Transcription-induced active forces suppress chromatin motion.

The organization of interphase chromosomes in a number of species is starting to emerge thanks to advances in a variety of experimental techniques. However, much less is known about the dynamics, especially in the functional states of chromatin. Some experiments have shown that the motility of individual loci in human interphase chromosome decreases during transcription and increases upon inhibiting transcription. This is a counterintuitive finding because it is thought that the active mechanical force (F) on the order of ten piconewtons, generated by RNA polymerase II (RNAPII) that is presumably transmitted to the gene-rich region of the chromatin, would render it more open, thus enhancing the mobility. We developed a minimal active copolymer model for interphase chromosomes to investigate how F affects the dynamical properties of chromatin. The movements of the loci in the gene-rich region are suppressed in an intermediate range of F and are enhanced at small F values, which has also been observed in experiments. In the intermediate F, the bond length between consecutive loci increases, becoming commensurate with the distance at the minimum of the attractive interaction between nonbonded loci. This results in a transient disorder-to-order transition, leading to a decreased mobility during transcription. Strikingly, the F-dependent change in the locus dynamics preserves the organization of the chromosome at [Formula: see text]. Transient ordering of the loci, which is not found in the polymers with random epigenetic profiles, in the gene-rich region might be a plausible mechanism for nucleating a dynamic network involving transcription factors, RNAPII, and chromatin.

Molecular mechanisms of steric pressure generation and membrane remodeling by disordered proteins.

Cellular membranes, which are densely crowded by proteins, take on an elaborate array of highly curved shapes. Steric pressure generated by protein crowding plays a significant role in shaping membrane surfaces. It is increasingly clear that many proteins involved in membrane remodeling contain substantial regions of intrinsic disorder. These domains have large hydrodynamic radii, suggesting that they may contribute significantly to steric congestion on membrane surfaces. However, it has been unclear to what extent they are capable of generating steric pressure, owing to their conformational flexibility. To address this gap, we use a recently developed sensor based on Förster resonance energy transfer to measure steric pressure generated at membrane surfaces by the intrinsically disordered domain of the endocytic protein, AP180. We find that disordered domains generate substantial steric pressure that arises from both entropic and electrostatic components. Interestingly, this steric pressure is largely invariant with the molecular weight of the disordered domain, provided that coverage of the membrane surface is held constant. Moreover, equivalent levels of steric pressure result in equivalent degrees of membrane remodeling, regardless of protein molecular weight. This result, which is consistent with classical polymer scaling relationships for semi-dilute solutions, helps to explain the molecular and physical origins of steric pressure generation by intrinsically disordered domains. From a physiological perspective, these findings suggest that a broad range of membrane-associated disordered domains are likely to play a significant and previously unknown role in controlling membrane shape.

Comparison between headless compression screws and tension band wires for the fixation of medial malleolar fractures: a prospective randomized trial.

INTRODUCTION: To date, there has been no prospective randomized trial supporting the rationale of the use of headless compression screw (HCS) compared to conventional fixation methods for medial malleolar fractures. This study aimed to prospectively compare the outcomes of the HCS and tension band wire (TBW) for the fixation of medial malleolar fractures. MATERIAL AND METHODS: Sixty patients were randomized to receive either an HCS or a TBW for the fixation of a medial malleolar fracture. Clinical outcomes were assessed using the Olerud-Molander ankle score (OMAS), EuroQoL five-dimensional instrument (EQ-5D) score, visual analog scale (VAS) score, patient satisfaction with implant-related symptoms, operative time, and incision length. Radiographic outcomes were assessed using the presence of nonunion, delayed union, and articular incongruity. Clinical and radiographic assessments were performed at 2 and 6 weeks and 3, 6, and 12 months postoperatively. RESULTS: The OMAS, EQ-5D score, VAS score, and operative time did not differ between the HCS and TBW groups; however, the HCS group had greater satisfaction with implant-related symptoms and smaller incision than the TBW group. There was no difference in the presence of nonunion, delayed union, and articular incongruity. CONCLUSION: HCS fixation for medial malleolar fractures is not inferior to TBW fixation, while reducing implant-related symptoms. These findings suggest that HCS is a viable alternative for the fixation of medial malleolar fractures.

Random First Order Transition Theory for Glassy Dynamics in a Single Condensed Polymer.

The number of compact structures of a single condensed polymer (SCP), with similar free energies, grows exponentially with the degree of polymerization. In analogy with structural glasses (SGs), we expect that at low temperatures chain relaxation should occur by activated transitions between the compact metastable states. By evolving the states of the SCP, linearly coupled to a reference state, we show that, below a dynamical transition temperature (T_{d}), the SCP is trapped in a metastable state leading to slow dynamics. At a lower temperature, T_{K}≠0, the configurational entropy vanishes, resulting in a thermodynamic random first order ideal glass transition. The relaxation time obeys the Vogel-Fulcher-Tamman law, diverging at T=T_{0}≈T_{K}. These findings, accord well with the random first order transition theory, establishing that SCP and SG exhibit similar universal characteristics.

Bone Defects After Surgery for Displaced Intraarticular Calcaneal Fractures Spontaneously Improve Without Bone Grafting.

BACKGROUND: Most intraarticular displaced calcaneal fractures are accompanied by bone defects after surgical treatment, but the concern about negative effects of bone defects has not been resolved yet owing to the few studies on this issue. Therefore, studies on volumetric changes in bone defects over time and the correlation between postoperative outcomes and residual bone defects will be helpful to address the controversy on the necessity of bone grafting in bone defects of calcaneal fractures. QUESTIONS/PURPOSES: (1) Do bone defects change in size in the first year after surgical treatment of displaced intraarticular calcaneal fractures? (2) Does the size of residual bone defects correlate with postoperative radiographic or clinical outcomes? METHODS: Between 2015 and 2019, 99 patients with displaced intraarticular calcaneal fractures visited the investigators' institution, of whom 95 received surgical treatment. Of the patients treated with surgery, 25% (24 of 95) did not undergo open reduction and internal fixation via an extensile lateral approach, and 19% (18 of 95) had multiple fractures, bilateral fractures, open fractures, or a history of previous surgery on the calcaneus; all of these patients were excluded. During the study period, CT was routinely performed for calcaneal fractures immediately after and 12 months after the surgery, but 6% (6 of 95) of the patients had insufficient CT data due to loss to follow-up before 12 months or other reasons, leaving 47 patients for evaluation in this retrospective study. Fractures were fixed with plate and screws, and bone grafting was not performed in all patients. To answer our first question, which was on the changes in bone defects over time, volumetric measurements of the bone defect were performed using CT via the ITK-SNAP software. The percentage of volumetric change was calculated as a fraction of the volumetric change over 12 months from the initial volume. The percentage of the residual bone defect was calculated as a fraction of the volume of the residual bone defect relative to the volume of the entire calcaneus. To answer our second question, which was on the correlation between residual bone defects and postoperative outcomes, we assessed the Böhler angle, Gissane angle, calcaneal height, Olerud-Molander Ankle Score (OMAS), and VAS score for pain and compared these parameters with the size of the residual bone defect using the Pearson correlation coefficient. The OMAS and VAS scores for pain were evaluated and recorded during patient visits, and we obtained the scores through a chart review. All volumetric measurements and radiographic evaluations were performed by two orthopaedic surgeons, and the intraobserver and interobserver reliability were assessed using the intraclass correlation coefficient. RESULTS: The mean volume of the bone defect measured using CT was 4 ± 3 cm3 immediately after surgery and 1 ± 1 cm3 12 months after surgery. During the first 12 months after surgery, the mean volume of the bone defect was reduced by 77% (95% confidence interval 73% to 80%). The mean residual bone defect in the entire calcaneus was 2% (95% CI 1% to 2%), and none of the postoperative outcomes were correlated with the residual bone defect. CONCLUSION: As bone defects substantially resolve without treatment, surgeons do not need to use bone graft for the surgical treatment of displaced intraarticular calcaneal fractures. Future studies that include patients who underwent bone grafting for the treatment of calcaneal fractures are needed to confirm our findings and to further investigate whether bone grafting has additional benefits for the recovery of bone defects. LEVEL OF EVIDENCE: Level III, therapeutic study.

Validation and cross-cultural adaptation of the Korean translation of the Achilles tendon Total Rupture Score.

BACKGROUND: The Achilles tendon Total Rupture Score (ATRS) is a widely used patient-reported outcome measure to assess clinical outcomes of Achilles tendon rupture, but it has not been validated in Korean yet. The purpose of this study was to translate the ATRS into Korean and evaluate its reliability and validity in a Korean population. METHODS: The ATRS was translated into Korean according to recommended guidelines for forward-backward translation. Thirty-eight patients who underwent surgical treatment for Achilles tendon rupture from 2017 to 2019 were enrolled. Reliability was evaluated by the intraclass correlation coefficient (ICC), standard error of measurement (SEM), and minimal detectable change (MDC). Construct validity was assessed with Spearman rank correlations with the Korean version of the Foot and Ankle Outcome Score (FAOS) and Numeric Rating Scale (NRS) for pain in daily activity. RESULTS: The Korean translation of the ATRS had excellent test-retest reliability (ICC = 0.84) and acceptable internal consistency (Cronbach's alpha = 0.84). The SEM was 6.61, and the MDC was 18.32 at the individual level and 2.97 at the group level. The Korean translation of the ATRS was strongly correlated with the FASO (r = 0.88). Correlation with the NRS in daily activity (r = - 0.66) was moderate. CONCLUSION: The Korean translation of the ATRS showed sufficient reliability and validity for use in the Korean population. LEVEL OF EVIDENCE: II.

Monolithic Dual Mobility Cup Total Hip Arthroplasty Has High Complication Rates With Surgical Fixation in Elderly With Femur Neck Fracture.

BACKGROUND: This study is prospectively conducted to evaluate surgical complications of monolithic dual mobility cup total hip arthroplasty (THA) in elderly patients with fractured neck of the femur. METHODS: Ninety-seven patients (97 hips) with displaced femoral neck fracture who gave informed consent for participation were prospectively enrolled. Their mean age was 76.6 years (range, 60-95 years), and the mean bone mineral density T-score of neck of the femur was -2.8 (range, -1.2 to -5.5). All patients underwent THA with monolithic dual mobility cup, and computed tomography scans were obtained to evaluate radiographic parameters including anteversion, inclination, and loosening of acetabular cups, and periprosthetic acetabular fractures. RESULTS: With regard to cup orientation, mean inclination angle was 40.2° (range, 23.5°-63°) and mean anteversion was 32.6° (range, 7°-66.2°). The proportion of surgical outliers was 10.3% (10/97) in inclination and 35.1% (34/97) in anteversion. Early cup loosening within 2 weeks was detected in 2 hips. Periprosthetic acetabular fractures were identified in 6 hips (6/97, 6.2%). Of the 6 fractures, 5 nondisplaced fractures were healed with conservative management, but 1 fracture with displacement eventually led to cup loosening and the patient underwent revision surgery. Reoperation rate of the monolithic dual mobility cup was 4.1% (4/97). CONCLUSION: The use of the monolithic dual mobility was associated with improper cup fixation and periprosthetic acetabular fractures in the elderly with poor bone stock, although the dual mobility cup lowered the risk of early dislocation after THA.

Orexin A-induced inhibition of leptin expression and secretion in adipocytes reducing plasma leptin levels and hypothalamic leptin resistance.

Orexin A (OXA) is a neuropeptide associated with plasma insulin and leptin levels involved in body weight and appetite regulation. However, little is known about the effect of OXA on leptin secretion in adipocytes and its physiological roles. Leptin secretion and expression were analysed in 3T3-L1 adipocytes. Plasma leptin, adiponectin and insulin levels were measured by ELISA assay. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) levels in the hypothalamus were evaluated by western blotting. OXA dose-dependently suppressed leptin secretion from 3T3-L1 adipocytes by inhibiting its gene expression while facilitating adiponectin secretion. The leptin inhibition by OXA was mediated via orexin receptors (OXR1 and OXR2). In addition to the pathway via extracellular signal-regulated kinases, OXA triggered adenylyl cyclase-induced cAMP elevation, which results in protein kinase A-mediated activation of cAMP response element-binding proteins (CREB). Accordingly, CREB inhibition restored the OXA-induced downregulation of leptin gene expression and secretion. Exogenous OXA for 4 weeks decreased fasting plasma leptin levels and increased hypothalamic pSTAT3 levels in high-fat diet-fed mice, regardless of increase in body weight and food intake. These results suggest that high dose of OXA directly inhibits leptin mRNA expression and thus secretion in adipocytes, which may be a peripheral mechanism of OXA for its role in appetite drive during fasting. It may be also critical for lowering basal plasma leptin levels and thus maintaining postprandial hypothalamic leptin sensitivity.

Ablation of catalase promotes non-alcoholic fatty liver via oxidative stress and mitochondrial dysfunction in diet-induced obese mice.

Hydrogen peroxide (H2O2) produced endogenously can cause mitochondrial dysfunction and metabolic complications in various cell types by inducing oxidative stress. In the liver, oxidative and endoplasmic reticulum (ER) stress affects the development of non-alcoholic fatty liver disease (NAFLD). Although a link between both stresses and fatty liver diseases has been suggested, few studies have investigated the involvement of catalase in fatty liver pathogenesis. We examined whether catalase is associated with NAFLD, using catalase knockout (CKO) mice and the catalase-deficient human hepatoma cell line HepG2. Hepatic morphology analysis revealed that the fat accumulation was more prominent in high-fat diet (HFD) CKO mice compared to that in age-matched wild-type (WT) mice, and lipid peroxidation and H2O2 release were significantly elevated in CKO mice. Transmission electron micrographs indicated that the liver mitochondria from CKO mice tended to be more severely damaged than those in WT mice. Likewise, mitochondrial DNA copy number and cellular ATP concentrations were significantly lower in CKO mice. In fatty acid-treated HepG2 cells, knockdown of catalase accelerated cellular lipid accumulation and depressed mitochondrial biogenesis, which was recovered by co-treatment with N-acetyl cysteine or melatonin. This effect of antioxidant was also true in HFD-fed CKO mice, suppressing fatty liver development and improving hepatic mitochondrial function. Expression of ER stress marker proteins and hepatic fat deposition also increased in normal-diet, aged CKO mice compared to WT mice. These findings suggest that H2O2 production may be an important event triggering NAFLD and that catalase may be an attractive therapeutic target for preventing NAFLD.

The breakdown of the local thermal equilibrium approximation for a polymer chain during packaging.

The conformational relaxation of a polymer chain often slows down in various biological and engineering processes. The polymer, then, may stay in nonequilibrium states throughout the process such that one may not invoke the local thermal equilibrium (LTE) approximation, which has been usually employed to describe the kinetics of various processes. In this work, motivated by recent single-molecule experiments on DNA packaging into a viral capsid, we investigate how the nonequilibrium conformations and the LTE approximation would affect the packaging of a polymer chain into small confinement. We employ a simple but generic coarse-grained model and Langevin dynamics simulations to investigate the packaging kinetics. The polymer segments (both inside and outside the confinement) stay away from equilibrium under strong external force. We devise a simulation scheme to invoke the LTE approximation during packaging and find that the relaxation of nonequilibrium conformations plays a critical role in regulating the packaging rate.

Subchronic toxicity evaluation of ethanol extract of Cassia tora L. seeds in rats.

Cassia tora Linn. is an annual or perennial plant of the Fabaceae/Leguminosae family. It is used in traditional medicine for various biological activities including anti-constipation, anti-inflammatory, visual acuity, and hepato-protective activities. The present study was carried out to investigate the potential toxicity of C. tora L. seed ethanol extract (CTSEE) following a 13-week repeated oral administration to Sprague-Dawley rats. CTSEE was administered orally to male and female rats for 13 weeks at 0 (control), 500, 1000, and 2000 mg/kg/day (n = 10, for male and female rats for each dose). Additional recovery groups from the control group and high dose group were observed for a 4-week recovery period. At the end of the treatment and recovery periods, animals were sacrificed, and their organs were weighed and blood samples collected. There were no treatment-related adverse effects in clinical signs, body weight, food consumption, estrous cycle, sperm parameters, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at any doses tested. Under the present experimental conditions, the no-observed-adverse-effect level of the CTSEE was >2000 mg/kg/day in both genders, and no target organs were identified.

Effect of Saururus chinensis leaves extract on type II collagen-induced arthritis mouse model.

BACKGROUND: Saururus chinensis leaves have been used as traditional medicine in Korea for pain, intoxication, edema, and furuncle. According to previous reports, these leaves exert renoprotective, neuroprotective, and antioxidant effects by attenuating inflammatory responses. However, the beneficial effect of Saururus chinensis leaves on arthritis has not been elucidated. Thus, we evaluated the water extract of Saururus chinensis leaves (SHW) using type II collagen-induced arthritis (CIA) mice models. METHODS: Quantitative analysis of major components from SHW was performed by HPLC. Arthritis was induced by injection of type II collagen. Each group was orally administered SHW (100 mg/kg and 500 mg/kg). Methotrexate (MTX) was used as a positive control. Serum levels of interleukin-6, TNF-alpha, and type II collagen IgG in the animal models were measured using ELISA. Histological features were observed by H&E staining. RESULTS: Quantitative analysis of SHW showed the contents as 56.4 ± 0.52 mg/g of miquelianin, 7.75 ± 0.08 mg/g of quercetin 3-O-(2"-O-ß -glucopyranosyl)-α-rhamnopyranoside, and 3.17 ± 0.02 mg/g of quercitrin. Treatment with 500 mg/kg SHW decreased the serum level of Interleukin-6 (IL-6), TNF-alpha, and collagen IgG in the CIA model. Moreover, SHW treatment diminished the swelling of hind limbs and monocyte infiltration in blood vessels in CIA animal models. The results indicate that SHW could decrease CIA-induced arthritis in vivo. CONCLUSIONS: The results indicate that SHW could be used to improving arthritis by reducing inflammatory factors (IL-6 and TNF-alpha). However, further experiments are required to determine how SHW influences signal transduction in animal models.

Antioxidant and Antimelanogenic Activities of Compounds Isolated from the Aerial Parts of Achillea alpina L.

Achillea alpina is widely distributed in Korea and is often used as a folk medicine for stomach disorders. Although a previous study isolated antioxidant compounds (flavonoid O-glucoside, sesquiterpene) from this plant, no systematic study of its chemical constituents had been reported. The present study aimed to identify the phytochemicals present in a methanol extract of A. alpina, assess their potential antioxidant activities in vitro, and determine their effects on melanogenesis in B16F10 melanoma cells. Column chromatographic separation of aqueous fractions of A. alpina led to the isolation of 17 compounds. The chemical structures of these compounds were determined using spectroscopic data from electrospray ionization-mass spectrometry and nuclear magnetic resonance. To the best of our knowledge, the present study is the first to identify compounds 2-10 and 12-17 in A. alpina. Furthermore, compound 6 possessed powerful antioxidant activity, while compound 15 suppressed intracellular tyrosinase activity and thus reduced melanogenesis in B16F10 cells. Therefore, our research suggested that these naturally occurring compounds have the potential to reduce oxidative stress and promote skin whitening. Further investigations will be required to elucidate the mechanisms underlying the antioxidant and antityrosinase activities of these compounds.

Nelumbo nucifera Receptaculum Extract Suppresses Angiotensin II-Induced Cardiomyocyte Hypertrophy.

Nelumbo nucifera Gaertn. (lotus) is an important medicinal plant, and many parts of the plant have been investigated for their therapeutic effects. However, the therapeutic effect of receptacles of lotuses on pathological cardiomyocyte hypertrophy has not been investigated yet. Therefore, the current study aimed to determine the protective effect of lotus against angiotensin II (Ang II)-induced cardiomyocyte hypertrophy in vitro. Ang II was used to induce hypertrophy of H9c2 cells. The lotus receptacle powder (MeOH extract of receptaculum Nelumbinis; MRN) used in the experiments was prepared by MeOH extraction and subsequent evaporation. To evaluate the effect of MRN on cardiomyocyte hypertrophy, cell size, protein synthesis, and hypertrophic marker expressions were examined. The antioxidant ability of MRN was determined by using CM-H2DCFDA, a general oxidative stress indicator. Ang II-induced cardiomyocyte hypertrophy was significantly attenuated by 5 µg/mL of MRN, as confirmed by the reductions in cell size, protein synthesis, and hypertrophic marker expression. MRN also attenuated Ang II-induced excessive intracellular reactive oxygen species (ROS) production through the suppression of protein kinase C (PKC), extracellular-signal-regulated kinase (ERK), and NF-κB activation and subsequent type I angiotensin receptor (AT1R), receptor for advanced glycation end products (RAGE), and NADPH oxidase (NOX) expression. MRN exerted a significant protective effect against Ang II-induced cardiomyocyte hypertrophy through suppression of PKC-ERK signaling, and this subsequently led to attenuation of intracellular ROS production.

Catalase and nonalcoholic fatty liver disease.

Obesity and insulin resistance are considered the main causes of nonalcoholic fatty liver disease (NAFLD), and oxidative stress accelerates the progression of NAFLD. Free fatty acids, which are elevated in the liver by obesity or insulin resistance, lead to incomplete oxidation in the mitochondria, peroxisomes, and microsomes, leading to the production of reactive oxygen species (ROS). Among the ROS generated, H2O2 is mainly produced in peroxisomes and decomposed by catalase. However, when the H2O2 concentration increases because of decreased expression or activity of catalase, it migrates to cytosol and other organelles, causing cell injury and participating in the Fenton reaction, resulting in serious oxidative stress. To date, numerous studies have been shown to inhibit the pathogenesis of NAFLD, but treatment for this disease mainly depends on weight loss and exercise. Various molecules such as vitamin E, metformin, liraglutide, and resveratrol have been proposed as therapeutic agents, but further verification of the dose setting, clinical application, and side effects is needed. Reducing oxidative stress may be a fundamental method for improving not only the progression of NAFLD but also obesity and insulin resistance. However, the relationship between NAFLD progression and antioxidants, particularly catalase, which is most commonly expressed in the liver, remains unclear. Therefore, this review summarizes the role of catalase, focusing on its potential therapeutic effects in NAFLD progression.

Rapid ex vivo expansion of highly enriched human invariant natural killer T cells via single antigenic stimulation for cell therapy to prevent graft-versus-host disease.

BACKGROUND AIMS: CD1d-restricted invariant natural killer (iNK) T cells are rare regulatory T cells that may contribute to the immune-regulation in allogeneic stem cell transplantation (ASCT). Here, we sought to develop an effective strategy to expand human iNK T cells for use in cell therapy to prevent graft-versus-host disease (GVHD) in ASCT. METHODS: Human iNK T cells were first enriched from peripheral blood mononuclear cells (PBMCs) using magnetic-activated cell sorting separation, then co-cultured with dendritic cells in the presence of agonist glycolipids, alpha-galactosylceramide, for 2 weeks. RESULTS: The single antigenic stimulation reliably expanded iNK T cells to an average of 2.8 × 107 per 5 × 108 PBMCs in an average purity of 98.8% in 2 weeks (N = 24). The expanded iNK T cells contained a significantly higher level of CD4+ and central memory phenotype (CD45RA-CD62L+) compared with freshly isolated iNK T cells, and maintained their ability to produce both Th-1 (interferon [IFN]γ and tumor necrosis factor [TNF]α) and Th-2 type cytokines (interleukin [IL]-4, IL-5 and IL-13) upon antigenic stimulation or stimulation with Phorbol 12-myristate 13-acetate/ionomycin. Interestingly, expanded iNK T cells were highly autoreactive and produced a Th-2 polarized cytokine production profile after being co-cultured with dendritic cells alone without exogenous agonist glycolipid antigen. Lastly, expanded iNK T cells suppressed conventional T-cell proliferation and ameliorated xenograft GVHD (hazard ratio, 0.1266; P < 0.0001). CONCLUSION: We have demonstrated a feasible approach for obtaining ex vivo expanded, highly enriched human iNK T cells for use in adoptive cell therapy to prevent GVHD in ASCT.

Tomatidine inhibits tumor necrosis factor-α-induced apoptosis in C2C12 myoblasts via ameliorating endoplasmic reticulum stress.

In this study, we examined the effect of tomatidine on tumor necrosis factor (TNF)-α-induced apoptosis in C2C12 myoblasts. TNF-α treatment increased cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP) protein levels in a dose- and time-dependent manner. Pretreatment of cells with 10 µM tomatidine prevented TNF-α-induced apoptosis, caspase 3 cleavage, and PARP cleavage. Cells were treated with 100 ng/mL TNF-α for 24 h, and flow cytometry was utilized to assess apoptosis using annexin-V and 7-aminoactinomycin D. TNF-α up-regulated activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression. This effect was suppressed by pretreatment with tomatidine. Pretreatment with 4-phenylbutyric acid (a chemical chaperone) also inhibited TNF-α-induced cleavage of caspase 3 and PARP and up-regulation of ATF4 and CHOP expression. In addition, tomatidine-mediated inhibition of phosphorylation of c-Jun amino terminal kinase (JNK) attenuated TNF-α-induced cleavage of PARP and caspase 3. However, tomatidine did not affect NF-κB activation in TNF-α-treated C2C12 myoblast cells. Taken together, the present study demonstrates that tomatidine attenuates TNF-α-induced apoptosis through down-regulation of CHOP expression and inhibition of JNK activation.

Fractional Viscosity Dependence of Reaction Kinetics in Glass-Forming Liquids.

The diffusion of molecules in complex systems such as glasses and cell cytoplasm is slow, heterogeneous, and sometimes nonergodic. The effects of such intriguing diffusion on the kinetics of chemical and biological reactions remain elusive. In this Letter, we report that the kinetics of the polymer loop formation reaction in a Kob-Andersen (KA) glass forming liquid is influenced significantly by the dynamic heterogeneity. The diffusion coefficient D of a KA liquid deviates from the Stokes-Einstein relation at low temperatures and D shows a fractional dependence on the solvent viscosity η_{s}, i.e., D∼η_{s}^{-ξ_{D}} with ξ_{D}=0.85. The dynamic heterogeneity of a KA liquid affects the rate constant k_{rxn} of the loop formation and leads to the identical fractional dependence of k_{rxn} on η_{s} with k_{rxn}∼η_{s}^{-ξ} and ξ=ξ_{D}, contrary to reactions in dynamically homogeneous solutions where k_{rxn}∼η_{s}^{-1}.

The glass transition and interfacial dynamics of single strand fibers of polymers.

We investigate the glass transition and interfacial dynamics of single strand fibers of flexible polymers by employing molecular dynamics (MD) simulations along with a coarse grained model. While the polymer fiber has drawn significant attention due to its applicability in tissue engineering and stretchable electronics, its dynamic properties, especially the glass transition temperature (Tg), are yet to be understood at the molecular level. For example, there has been a controversy on the effect of the polymer fiber radius (R) on Tg: Tg decreased with a decrease in R for some polymer fibers, whereas Tg of other polymer fibers was not sensitive to R. In this article, we estimate the bond relaxation time of polymers and evaluate both Tg and fragility (m) as a function of R. We illustrate that Tg of the polymer fiber decreased with a decrease in R monotonically and also that the values of Tg follow faithfully the empirical equation proposed by Keddie et al. as a function of R, which was successfully employed to fit the values of Tg of both polyvinyl alcohol (PVA) fibers and polyethylene (PE) fibers. We also find that the dynamics of polymers at the interface between a polymer fiber and air is faster than that of polymers at the center. By employing Adam-Gibbs theory, we show that the fast interface dynamics of polymer fibers should influence the cooperative motion of monomers, which should be responsible for the decrease in Tg for smaller values of R. Near the interface there are more mobile monomers that participate in the cooperative motions of polymers. Interesting is that due to the curved surface (unlike flat polymer films) the cooperative motion of monomers is anisotropic in polymer fibers.

The spatial arrangement of a single nanoparticle in a thin polymer film and its effect on the nanoparticle diffusion.

The spatial arrangement of nanoparticles (NPs) within thin polymer films may influence their properties such as the glass transition temperature. Questions regarding what may affect the spatial arrangement of NPs, however, still remain unanswered at a molecular level. In this work, we perform molecular dynamics simulations for a free-standing thin polymer film with a single NP. We find from simulations that depending on the NP size and the inter-particle interaction between the NP and polymers, one may control the spatial arrangement of the NP. When the interaction between the NP and polymers is sufficiently attractive (repulsive), the NP is likely to be placed at the center (at the surface) of the thin film in equilibrium. Interestingly, for a moderate interaction between the NP and polymers, the first-order transition occurs in the spatial arrangement of the NP as one increases the NP size: a small NP prefers the surface of the polymer film whereas a large NP prefers the center. Such a first-order transition is corroborated by calculating the free energy of the NP as a function of the position and can be understood in terms of a sixth-order Landau free energy. More interestingly, the diffusion of the NP also changes drastically due to the first-order transition in the spatial arrangement. The NP diffusion is enhanced drastically (more than expected in bulk polymer melts) as the NP is shifted to the polymer film surface.