Nonequilibrium diffusion of active particles bound to a semiflexible polymer network: Simulations and fractional Langevin equation.

In a viscoelastic environment, the diffusion of a particle becomes non-Markovian due to the memory effect. An open question concerns quantitatively explaining how self-propulsion particles with directional memory diffuse in such a medium. Based on simulations and analytic theory, we address this issue with active viscoelastic systems where an active particle is connected with multiple semiflexible filaments. Our Langevin dynamics simulations show that the active cross-linker displays superdiffusive and subdiffusive athermal motion with a time-dependent anomalous exponent α. In such viscoelastic feedback, the active particle always exhibits superdiffusion with α = 3/2 at times shorter than the self-propulsion time (τA). At times greater than τA, the subdiffusive motion emerges with α bounded between 1/2 and 3/4. Remarkably, active subdiffusion is reinforced as the active propulsion (Pe) is more vigorous. In the high Pe limit, athermal fluctuation in the stiff filament eventually leads to α = 1/2, which can be misinterpreted with the thermal Rouse motion in a flexible chain. We demonstrate that the motion of active particles cross-linking a network of semiflexible filaments can be governed by a fractional Langevin equation combined with fractional Gaussian noise and an Ornstein-Uhlenbeck noise. We analytically derive the velocity autocorrelation function and mean-squared displacement of the model, explaining their scaling relations as well as the prefactors. We find that there exist the threshold Pe (Pe∗) and crossover times (τ∗ and τ†) above which active viscoelastic dynamics emerge on timescales of τ∗≲ t ≲ τ†. Our study may provide theoretical insight into various nonequilibrium active dynamics in intracellular viscoelastic environments.

Metformin Resistance Is Associated with Expression of Inflammatory and Invasive Genes in A549 Lung Cancer Cells.

Metformin, the most commonly used drug for type 2 diabetes, has recently been shown to have beneficial effects in patients with cancer. Despite growing evidence that metformin can inhibit tumor cell proliferation, invasion, and metastasis, studies on drug resistance and its side effects are lacking. Here, we aimed to establish metformin-resistant A549 human lung cancer cells (A549-R) to determine the side effects of metformin resistance. Toward this, we established A549-R by way of prolonged treatment with metformin and examined the changes in gene expression, cell migration, cell cycle, and mitochondrial fragmentation. Metformin resistance is associated with increased G1-phase cell cycle arrest and impaired mitochondrial fragmentation in A549 cells. We demonstrated that metformin resistance highly increased the expression of proinflammatory and invasive genes, including BMP5, CXCL3, VCAM1, and POSTN, using RNA-seq analysis. A549-R exhibited increased cell migration and focal adhesion formation, suggesting that metformin resistance may potentially lead to metastasis during anti-cancer therapy with metformin. Taken together, our findings indicate that metformin resistance may lead to invasion in lung cancer cells.

α-ketoglutarate suppresses immediate early gene expression in cancer cells.

Cancer cells exhibit increased glutamine consumption compared to normal cells, supporting cell survival and proliferation. Glutamine is converted to α-ketoglutarate (αKG), which then enters the tricarboxylic acid cycle to generate ATP. Recently, therapeutic modulation of glutamine metabolism has become an attractive metabolic anti-cancer strategy. However, how synergistic combination therapy is required to overcome glutamine metabolism drug resistance remains elusive. To address this issue, we first investigated the role of αKG in regulating gene expression in several cancer cell lines. Using RNA-seq analysis and histone modification screening, we demonstrated that αKG reduced the expression of the immediate early gene (IEG) in cancer cells in an H3K27 acetylation-dependent manner. Conversely, glutaminase (GLS) inhibitors induce IEG expression in cancer cells. Furthermore, we showed that siRNA knockdown of orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) induces IEG expression. Notably, the NR4A1 agonist cytosporone B sensitizes GLS inhibitor resistance to cancer cell death. Together, these findings indicate that therapeutic targeting of IEG dysregulation by αKG can be a potentially effective anti-cancer therapeutic strategy for glutamine metabolism inhibitors.

Enhanced Long-Term Reliability of Seal DeltaSpot Welded Dissimilar Joint between 6061 Aluminum Alloy and Galvannealed Steel via Excimer Laser Irradiation.

Structural-adhesive-assisted DeltaSpot welding was used to improve the weldability and mechanical properties of dissimilar joints between 6061 aluminum alloy and galvannealed HSLA steel. Evaluation of the spot-weld-bonded surfaces from lap shear tests after long-term exposure to chloride and a humid atmosphere (5% NaCl, 35 °C) indicated that the long-term mechanical reliability of the dissimilar weld in a corrosive environment depends strongly on the adhesive-Al6061 alloy bond strength. Corrosive electrolyte infiltrated the epoxy-based adhesive/Al alloy interface, disrupting the chemical interactions and decreasing the adhesion via anodic undercutting of the Al alloy. Due to localized electrochemical galvanic reactions, the surrounding nugget matrix suffered accelerated anodic dissolution, resulting in an Al6061-T6 alloy plate with degraded adhesive strength and mechanical properties. KrF excimer laser irradiation of the Al alloy before adhesive bonding removed the weakly bonded native oxidic overlayers and altered the substrate topography. This afforded a low electrolyte permeability and prevented adhesive delamination, thereby enhancing the long-term stability of the chemical interactions between the adhesive and Al alloy substrate. The results demonstrate the application of excimer laser irradiation as a simple and environmentally friendly processing technology for robust adhesion and reliable bonding between 6061 aluminum alloy and galvannealed steel.

Anomalous diffusion of active Brownian particles cross-linked to a networked polymer: Langevin dynamics simulation and theory.

Quantitatively understanding the dynamics of an active Brownian particle (ABP) interacting with a viscoelastic polymer environment is a scientific challenge. It is intimately related to several interdisciplinary topics such as the microrheology of active colloids in a polymer matrix and the athermal dynamics of the in vivo chromosomes or cytoskeletal networks. Based on Langevin dynamics simulation and analytic theory, here we explore such a viscoelastic active system in depth using a star polymer of functionality f with the center cross-linker particle being ABP. We observe that the ABP cross-linker, despite its self-propelled movement, attains an active subdiffusion with the scaling ΔR2(t) ∼ tα with α ≤ 1/2, through the viscoelastic feedback from the polymer. Counter-intuitively, the apparent anomaly exponent α becomes smaller as the ABP is driven by a larger propulsion velocity, but is independent of functionality f or the boundary conditions of the polymer. We set forth an exact theory and show that the motion of the active cross-linker is a Gaussian non-Markovian process characterized by two distinct power-law displacement correlations. At a moderate Péclet number, it seemingly behaves as fractional Brownian motion with a Hurst exponent H = α/2, whereas, at a high Péclet number, the self-propelled noise in the polymer environment leads to a logarithmic growth of the mean squared displacement (∼ln t) and a velocity autocorrelation decaying as -t-2. We demonstrate that the anomalous diffusion of the active cross-linker is precisely described by a fractional Langevin equation with two distinct random noises.

Single-molecule observation of ATP-independent SSB displacement by RecO in Deinococcus radiodurans.

Deinococcus radiodurans (DR) survives in the presence of hundreds of double-stranded DNA (dsDNA) breaks by efficiently repairing such breaks. RecO, a protein that is essential for the extreme radioresistance of DR, is one of the major recombination mediator proteins in the RecA-loading process in the RecFOR pathway. However, how RecO participates in the RecA-loading process is still unclear. In this work, we investigated the function of drRecO using single-molecule techniques. We found that drRecO competes with the ssDNA-binding protein (drSSB) for binding to the freely exposed ssDNA, and efficiently displaces drSSB from ssDNA without consuming ATP. drRecO replaces drSSB and dissociates it completely from ssDNA even though drSSB binds to ssDNA approximately 300 times more strongly than drRecO does. We suggest that drRecO facilitates the loading of RecA onto drSSB-coated ssDNA by utilizing a small drSSB-free space on ssDNA that is generated by the fast diffusion of drSSB on ssDNA.

Redistribution of Welding Residual Stresses of Crack Tip Opening Displacement Specimen by Local Compression.

The demand of crack tip opening displacement (CTOD) test which evaluates fracture toughness of a cracked material is very important to ensure the stability of structure under severe service environment. The validity of the CTOD test result is judged using several criterions of the specification standards. One of them is the artificially generated fatigue pre-crack length inside the specimen. For acceptable CTOD test results, fatigue pre-crack must have a reasonable sharp crack front. The propagation of fatigue crack started from the tip of the machined notch, which might have propagated irregularly due to residual stress field. To overcome this problem, test codes suggest local compression method, reversed bending method and stepwise high-R ratio method to reduce the disparity of residual stress distribution inside the specimen. In this paper, the relation between the degree of local compression and distribution of welding residual stress has been analyzed by finite element analyses in order to determine the amount of effective local compression of the test piece. Analysis results show that initial welding residual stress is dramatically varied three-dimensionally while cutting, notch machining and local compressing due to the change of internal restraint force. From the simulation result, the authors find that there is an optimum amount of local compression to modify regularly for generating fatigue pre-crack propagation. In the case of 0.5% compressions of the model width is the most effective for uniforming residual stress distribution.

Range of S-100ß levels during functional endoscopic sinus surgery with moderately controlled hypotension.

The aim of this study is to determine the range of S-100ß levels during functional endoscopic sinus surgery (FESS) when the mean arterial pressure (MAP) was controlled within 60-70 mmHg. After anesthesia induction with propofol and remifentanil, the patient was positioned in the reverse Trendelenburg position and MAP was controlled within 60-70 mmHg during surgery. For the S-100ß assay, blood was taken from a radial arterial catheter before (baseline) and at 20 (T 20) and 60 (T 60) min after setting the reverse Trendelenburg position and controlled hypotension, and at 60 (T post60) min after the end of the operation. In total, 34 patients completed the study. Baseline S-100ß was 0.00837 ± 0.00785 ng/mL. The levels at T 20 and T 60 were 0.02057 ± 0.01739 and 0.01987 ± 0.01145 ng/mL, respectively. The level of T post60 was 0.05436 ± 0.02318 ng/mL. The level at T 20 increased significantly versus the baseline level (P < 0.001); there were no significant differences between T 20 and T 60. The level at T post60 was significantly different versus T 20 and T 60 (P < 0.001). However, all S-100ß levels were within the normal range. S-100ß-a sensitive biomarker of cerebral ischemia-was within the normal range during FESS when moderate hypotension (MAP >60 mmHg) was provided. Thus, moderate hypotension would be seemed to be a safe and effective anesthetic technique for FESS without risk for cerebral ischemia.