Search Results (20)

The paradigm of craniomaxillofacial (CMF) reconstruction is shifting from traditional bone grafting and biochemical adjuncts toward a nucleomechanical framework that leverages the cell nucleus as a mechanosensitive organelle. By utilizing computer-aided design and computer-aided manufacturing (CAD/CAM)-derived scaffolds with 10 µm micropillar arrays and specific interfacial stiffness (25–40 kPa), surgeons can physically manipulate the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex to achieve a nuclear aspect ratio above 2.5. This structural deformation mechanically expands nuclear pores to trigger cytoskeletal and molecular responses, such as Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) translocation. Resultantly, this physical tension pulls open chromatin fibers to activate master osteogenic regulators like RUNX2, effectively bypassing the risks and limitations associated with supraphysiologic growth factor delivery (e.g., rhBMP-2). Clinically, translating these principles involves moving away from absolute rigid internal fixation toward advanced resorbable biomaterials that permit controlled micro-motions (100–200 µm) under functional masticatory loads. This review provides a structured synthesis of the field, outlining deterministic topographic criteria, clinical boundary conditions, and the potential strategies needed to overcome age-related mechanosensory blockades. Ultimately, we establish a multidisciplinary framework that bridges precision bioengineering with native oral and maxillofacial surgical realities to drive living, biophysically mediated bone repair. Full article

Life is defined by self-governing networks of molecules that change conformation cyclically, converting thermodynamic motion into directional work and structure. A spectrum of scale, from nanoscopic to macroscopic, involves a shift from intracellular thermodynamically driven processes (thermal agitation ultimately rooted in quantum phenomena) to intercellular bulk flows described by classical physics; from short-distance transport involving diffusion and cytoskeletal transport to long-distance pressure fluxes in hydraulic networks. A review of internal transport systems in macroscopic eukaryotes suggests that a key evolutionary step favoring large size and multicellularity involved exploiting molecular-scale stochasticity to generate organized bulk flows (e.g., motor proteins collectively generating mechanical pressures in metazoan tissues such as cardiac muscle; within tracheophytes, active and passive phloem loading/unloading inducing pressure gradients, and active regulation enabling passive xylem function and hydraulic reliability; sieve-like conduction in heterokonts; and peristaltic shuttle streaming in myxogastrian plasmodia). Macroscopic physiologies are underpinned by Brownian molecular thermodynamics and thus quantum mechanics; the apparently disparate physiologies of large organisms share a fundamental operating principle at small scales. However, the specific translocation mechanisms that extend this functioning to larger scales are embroiled in bauplans, representing phylogenetic constraints to body size. Full article

In healthy cells, the cytomatrix mechanics utilize mitochondrial respiration to control cytosolic motion and fine-tune the chemical processes. In cancer, the cytosolic motion is energized by glycolytic fermentation (the Warburg effect), which provides additional energy to supply the needs of the cytomatrix. Here, we describe the physical and chemical processes of the integrated and cooperative cytomatrix cytoarchitecture, in which structure and function are inseparable. The extracellular matrix is interconnected with the intracellular cytomatrix and functions as two integrated elastic solid phases. This finding led us to propose mechanisms of tumor microenvironment formation resulting from the mutational burden, in which altered proteins with corresponding post-translational modifications translocate to the cell surface, where they attract immunocompetent cells and activated fibroblasts, producing a tumor-insulating niche. This insulation disrupts cell-to-cell recognition and other signaling pathways that affect the intracellular cytomatrix, particularly actin dynamics, which influence both cell size and shape, recognized as the dedifferentiated state of cancer cells. We also discuss the perspectives of AI in cytomatrix modeling and neural network modeling, focusing on the effects of intracellular and extracellular matrices on the development of the tumor microenvironment. Full article

Adipose tissue in vivo is physiologically exposed to compound mechanical loading due to bodyweight bearing, posture, and motion. The capability of adipocytes to sense and respond to mechanical loading milieus to influence metabolic functions may provide a new insight into obesity and metabolic diseases such as type 2 diabetes (T2D). Here, we evidenced physiological mechanical loading control of adipocyte insulin signaling cascades. We exposed differentiated 3T3-L1 adipocytes to mechanical stretching and assessed key markers of insulin signaling, AKT activation, and GLUT4 translocation, required for glucose uptake. We showed that cyclic stretch loading at 5% strain and 1 Hz frequency increases AKT phosphorylation and GLUT4 translocation to the plasma membrane by approximately two-fold increases compared to unstretched controls for both markers as assessed by immunoblotting (p < 0.05). These results indicate that cyclic stretching activates insulin signaling and GLUT4 trafficking in adipocytes. In the mechanosensing mechanism study, focal adhesion kinase (FAK) inhibitor (FAK14) and RhoA kinase (ROCK) inhibitor (Y-27632) impaired actin cytoskeleton structural formation and significantly suppressed the stretch induction of AKT phosphorylation in adipocytes (p < 0.001). This suggests the regulatory role of focal adhesion and cytoskeletal mechanosensing in adipocyte insulin signaling under stretch loading. Our finding on the impact of mechanical stretch loading on key insulin signaling effectors in differentiated adipocytes and the mediatory role of focal adhesion and cytoskeleton mechanosensors is the first of its kind to our knowledge. This may suggest a therapeutic potential of mechanical loading cue in improving conditions of obesity and T2D. For instance, cyclic mechanical stretch loading of adipose tissue could be explored as a tool to improve insulin sensitivity in patients with obesity and T2D, and the mediatory mechanosensors such as FAK and ROCK may be targeted to further invigorate stretch-induced insulin signaling activation. Full article

The smooth movement of hand/surgical instruments is considered an indicator of skilled, coordinated surgical performance. Jerky surgical instrument movements or hand tremors can cause unwanted damages to the surgical site. Different methods have been used in previous studies for assessing motion smoothness, causing conflicting results regarding the comparison among surgical skill levels. We recruited four attending surgeons, five surgical residents, and nine novices. The participants conducted three simulated laparoscopic tasks, including peg transfer, bimanual peg transfer, and rubber band translocation. Tooltip motion smoothness was computed using the mean tooltip motion jerk, logarithmic dimensionless tooltip motion jerk, and 95% tooltip motion frequency (originally proposed in this study) to evaluate their capability of surgical skill level differentiation. The results revealed that logarithmic dimensionless motion jerk and 95% motion frequency were capable of distinguishing skill levels, indicated by smoother tooltip movements observed in high compared to low skill levels. Contrarily, mean motion jerk was not able to distinguish the skill levels. Additionally, 95% motion frequency was less affected by the measurement noise since it did not require the calculation of motion jerk, and 95% motion frequency and logarithmic dimensionless motion jerk yielded a better motion smoothness assessment outcome in distinguishing skill levels than mean motion jerk. Full article

Chromosomal translocations are products of the illegitimate repair of DNA double-strand breaks (DSBs). Their formation can bring about significant structural and molecular changes in the cell that can be physiologically and pathologically relevant. The induced changes may lead to serious and life-threatening diseases such as cancer. As a growing body of evidence suggests, the formation of chromosomal translocation is not only affected by the mere close spatial proximity of gene loci as potential translocation partners. Several factors may affect formation of chromosomal translocations, including chromatin motion to the potential sources of DSBs in the cell. While these can be apparently random events, certain chromosomal translocations appear to be cell-type-specific. In this review, we discuss how chromosomal translocations are formed and explore how different cellular factors contribute to their formation. Full article

Clostridium botulinum neurotoxin A (BoNT/A) targets the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, by cleaving synaptosomal-associated protein of 25 kDa size (SNAP-25). Cleavage of SNAP-25 results in flaccid paralysis due to repression of synaptic transmission at the neuromuscular junction. This activity has been exploited to treat a range of diseases associated with hypersecretion of neurotransmitters, with formulations of BoNT/A commercially available as therapeutics. Generally, BoNT activity is facilitated by three essential domains within the molecule, the cell binding domain (H_C), the translocation domain (H_N), and the catalytic domain (LC). The H_C, which consists of an N-terminal (H_CN) and a C-terminal (H_CC) subdomain, is responsible for BoNT’s high target specificity where it forms a dual-receptor complex with synaptic vesicle protein 2 (SV2) and a ganglioside receptor on the surface of motor neurons. In this study, we have determined the crystal structure of botulinum neurotoxin A6 cell binding domain (H_C/A6) in complex with GD1a and describe the interactions involved in ganglioside binding. We also present a new crystal form of wild type H_C/A6 (crystal form II) where a large ‘hinge motion’ between the H_CN and H_CC subdomains is observed. These structures, along with a comparison to the previously determined wild type crystal structure of H_C/A6 (crystal form I), reveals the degree of conformational flexibility exhibited by H_C/A6. Full article

Botulinum neurotoxins (BoNT) are a group of clostridial toxins that cause the potentially fatal neuroparalytic disease botulism. Although highly toxic, BoNTs are utilized as therapeutics to treat a range of neuromuscular conditions. Several serotypes (BoNT/A-/G, /X) have been identified with vastly differing toxicological profiles. Each serotype can be further sub-categorised into subtypes due to subtle variations in their protein sequence. These minor changes have been attributed to differences in both the duration of action and potency for BoNT/A subtypes. BoNTs are composed of three domains—a cell-binding domain, a translocation domain, and a catalytic domain. In this paper, we present the crystal structures of the botulinum neurotoxin A2 cell binding domain, both alone and in complex with its receptor ganglioside GD1a at 1.63 and 2.10 Å, respectively. The analysis of these structures reveals a potential redox-dependent Lys-O-Cys bridge close to the ganglioside binding site and a hinge motion between the H_CN and H_CC subdomains. Furthermore, we make a detailed comparison with the previously reported H_C/A2:SV2C structure for a comprehensive structural analysis of H_C/A2 receptor binding. Full article

A group of seven peptides from spider venom with diverse sequences constitute the latarcin family. They have been described as membrane-active antibiotics, but their lipid interactions have not yet been addressed. Using circular dichroism and solid-state ¹⁵N-NMR, we systematically characterized and compared the conformation and helix alignment of all seven peptides in their membrane-bound state. These structural results could be correlated with activity assays (antimicrobial, hemolysis, fluorescence vesicle leakage). Functional synergy was not observed amongst any of the latarcins. In the presence of lipids, all peptides fold into amphiphilic α-helices as expected, the helices being either surface-bound or tilted in the bilayer. The most tilted peptide, Ltc2a, possesses a novel kind of amphiphilic profile with a coiled-coil-like hydrophobic strip and is the most aggressive of all. It indiscriminately permeabilizes natural membranes (antimicrobial, hemolysis) as well as artificial lipid bilayers through the segregation of anionic lipids and possibly enhanced motional averaging. Ltc1, Ltc3a, Ltc4a, and Ltc5a are efficient and selective in killing bacteria but without causing significant bilayer disturbance. They act rather slowly or may even translocate towards intracellular targets, suggesting more subtle lipid interactions. Ltc6a and Ltc7, finally, do not show much antimicrobial action but can nonetheless perturb model bilayers. Full article

Mobile robots that can survive in unstructured wildernesses is essential in many applications such as environment detecting and security surveillance. In many of these applications, it is highly desirable that the robot can adapt robustly to both terrestrial environment and aquatic environment, and translocate swiftly between various environments. A novel concept of amphibious spherical robot with fins is proposed in this paper, capable of both terrestrial locomotion and aquatic locomotion. Unlike the traditional amphibious robots, whose motions are commonly induced by propellers, legs or snake-like tandem joints, the proposed amphibious spherical robot utilizes the rolling motion of a spherical shell as the principal locomotion mode in the aquatic environment. Moreover, spinning motion of the spherical shell is used to steer the spherical robot efficiently and agilely; several fins are attached to the outer spherical shell as an assistance to the rolling motion. These two motion modes, rolling and spinning, can be used unchangeably in the terrestrial environment, leading to a compact and highly adaptive design of the robot. The work introduced in this paper brings in an innovative solution for the design of an amphibious robot. Full article

A “DNA crunching” linear motor mechanism that employs a grip-and-release transient spring like compression of B- to A-form DNA has been found in our previous studies. Our FRET measurements in vitro show a decrease in distance from TerL to portal during packaging; furthermore, there is a decrease in distance between closely positioned dye pairs in the Y-stem of translocating Y-DNA that conforms to B- and A- structure. In normal translocation into the prohead the TerL motor expels all B-form tightly binding YOYO-1 dye that cannot bind A-form. The TerL motor cannot package A-form dsRNA. Our work reported here shows that addition of helper B form DNA:DNA (D:D) 20mers allows increased packaging of heteroduplex A-form DNA:RNA 20mers (D:R), evidence for a B- to A-form spring motor pushing duplex nucleic acid. A-form DNA:RNA 25mers, 30mers, and 35mers alone are efficiently packaged into proheads by the TerL motor showing that a proposed hypothetical dehydration motor mechanism operating on duplex substrates does not provide the packaging motor force. Taken together with our previous studies showing TerL motor protein motion toward the portal during DNA packaging, our present studies of short D:D and D:R duplex nucleic acid substrates strongly supports our previous evidence that the protein motor pushes rather than pulls or dehydrates duplex substrates to provide the translocation into prohead packaging force. Full article

Polysialic acid (polySia) is an unusual glycan that posttranslational modifies neural cell adhesion molecule (NCAM) proteins in mammalian cells. The up-regulated expression of polySia-NCAM is associated with tumor progression in many metastatic human cancers and in neurocognitive processes. Two members of the ST8Sia family of α2,8-polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST) both catalyze synthesis of polySia when activated cytidine monophosphate(CMP)-Sialic acid (CMP-Sia) is translocate into the lumen of the Golgi apparatus. Two key polybasic domains in the polySTs, the polybasic region (PBR) and the polysialyltransferase domain (PSTD) areessential forpolysialylation of the NCAM proteins. However, the precise molecular details to describe the interactions required for polysialylation remain unknown. In this study, we hypothesize that PSTD interacts with both CMP-Sia and polySia to catalyze polysialylation of the NCAM proteins. To test this hypothesis, we synthesized a 35-amino acid-PSTD peptide derived from the ST8Sia IV gene sequence and used it to study its interaction with CMP-Sia, and polySia. Our results showed for the PSTD-CMP-Sia interaction, the largest chemical-shift perturbations (CSP) were in amino acid residues V251 to A254 in the short H1 helix, located near the N-terminus of PSTD. However, larger CSP values for the PSTD-polySia interaction were observed in amino acid residues R259 to T270 in the long H2 helix. These differences suggest that CMP-Sia preferentially binds to the domain between the short H1 helix and the longer H2 helix. In contrast, polySia was principally bound to the long H2 helix of PSTD. For the PSTD-polySia interaction, a significant decrease in peak intensity was observed in the 20 amino acid residues located between the N-and C-termini of the long H2 helix in PSTD, suggesting a slower motion in these residues when polySia bound to PSTD. Specific features of the interactions between PSTD-CMP-Sia, and PSTD-polySia were further confirmed by comparing their 800 MHz-derived HSQC spectra with that of PSTD-Sia, PSTD-TriSia (DP 3) and PSTD-polySia. Based on the interactions between PSTD-CMP-Sia, PSTD-polySia, PBR-NCAM and PSTD-PBR, these findingsprovide a greater understanding of the molecular mechanisms underlying polySia-NCAM polysialylation, and thus provides a new perspective for translational pharmacological applications and development by targeting the two polysialyltransferases. Full article

Although it is widely accepted that juvenile turtles experience high levels of predation, such events are rarely observed, providing limited evidence regarding predator identities and how juvenile habitat selection and availability of sensory cues to predators affects predation risk. We placed three-dimensional printed models resembling juvenile box turtles (Terrapene carolina) across habitats commonly utilized by the species at three sites within their geographical range and monitored models with motion-triggered cameras. To explore how the presence or absence of visual and olfactory cues affected predator interactions with models, we employed a factorial design where models were either exposed or concealed and either did or did not have juvenile box turtle scent applied on them. Predators interacted with 18% of models during field trials. Nearly all interactions were by mesopredators (57%) and rodents (37%). Mesopredators were more likely to attack models than rodents; most (76%) attacks occurred by raccoons (Procyon lotor). Interactions by mesopredators were more likely to occur in wetlands than edges, and greater in edges than grasslands. Mesopredators were less likely to interact with models as surrounding vegetation height increased. Rodents were more likely to interact with models that were closer to woody structure and interacted with exposed models more than concealed ones, but model exposure had no effect on interactions by mesopredators. Scent treatment appeared to have no influence on interactions by either predator group. Our results suggest raccoons can pose high predation risk for juvenile turtles (although rodents could also be important predators) and habitat features at multiple spatial scales affect predator-specific predation risk. Factors affecting predation risk for juveniles are important to consider in management actions such as habitat alteration, translocation, or predator control. Full article

We developed a finite element model (FEM) of the equine stifle joint to identify pressure peaks and simulate translocation and deformation of the menisci. A series of sectional magnetic resonance images (1.5 T) of the stifle joint of a 23 year old Shetland pony gelding served as basis for image segmentation. Based on the 3D polygon models of femur, tibia, articular cartilages, menisci, collateral ligaments and the meniscotibial ligaments, an FEM model was generated. Tissue material properties were assigned based on data from human (Open knee(s) project) and bovine femoro-tibial joint available in the literature. The FEM model was tested across a range of motion of approximately 30°. Pressure load was overall higher in the lateral meniscus than in the medial. Accordingly, the simulation showed higher translocation and deformation in the lateral compared to the medial meniscus. The results encourage further refinement of this model for studying loading patterns on menisci and articular cartilages as well as the resulting mechanical stress in the subchondral bone (femur and tibia). A functional FEM model can not only help identify segments in the stifle which are predisposed to injury, but also to better understand the progression of certain stifle disorders, simulate treatment/surgery effects and to optimize implant/transplant properties. Full article

Motions of circular and linear DNA molecules of various lengths near a nanopore of 100 or 200 nm diameter were experimentally observed and investigated by fluorescence microscopy. The movement of DNA molecules through nanopores, known as translocation, is mainly driven by electric fields near and inside the pores. We found significant clogging of nanopores by DNA molecules, particularly by circular DNA and linear T4 DNA (165.65 kbp). Here, the probabilities of DNA clogging events, depending on the DNA length and shape—linear or circular—were determined. Furthermore, two distinct DNA motions were observed: clog and release by linear T4 DNA, and a reverse direction motion at the pore entrance by circular DNA, after which both molecules moved away from the pore. Finite element method-based numerical simulations were performed. The results indicated that DNA molecules with pores 100–200 nm in diameter were strongly influenced by opposing hydrodynamic streaming flow, which was further enhanced by bulky DNA configurations. Full article