. Small molecules, such as the drug-like compound PF-3450074 (PF74) and the anionic sugar inositolhexakisphosphate (IP6), are known to impact capsid stability, although the mechanisms through which they do so remain unknown. In this study, we employed

Breast tumors are typically surrounded by extracellular matrix (ECM), which is heterogeneous, not just structurally but also mechanically. Conventional rheometry is inadequate for describing cell-size-level spatial differences in ECM mechanics that are evident at micrometer scales. Optical tweezers and passive microrheometry provide a microscale resolution for the purpose but are incapable of measuring

G-Protein coupled receptors (GPCRs) represent one of the largest classes of therapeutic targets. However, developing successful therapeutics to target GPCRs is a challenging endeavor with many molecules failing during in vivo clinical trials due to a lack of efficacy. The in vitro identification of drug targeted residence time (1/koff) has been suggested to improve prediction of in vivo success. Here

Biological condensates often emerge as a multidroplet state and never coalesce into one large droplet within the experimental timespan. Previous work revealed that the sticker-spacer architecture of biopolymers may dynamically stabilize the multidroplet state. Here, we simulate the condensate coalescence using metadynamics approach and reveal two distinct physical mechanisms underlying the fusion of

In eukaryotic cells, the phospholipid cardiolipin (CL) is a crucial component that influences the function and organization of the mitochondrial inner membrane. In this study, we examined its potential role in passive proton transmembrane flux using unilamellar vesicles composed of natural egg phosphatidylcholine (PC) alone or with the inclusion of 18 or 34 mol % CL. A membrane potential was induced

NOTCH, a single-pass transmembrane protein, plays a crucial role in cell fate determination through cell-to-cell communication. It interacts with two canonical ligands, Delta-like (DLL) and Jagged (JAG), located on neighboring cells to regulate diverse cellular processes. Despite extensive studies on the functional roles of NOTCH and its ligands in cellular growth, the structural details of full-length

Cyanobacteria are responsible for up to 80% of aquatic carbon dioxide fixation and have evolved a specialized carbon concentrating mechanism to increase photosynthetic yield. As such, cyanobacteria are attractive targets for synthetic biology and engineering approaches to address the demands of global energy security, food production, and climate change for an increasing world’s population. The bicarbonate

Under standard physiological conditions, budding relies on asymmetries, including differences in leaflet composition, area, and osmotic conditions, and involves large curvature changes in nanoscale lipid vesicles. So far, the combined impact of asymmetry and high curvatures on budding has remained unknown. Here, using the continuum elastic theory, the budding pathway is detailed under realistic conditions

The accumulation-associated protein (Aap) is the primary determinant of Staphylococcus epidermidis device-related infections. The B-repeat superdomain is responsible for intercellular adhesion that leads to the development of biofilms occurring in such infections. It was recently demonstrated that Zn-induced B-repeat assembly leads to formation of functional amyloid fibrils, which offer strength and

Embryonic development is orchestrated by the action of morphogens, which spread out from a local source and activate, in a field of target cells, different cellular programs based on their concentration gradient. Fibroblast growth factor 8 (Fgf8) is a morphogen with important functions in embryonic organizing centers. It forms a gradient in the extracellular space by free diffusion, interaction with

The SLC (solute carrier) superfamily mediates the passive transport of small molecules across apical and basolateral cell membranes in nearly all tissues. In this paper, we employ bond-graph approaches to develop models of SLC transporters that conserve mass, charge, and energy, respectively, and can be parameterized for a specific cell and tissue type for which the experimental kinetic data are available

Physical spatiotemporal characteristics of cellular cortex dominate cell functions and even determine cell fate. The cellular cortex is able to reorganize to a dynamic steady status with changed stiffnesses once stimulated, and thus alter the physiological and pathological activities of almost all types of cells. TGF-β2, a potent pleiotropic growth factor, plays important roles in cartilage development

Experimentally monitoring the kinematics of branching network growth is a tricky task, given the complexity of the structures generated in three dimensions. One option is to drive the network in such a way as to obtain two-dimensional growth, enabling a collection of independent images to be obtained. The density of the network generates ambiguous structures, such as overlaps and meetings, which hinder

Stomatocyte-discocyte-echinocyte (SDE) transformations in human red blood cells (RBCs) have significant influences on blood dynamics and related disorders. The mechanical properties of the RBC membrane, such as shear modulus and bending elasticity, play crucial roles in determining RBC shapes. Recent biophysical findings reveal that building a comprehensive model capable of describing SDE shape transformations

The cochlea’s mechanical response to sound stimulation is nonlinear, likely due to saturation of the mechanoelectric transduction current that is part of an electromechanical feedback loop. The ability of a second tone or tones to reduce the response to a probe tone is one manifestation of nonlinearity, termed suppression. Using optical coherence tomography to measure motion within the organ of Corti

We review empirical methods that can be used to provide physical descriptions of dynamic cellular processes during development and disease. Our focus will be nonspatial descriptions and the inference of underlying interaction networks including cell-state lineages, gene regulatory networks, and molecular interactions in living cells. Our overarching questions are: How much can we learn from just observing

Chromaffin cells of the adrenal medulla have an important role in the sympathetic stress response. They secrete catecholamines and other hormones into the bloodstream upon stimulation by the neurotransmitter pituitary adenylate cyclase-activating polypeptide (PACAP). PACAP causes a long-lasting and robust secretory response from chromaffin cells. However, the cellular mechanisms by which PACAP causes

The structure and dynamics of the nucleus regulate cellular functions, with shape changes impacting cell motility. Although the nucleus is generally seen as the stiffest organelle in the cell, cells can nevertheless deform the nucleus to large strains by small mechanical stresses. Here, we show that the mechanical response of the cell nucleus exhibits active fluidization that is driven by the BRG1

Rectification, the tendency of bidirectional ionic conductors to favor ion flow in a specific direction, is an intrinsic property of many ion channels and synthetic nanopores. Despite its frequent occurrence in ion channels and its phenomenological explanation using Eyring’s rate theory, a quantitative relationship between the rectified current and the underlying ion-specific and voltage-dependent

Optical tweezer (OT) single-molecule force spectroscopy is a powerful method to map out the energy landscape of biological complexes and has found increasing applications in academic and pharmaceutical research. The dominant method to extract molecular conformation transitions from the thermal diffusion-broadened trajectories of the microscopic OT probes attached to the single molecule of interest

Fluorine-19 is an ideal nucleus for studying biological systems using NMR due to its rarity in biological environments and its favorable magnetic properties. In this work, we used a mixture of monofluorinated palmitic acids (PAs) as tracers to investigate the molecular interaction of the fluorinated drug rosuvastatin in model lipid membranes. More specifically, PAs labeled at the fourth and eighth

Microtubule stability is known to be governed by a stabilizing GTP/GDP-Pi cap, but the exact relation between growth velocity, GTP hydrolysis, and catastrophes remains unclear. We investigate the dynamics of the stabilizing cap through in vitro reconstitution of microtubule dynamics in contact with microfabricated barriers, using the plus-end binding protein GFP-EB3 as a marker for the nucleotide state

Ca2+ blinks measure the exit of Ca2+ from the junctional sarcoplasmic reticulum (JSR) in a cardiac myocyte during a Ca2+ spark. Here, the relationship between experimental blink fluorescence measurements and the [Ca2+] in the JSR is explored using long 3D simulations of diastolic Ca2+ release. For a fast intra-SR Ca2+-activated fluorophore such as Fluo-5N, we show that a simple mathematical formula

It is interesting to find pathologically that leukocytes, especially neutrophils, tend to adhere in the liver sinusoids dominantly but not in the postsinusoidal venules. While both views of receptor-ligand interactions and physical trapping are proposed for mediating leukocyte adhesion in liver sinusoids, integrated investigations for classifying their respective contributions are poorly presented

Cardiomyopathies, often caused by mutations in genes encoding muscle proteins, are traditionally treated by phenotyping hearts and addressing symptoms post irreversible damage. With advancements in genotyping, early diagnosis is now possible, potentially introducing earlier treatment. However, the intricate structure of muscle and its myriad proteins make treatment predictions challenging. Here, we

Most kinesin molecular motors dimerize to move processively and efficiently along microtubules; however, some can maintain processivity even in a monomeric state. Previous studies have suggested that asymmetric potentials between the motor domain and microtubules underlie this motility. In this study, we demonstrate that the kinesin-3 family motor protein KLP-6 can move forward along microtubules as

Recent developments of single-molecule and superresolution microscopies reveal novel spatial-temporal features of various cellular processes with unprecedented details, and greatly facilitate the development of theoretical models. In this review, we synthesize our view of how to meaningfully integrate these experimental approaches with theoretical modeling to obtain deeper understanding of the physical

The nuclear pore complex (NPC) is responsible for the selective transport of biomolecules in and out of the nucleus. This selective feature is achieved through intrinsically disordered proteins, FG-Nups, that are anchored to the inner wall of the NPC. Cargo smaller than approximately 5 nm can rapidly diffuse through the NPC whereas larger cargo is increasingly slowed down. Larger cargos bound to chaperone

T cell-based immunotherapy has recently emerged as a promising strategy to treat cancer, requiring the activation of antigen-directed cytotoxicity to eliminate cancer cells. Mechanical signaling, although often overshadowed by its biochemical counterpart, plays a crucial role in T cell anticancer responses, from activation to cytolytic killing. Rapid advancements in the fields of chemistry, biomaterials

Hirudin is a bioactive small protein that binds thrombin to interrupt the blood clotting cascade. It contains an ordered and a disordered (IDR) region. Conjugating with polyethylene glycol (PEGylation) is an important modification of biopharmaceuticals to improve their lifetime and retention. Here, we studied by molecular dynamics (MD) simulation how hirudin P18 and its PEGylated variant differ in

The dynamics of many macromolecular machines are characterized by chemically mediated structural changes that achieve large-scale functional deployment through local rearrangements of constitutive protein subunits. Motivated by recent high-resolution structural microscopy of a particular class of such machines, contractile injection systems (CISs), we construct a coarse-grained semianalytical model

Cells can dynamically organize reactions through the formation of biomolecular condensates. These viscoelastic networks exhibit complex material properties and mesoscale architectures, including the ability to form multiphase assemblies. It was shown previously that condensates with complex architectures may arise at equilibrium in multicomponent systems or in condensates that were driven out of equilibrium

The flaviviral NS2B/NS3 protease is a conserved enzyme required for flavivirus replication. Its highly dynamic conformation poses major challenges but also offers opportunities for antiviral inhibition. Here, we established a nanopore tweezers-based platform to monitor NS2B/NS3 conformational dynamics in real time. Molecular simulations coupled with single-channel current recording measurements revealed

Synaptotagmin-1 (syt1) functions as the Ca2+-dependent sensor that triggers the rapid and synchronous release of neurotransmitters from neurotransmitter-containing vesicles during neuronal exocytosis. The syt1 protein has two homologous tandem C2 domains that interact with phospholipids in a Ca2+-dependent manner. Despite the crucial role of syt1 in exocytosis, the precise interactions between Ca2+

Supraphysiological shear rates (>2000 s−1) amplify von Willebrand factor unfurling and increase platelet activation and adhesion. These elevated shear rates and shear rate gradients also play a role in shear-induced platelet aggregation (SIPA). The primary objective of this study is to investigate the contributions of major binding receptors to platelet deposition and SIPA in a stenotic model. Microfluidic

Influenza A virus particles assemble at the plasma membrane of infected cells. During assembly all components of the virus come together in a coordinated manner to deform the membrane into a protrusion eventually forming a new, membrane-enveloped virus. Here, we integrate recent molecular insights of this process, particularly concerning the structure of the matrix protein 1 (M1), within a theoretical

Living cells are known to exhibit power-law viscoelastic responses and localized stress relaxation behaviors in the frequency spectrum. However, the precise interplay between molecular-scale cytoskeletal dynamics and macroscale dynamical rheological responses remains elusive. Here, we propose a mechanism-based general theoretical model showing that cytoskeleton dissociation generates a peak in the

Structural biology relies on several powerful techniques, but these tend to be limited in their ability to characterize protein fluctuations and mobility. Overreliance on structural approaches can lead to omission of critical information regarding biological function. Currently there is a need for complementary biophysical methods to visualize these mobile aspects of protein function. Here, we review

Cell-cell communication through direct contact, or juxtacrine signaling, is important in development, disease, and many areas of physiology. Synthetic forms of juxtacrine signaling can be precisely controlled and operate orthogonally to native processes, making them a powerful reductionist tool with which to address fundamental questions in cell-cell communication in vivo. Here, we investigate how

Under physiological conditions, mammalian PIEZO channels (PIEZO1 and PIEZO2) elicit transient currents mostly carried by monovalent and divalent cations. PIEZO1 is also known to permeate chloride ions, with a Cl−/Na+ permeability ratio of about 0.2. Yet, little is known about how anions permeate PIEZO channels. Here, by separately measuring sodium and chloride currents using nonpermanent counterions

The ability of biological systems to withstand and recover from various disruptions, such as spontaneous genetic mutations and environmental damage, largely relies on intricate feedback mechanisms. We theoretically study the mechanical response of an epithelial tissue facing damage in the form of a circular wound. Our model describes a feedback loop between the generation of active forces in the actomyosin

Protein post-translational modifications, such as phosphorylation, are important regulatory signals for diverse cellular functions. In particular, intrinsically disordered protein regions (IDRs) are subject to phosphorylation as a means to modulate their interactions and functions. Toward understanding the relationship between phosphorylation in IDRs and specific functional outcomes, we must consider

The ability of cells to sense and respond to mechanical forces is crucial for navigating their environment and interacting with neighboring cells. Myosin II and cortexillin I form complexes known as contractility kits (CKs) in the cytosol, which facilitate a cytoskeletal response by accumulating locally at the site of inflicted stress. Here, we present a computational model for mechanoresponsiveness

Synaptic vesicle clusters or pools are functionally important constituents of chemical synapses. In the so-called reserve and the active pools, neurotransmitter-loaded synaptic vesicles (SVs) are stored and conditioned for fusion with the synaptic membrane and subsequent neurotransmitter release during synaptic activity. Vesicle clusters can be considered as so-called membraneless compartments, which

T cell receptor (TCR) and peptide-major histocompatibility complex (pMHC) interactions that result in T cell activation are complex and have been distinguished by their equilibrium affinity and kinetic profiles. While prior affinity-based models can successfully predict meaningful TCR-pMHC interactions in many cases, they occasionally fail at identifying TCR-pMHC interactions with low binding affinity

Three analog solvatochromic probes, Laurdan, Prodan, and Acdan, are extensively used in the study of biological sciences. Their locations in lipid membranes vary greatly in depth, and their fluorescence responds to their surrounding environment based on their corresponding locations in the membrane. Utilizing the fluorescence lifetimes (τ) and emission peak positions (λ) acquired from the time-resolved