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Activation entropy (ΔS‡) is not normally considered the main factor in determining the reactivity of unimolecular reactions. Here, we report that the intramolecular degradation of six-membered ring compounds is mainly determined by the ΔS‡, which is strongly influenced by the ring-flipping motion and substituent geometry. Starting from the unique difference between the pH-dependent degradation kinetics of geometric isomers of 1,2-cyclohexanecarboxylic acid amide (1,2-CHCAA), where only the cis isomer can readily degrade under weakly acidic conditions (pH < 5.5), we found that the difference originated from the large difference in ΔS‡ of 16.02 cal·mol–1·K–1. While cis-1,2-CHCAA maintains a preference for the classical chair cyclohexane conformation, trans-1,2-CHCAA shows dynamic interconversion between the chair and twisted boat conformations, which was supported by both MD simulations and VT-NMR analysis. Steric repulsion between the bulky 1,2-substituents of the trans isomer is one of the main reasons for the reduced energy barrier between ring conformations that facilitates dynamic ring inversion motions. Consequently, the more dynamic trans isomer exhibits much a larger loss in entropy during the activation process due to the prepositioning of the reactant than the cis isomer, and the pH-dependent degradation of the trans isomer is effectively suppressed. When the ring inversion motion is inhibited by an additional methyl substituent on the cyclohexane ring, the pH degradability can be dramatically enhanced for even the trans isomer. This study shows a unique example in which spatial arrangement and dynamic properties can strongly influence molecular reactivity in unimolecular reactions, and it will be helpful for the future design of a reactive structure depending on dynamic conformational changes.

The surface of human silicone breast implants is covalently grafted at a high density with a 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymer. Addition of cross-linkers is essential for enhancing the density and mechanical durability of the MPC graft. The MPC graft strongly inhibits not only adsorption but also the conformational deformation of fibrinogen, resulting in the exposure of a buried amino acid sequence, γ377-395, which is recognized by inflammatory cells. Furthermore, the numbers of adhered macrophages and the amounts of released cytokines (MIP-1α, MIP-1β, IL-8, TNFα, IL-1α, IL-1β, and IL-10) are dramatically decreased when the MPC network is introduced at a high density on the silicone surface (cross-linked PMPC-silicone). We insert the MPC-grafted human silicone breast implants into Yorkshire pigs to analyze the in vivo effect of the MPC graft on the capsular formation around the implants. After 6 month implantation, marked reductions of inflammatory cell recruitment, inflammatory-related proteins (TGF-β and myeloperoxidase), a myoblast marker (α-smooth muscle actin), vascularity-related factors (blood vessels and VEGF), and, most importantly, capsular thickness are observed on the cross-linked PMPC-silicone. We propose a mechanism of the MPC grafting effect on fibrous capsular formation around silicone implants on the basis of the in vitro and in vivo results.

Implants based on silicone elastomers, polydimethylsiloxane (PDMS), have been widely used for breast augmentation and reconstruction, but excessive foreign body reactions around implants often cause serious side effects such as capsular contracture. In our previous study, we covalently grafted 2-methacryloyloxyethyl phosphorylcholine (MPC)-based polymers on the surface of PDMS blocks by UV-induced polymerization and showed effective reduction of capsular formation around the MPC-grafted PDMS in rats. In the present study, we examined the efficacy of heat-induced polymerization of MPC grafting on silicone breast implants intended for humans, and analyzed the in vivo inhibitory effect against capsular formation and inflammation in pigs, which are closely related to humans in terms of epidermal structures and fibrotic processes. The heat-induced polymerization provided a thicker MPC-grafted surface and was more effective than UV-induced polymerization for the grafting of complex shaped non-transparent implants. After 24-week implantation in the submuscular pockets of Yorkshire pigs, the heat-induced MPC-grafted breast implants showed 45% smaller capsular thickness and 20-30% lower levels of inflammatory markers such as myeloperoxidase (MPO), transforming growth factor-β (TGF-β), and α-smooth muscle actin (α-SMA) in surrounding tissues compared to non-grafted implants. This study provides important information for future clinical trials of MPC-grafted silicone implants.

SummaryMany mammalian neurons release multiple neurotransmitters to activate diverse classes of ionotropic receptors on their postsynaptic targets. Entopeduncular nucleus somatostatin (EP Sst+) neurons that project to the lateral habenula (LHb) release both glutamate and GABA, but it is unclear if these are packaged into the same or segregated pools of synaptic vesicles. Here we describe a novel method combining electrophysiology, spatially-patterned optogenetics, and computational modeling designed to analyze the mechanism of glutamate/GABA corelease. We find that the properties of PSCs elicited in LHb neurons by optogenetic activation of EP Sst+ terminals are only consistent with co-packaging of glutamate and GABA into individual vesicles. Furthermore, serotonin, which acts presynaptically to weaken EP Sst+ to LHb synapses, does so by altering the release probability of vesicles containing both transmitters. Our approach is broadly applicable to the study of multi-transmitter neurons throughout the brain and our results constrain mechanisms of neuromodulation in LHb.

Many mammalian neurons release multiple neurotransmitters to activate diverse classes of postsynaptic ionotropic receptors. Entopeduncular nucleus somatostatin (EP Sst+) projection neurons to the lateral habenula (LHb) release both glutamate and GABA, but it is unclear whether these are packaged into the same or segregated pools of synaptic vesicles. Here, we describe a method combining electrophysiology, spatially patterned optogenetics, and computational modeling designed to analyze the mechanism of glutamate/GABA co-release in mouse brain. We find that the properties of postsynaptic currents elicited in LHb neurons by optogenetically activating EP Sst+ terminals are only consistent with co-packaging of glutamate/GABA into individual vesicles. Furthermore, presynaptic neuromodulators that weaken EP Sst+ to LHb synapses maintain the co-packaging of glutamate/GABA while reducing vesicular release probability. Our approach is applicable to the study of multi-transmitter neurons throughout the brain, and our results constrain the mechanisms of neuromodulation and synaptic integration in LHb.

A variety of UCST-type thermoresponsive ammonium iodide salts is systematically designed and synthesised with desired aqueous solubility, phase-transition temperature, osmolality change, phase-transition concentration range, stability, and toxicity by controlling the ionic interactions, hydrophobicity, and symmetry of the salt structure. Suitable draw solutes can be selected based on the characteristics of the ammonium iodide salts as well as the feed solutions for feasible forward osmosis (FO)-based water purification. In this research, highly concentrated wastewater from a flue gas desulfuriser (FGD), with osmotic pressure three times higher than seawater, is targeted for purification by FO using the draw solutes. Two ammonium iodide salts (HM8I and HM10I) show a remarkable water flux from the wastewater samples and significantly lower salt leakage compared to conventional draw solutes. The osmolality of the phase-separated draw solution drops to less than one tenth of that of the initial feed solution, and reverse osmosis or nanofiltration can be applied to the solution with much lower external pressure for the final purification to produce fresh water. This systematic approach to the design and selection of suitable draw solutes can be an effective strategy for future practical FO-based wastewater treatment and seawater desalination.

The importance of preserving intangible cultural heritage (ICH) for sustainable development has been widely acknowledged by the international society. Various forms of cooperation have taken place to prevent deterioration and destruction due to its inherent characteristic of &lsquo, intangibleness&rsquo, Public engagement, however, has largely been excluded from the system in spite of its significance in safeguarding ICH by inducing people to be trained as successors. In this respect, this paper discusses and emphasises the necessity of public engagement in safeguarding ICH. To this end, it suggests the use of digital technologies to create museum content to encourage public involvement with and learning about ICH. Focusing on ICH in Korea, digital exhibitions on Jultagi and Daemokjang utilising virtual reality technology are proposed. The ultimate aim of this article is to contribute to the sustainability of world ICH for humanity through digital exhibitions.

s Combinatorial introduction of acyl, alkylsulfonyl and azobenzene (Ab) functionalities into amine-rich branched polyethylenimine produces dual-signal-responsive polymers with both temperature- and light-responsiveness in aqueous solutions. Light-tunable L/UCST polymers were synthesized by simple introduction of acyl and Ab groups or alkylsulfonyl and Ab groups, respectively. The phase transition temperatures of the polymers were dependent upon the ratios of the functionalities and reversibly controlled by light irradiation. More than 35°C-shift of the LCST was obtained by UV-irradiation, which is the largest shift reported in water. Moreover, 19°C-shift of the UCST was obtained by UV-irradiation, which is the first UCST shift reported in polymer–water binary systems.

Two representative antibiotics, cephradine (CP) and moxifloxacin (MX), are covalently conjugated with a β-cyclodextrin (β-CD)-based carrier via pH-responsive 1-methyl-2-(2'-carboxyethyl) maleic acid amide (MCM) linkers with excellent conjugation efficiency via simple mixing. At pH 5.5, 90% and 80% of the CP and MX, respectively, are released from the carriers within 30 min, in contrast with the much-delayed release profile at pH 7.4. The in vitro inhibitory effect of β-CD-MCM-CP on the growth of Staphylococcus aureus is significantly lower than that of free CP at pH 7.4, but it reaches the level of free CP at pH 5.5. Moreover, S. aureus develops significant CP resistance after pretreatment with free CP, whereas the initial CP sensitivity is maintained after pretreatment with β-CD-MCM-CP at pH 7.4. However, β-CD-MCM-MX exhibits no such pH-responsive activity against Bacteroides fragilis, probably due to the insufficient stability of the MX conjugation at pH 7.4. In nondiabetic and diabetic mouse models, β-CD-MCM-CP significantly reduces the subcutaneous abscess scores and the bacterial counts in the abscess, although this represents only a marginal improvement in antimicrobial activity compared to free CP.

Dioscoreae Rhizome (DR) has been used in traditional medicine to treat numerous diseases and is reported to have anti-diabetes and anti-tumor activities. To identify a bioactive traditional medicine with anti-inflammatory activity of a water extract of DR (EDR), we determined the mRNA and protein levels of proinflammatory cytokines in macrophages through RT-PCR and western blot analysis and performed a FACS analysis for measuring surface molecules. EDR dose-dependently decreased the production of NO and pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and PGE(2), as well as mRNA levels of iNOS, COX-2, and pro-inflammatory cytokines, as determined by western blot and RT-PCR analysis, respectively. The expression of co-stimulatory molecules such as B7-1 and B7-2 was also reduced by EDR. Furthermore, activation of the nuclear transcription factor, NF-κB, but not that of IL-4 and IL-10, in macrophages was inhibited by EDR. These results show that EDR decreased pro-inflammatory cytokines via inhibition of NF-κB-dependent inflammatory protein level, suggesting that EDR could be a useful immunomodulatory agent for treating immunological diseases.

The effects of copolymer architecture on phase separation dynamics of an immiscible binary blend A/B in the presence of copolymer were investigated by Monte Carlo simulation. Five types of copolymers, with each having the same composition (f=0.5) but different sequence distribution, are used for simulation. The sequence distribution is varied from the symmetric diblock copolymer to the alternating copolymer. It is found that the rate of phase separation is significantly suppressed by the addition of copolymer due to the reduction of interfacial tension. This retardation effect is considerably dependent on the sequence distribution of the copolymer and such an effect is more pronounced when the block copolymer is added. It is also found that the longer the chain length of copolymer, the better such a retardation effect. When the chain extension of copolymer at the interface is examined, the block copolymer chains are extended to each corresponding homopolymer phase across the interface, whereas the alternating copolymers lie on the interface and the random copolymers weave back and forth across the interface.

The temperature effect for buried channel PMOS transistor characteristics was investigated. Generally, only dose, energy and implant angle have been considered as the major parameters for process matching between different high current implanters in transistor manufacturing. However, as the device is scaled down to sub-100 nm size, additional parameters such as instantaneous dose rate and wafer temperature have become increasingly important for controlling the dopant profile by changing the annealing behavior of defects. By changing the wafer temperature, the threshold voltage (VT) changed dramatically while the active area sheet resistance remained constant. The peak height of both the boron and fluorine profiles corresponding to the location of the amorphous/crystalline (a/c) interface increased proportionally with increasing wafer temperature and to a lesser degree with increasing instantaneous dose rate. This higher secondary peak height resulted in reduced lateral diffusion, shorter effective channel length, and therefore a lower threshold voltage (VT).

Obesity-induced disorders contribute to the development of metabolic diseases such as insulin resistance, fatty liver diseases, and type 2 diabetes (T2D). In this study, we evaluated whether the Aloe QDM complex could improve metabolic disorders related to blood glucose levels and insulin resistance. Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of Aloe QDM complex or pioglitazone (PGZ) or metformin (Met) and were compared with unsupplemented controls (high-fat diet; HFD) or mice fed a regular diet (RD). RT-PCR and western blot analysis were used to quantify the expression of obesity-induced inflammation. Dietary Aloe QDM complex lowered body weight, fasting blood glucose, plasma insulin, and leptin levels, and markedly reduced the impairment of glucose tolerance in obese mice. Also, Aloe QDM complex significantly enhanced plasma adiponectin levels and insulin sensitivity via AMPK activity in muscles. At the same time, Aloe QDM decreased the mRNA and protein of PPARγ/LXRα and scavenger receptors in white adipose tissue (WAT). Dietary Aloe QDM complex reduces obesity-induced glucose tolerance not only by suppressing PPARγ/LXRα but also by enhancing AMPK activity in the WAT and muscles, both of which are important peripheral tissues affecting insulin resistance. The Aloe QDM complex could be used as a nutritional intervention against T2D.

Dioscoreae rhizome (DR) has been used in traditional medicine to treat numerous diseases and reported to have anti-diabetes and antitumor activities. The pharmacological and biochemical mechanisms of the water extracts of DR (EDR) on macrophages in immune responses have not been clearly elucidated. We examined whether EDR suppresses the production of pro-inflammatory cytokines and the expression of co-stimulatory molecules. EDR reduced the production of NO and PGE2 through the suppressed gene and protein expression of iNOS and COX-2 in the both RAW 264.7 cells and peritoneal macrophages. The production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 production were suppressed by EDR. The change of gene expression by EDR treatment was analyzed by using RT-PCR, and the associated mRNA expression was inhibited same as cytokine production. Western blot analysis showed the augmentation of cytokine related protein on EDR treatment whereas anti-inflammatory cytokines, IL-4 and IL-10, did not significantly change. The expression level of co-stimulatory molecules such as ICAM-1, B7-1, and B7-2 also was reduced with the increment of EDR concentration. The nuclear translocation of NF-κB activity in LPS-activated macrophages was suppressed by EDR. These results showed EDR decreased pro-inflammatory cytokines via the inhibition of NF-κB dependent inflammatory protein level and suggesting that how EDR could be useful immunomodulatory agent for treating immunological diseases.

Aloe is known to have various medical effects. These include healing damaged skin, as well as anti-diabetic, anticancer, and anti-arthritis activity. This study was performed to investigate the therapeutic effect of Aloe complex on diabetic symptoms in die-induced obesity (DIO) C57BL/6N mice. Aloe complex was orally administrated to diabetic mice for 8 weeks and the diabetic clinical markers, including blood glucose level, body weight, and insulin level were measured. The oral administration of Aloe complex in DIO mice significantly decreased of blood glucose and body weight level including total WATs compared with diabetic control group. The levels of serum insulin, tissue insulin, GTT, and ITT were improved after Aloe complex treatment. Moreover, both serum and tissue adiponectin increased whereas serum leptin decreased by Aloe complex. Aloe exerted beneficial effects on lipogenesis related transcription factor genes, PPARγ and LXRα, and aP2 expression in WAT. The gene expression of pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, and Th1 cytokines, IFN-γ, IL-12, protein levels were suppressed via inhibiting nuclear NF-κB by Aloe complex. In contrast, protein levels of Th2 cytokines, IL-4 and IL-10, in WAT and AMPK activity in muscles were increased. The results suggest that Aloe complex has hypoglycemic effects resulting the attenuation of glucose and lipogenesis and that Aloe-containing diet or drugs may give a benefit for controlling type II diabetes patients.

Background Salvia miltiorrhiza (SM) has been used to treat inflammatory diseases including edema and arthritis; however, the anti-inflammatory mechanism of SM action remains unresolved. Methods The effects of an ethanol extract of SM (ESM) on pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and NO, on anti-inflammatory cytokines including IL-4, IL-10, TGF-β, and IL-1Ra have been studied in an attempt to elucidate the anti-inflammatory mechanism in murine macrophages. Results ESM inhibited the production of pro-inflammatory cytokines via down-regulation of gene and protein expression whereas it increased the anti-inflammatory cytokines. Furthermore, ESM inhibited the expression of the chemokines, RANTES and CX3CL1, as well as of inflammatory mediators such as TLR-4 and 11β-HSD1. Conclusion These results indicated that the regulatory effects of ESM may be mediated though the suppression of pro-inflammatory cytokines as well as the induction of anti-inflammatory cytokines. Consequently, we speculate that ESM has therapeutic potential for inflammation-associated disorders.

Background: Cordyceps militarys water extract (CME) has been reported to exert antitumor and immunomodulatory activities in vivo and in vitro. However, the therapeutic mechanism has not yet been elucidated. In this study, we examined the effects of CME on the antigen presenting function of antigen presenting cells (APCs). Methods: Dendritic cells (DCs) were cultured in the presence of CME, and then allowed to phagocytose microspheres containing ovalbumin (OVA). After washing and fixing the efficacy of OVA, peptide presentation by DCs were evaluated using CD8 and CD4 T cells. Also, we confirmed the protein levels of proinflammatory cytokines through western blot analysis. Results: CME enhanced both MHC class I and class II-restricted presentation of OVA in DCs. In addition, the expression of both MHC class I and II molecules was enhanced, but there was no changes in the phagocytic activity of exogenous OVA. Furthermore, CME induced the protein levels of iNOS, COX-2, proinflammatory cytokines, and nuclear p65 in a concentration-dependent manner, as determined by western blot. Conclusion: These results provide an understanding of the mechanism of the immuno-enhancing activity of CME on the induction of MHC-restricted antigen presentation in relation to their actions on APCs. [Immune Network 2010;10(4):135-143]