TRPC4 deletion elicits behavioral defects in sociability by dysregulating expression of microRNA-138-2.

To investigate whether the defects in transient receptor potential canonical 4 (TRPC4), which is strongly expressed in the hippocampus, are implicated in ASD, we examined the social behaviors of mice in which Trpc4 was deleted (Trpc4-/-). Trpc4-/- mice displayed the core symptoms of ASD, namely, social disability and repetitive behaviors. In microarray analysis of the hippocampus, microRNA (miR)-138-2, the precursor of miR-138, was upregulated in Trpc4-/- mice. We also found that binding of Matrin3 (MATR3), a selective miR-138-2 binding nuclear protein, to miR-138-2 was prominently enhanced, resulting in the downregulation of miR-138 in Trpc4-/- mice. Some parameters of the social defects and repetitive behaviors in the Trpc4-/- mice were rescued by increased miR-138 levels following miR-138-2 infusion in the hippocampus. Together, these results suggest that Trpc4 regulates some signaling components that oppose the development of social behavioral deficits through miR-138 and provide a potential therapeutic strategy for ASD.

Modeling Long-term Spike Frequency Adaptation in SA-I Afferent Neurons Using an Izhikevich-based Biological Neuron Model.

To develop a biomimetic artificial tactile sensing system capable of detecting sustained mechanical touch, we propose a novel biological neuron model (BNM) for slowly adapting type I (SA-I) afferent neurons. The proposed BNM is designed by modifying the Izhikevich model to incorporate long-term spike frequency adaptation. Adjusting the parameters renders the Izhikevich model describing various neuronal firing patterns. We also search for optimal parameter values for the proposed BNM to describe firing patterns of biological SA-I afferent neurons in response to sustained pressure longer than 1-second. We obtain the firing data of SA-I afferent neurons for six different mechanical pressure ranging from 0.1 mN to 300 mN from the ex-vivo experiment on SA-I afferent neurons in rodents. Upon finding the optimal parameters, we generate spike trains using the proposed BNM and compare the resulting spike trains to those of biological SA-I afferent neurons using the spike distance metrics. We verify that the proposed BNM can generate spike trains showing long-term adaptation, which is not achievable by other conventional models. Our new model may offer an essential function to artificial tactile sensing technology to perceive sustained mechanical touch.

Prevention of Chemotherapy-Induced Peripheral Neuropathy by Inhibiting C-X-C Motif Chemokine Receptor 2.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major drawback in the use of chemotherapeutic agents for patients with cancer. Although studies have investigated a broad number of molecules that might be related to CIPN, the differences in the chemokine pathways between various chemotherapeutic agents, such as vincristine and oxaliplatin, which are some of the most widely used treatments, have not been fully elucidated. We confirmed that the administration (intraperitoneal injections for seven days) of vincristine (0.1 mg/kg) and oxaliplatin (3 mg/kg) induced pain by using the von Frey behavioral test. Subsequent applications with vincristine and oxaliplatin led to mechanical allodynia that lasted more than one week from the fifth day. After the induction of mechanical allodynia, the mRNA expression of CXCR2, CXCL1, CXCL3, and CXCL5 was examined in the dorsal root ganglia (DRG) and spinal cord of the CIPN models. As a result, the mRNA expression of CXCR2 robustly increased in the lumbar spinal cord in the oxaliplatin-treated mice. Next, to evaluate the involvement of CXCR2 in CIPN, reparixin, a CXCR1/2 inhibitor, was administered intrathecally or intraperitoneally with vincristine or oxaliplatin and was further verified by treatment with ruxolitinib, which inhibits Janus kinase 2 downstream of the CXCR1/2 pathway. Reparixin and ruxolitinib blocked oxaliplatin-induced allodynia but not vincristine-induced allodynia, which suggests that CXCR2-related pathways are associated with the development of oxaliplatin-induced neuropathy. Together with the above results, this suggests that the prevention of oxaliplatin-induced neuropathy by CXCR2 inhibition can lead to successful chemotherapy, and it is important to provide appropriate countermeasures against CIPN development for each specific chemotherapeutic agent.

The Role of Prostaglandin E1 as a Pain Mediator through Facilitation of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 2 via the EP2 Receptor in Trigeminal Ganglion Neurons of Mice.

Cyclooxygenase metabolizes dihomo-γ-linolenic acid and arachidonic acid to form prostaglandin (PG) E, including PGE1 and PGE2, respectively. Although PGE2 is well known to play an important role in the development and maintenance of hyperalgesia and allodynia, the role of PGE1 in pain is unknown. We confirm whether PGE1 induced pain using orofacial pain behavioral test in mice and determine the target molecule of PGE1 in TG neurons with whole-cell patch-clamp and immunohistochemistry. Intradermal injection of PGE1 to the whisker pads of mice induced a reduced threshold, enhancing the excitability of HCN channel-expressing trigeminal ganglion (TG) neurons. The HCN channel-generated inward current (Ih) was increased by 135.3 ± 4.8% at 100 nM of PGE1 in small- or medium-sized TG, and the action of PGE1 on Ih showed a concentration-dependent effect, with a median effective dose (ED50) of 29.3 nM. Adenylyl cyclase inhibitor (MDL12330A), 8-bromo-cAMP, and the EP2 receptor antagonist AH6809 inhibited PGE1-induced Ih. Additionally, PGE1-induced mechanical allodynia was blocked by CsCl and AH6809. PGE1 plays a role in mechanical allodynia through HCN2 channel facilitation via the EP2 receptor in nociceptive neurons, suggesting a potential therapeutic target in that PGE1 could be involved in pain as endogenous substances under inflammatory conditions.

Riboflavin Inhibits Histamine-Dependent Itch by Modulating Transient Receptor Potential Vanilloid 1 (TRPV1).

Riboflavin, also known as vitamin B2, isfound in foods and is used as a dietary supplement. Its deficiency (also called ariboflavinosis) results in some skin lesions and inflammations, such as stomatitis, cheilosis, oily scaly skin rashes, and itchy, watery eyes. Various therapeutic effects of riboflavin, such as anticancer, antioxidant, anti-inflammatory, and anti-nociceptive effects, are well known. Although some studies have identified the clinical effect of riboflavin on skin problems, including itch and inflammation, its underlying mechanism of action remains unknown. In this study, we investigated the molecular mechanism of the effects of riboflavin on histamine-dependent itch based on behavioral tests and electrophysiological experiments. Riboflavin significantly reduced histamine-induced scratching behaviors in mice and histamine-induced discharges in single-nerve fiber recordings, while it did not alter motor function in the rotarod test. In cultured dorsal root ganglion (DRG) neurons, riboflavin showed a dose-dependent inhibitory effect on the histamine- and capsaicin-induced inward current. Further tests wereconducted to determine whether two endogenous metabolites of riboflavin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), have similar effects to those of riboflavin. Here, FMN, but not FAD, significantly inhibited capsaicin-induced currents and itching responses caused by histamine. In addition, in transient receptor potential vanilloid 1 (TRPV1)-transfected HEK293 cells, both riboflavin and FMN blocked capsaicin-induced currents, whereas FAD did not. These results revealed that riboflavin inhibits histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how riboflavin exerts antipruritic effects and suggests that it might be a useful drug for the treatment of histamine-dependent itch.

GPR171 Activation Modulates Nociceptor Functions, Alleviating Pathologic Pain.

Modulation of the function of somatosensory neurons is an important analgesic strategy, requiring the proposal of novel molecular targets. Many G-protein-coupled receptors (GPRs) have been deorphanized, but the receptor locations, outcomes due to their activations, and their signal transductions remain to be elucidated, regarding the somatosensory nociceptor function. Here we report that GPR171, expressed in a nociceptor subpopulation, attenuated pain signals via Gi/o-coupled modulation of the activities of nociceptive ion channels when activated by its newly found ligands. Administration of its natural peptide ligand and a synthetic chemical ligand alleviated nociceptor-mediated acute pain aggravations and also relieved pathologic pain at nanomolar and micromolar ranges. This study suggests that functional alteration of the nociceptor neurons by GPR171 signaling results in pain alleviation and indicates that GPR171 is a promising molecular target for peripheral pain modulation.

Dual-responsive Gemini Micelles for Efficient Delivery of Anticancer Therapeutics.

Polymeric micelles as drug delivery vehicles are popular owing to several advantages. In this study, a gemini amphiphile (gemini mPEG-Cys-PMT) consisting of hydrophilic poly(ethylene glycol) and hydrophobic poly(methionine) with cystine disulfide spacer was synthesized and its micellar properties for thiol- or reactive oxygen species (ROS)-dependent intracellular drug delivery were described. The cleavage of cystine linkage in a redox environment or the oxidation of methionine units in a ROS environment caused the destabilization of micelles. Such redox- or ROS-triggered micellar destabilization led to enhanced release of encapsulated doxorubicin (DOX) to induce cytotoxicity against cancer cells. Further, the therapeutic effects of the DOX-loaded micelles were demonstrated using the KB cell line. This study shows that thiol and ROS dual-responsive gemini micelles are promising platforms for nano-drug delivery in various cancer therapies.

Stretchable and transparent nanofiber-networked electrodes based on nanocomposites of polyurethane/reduced graphene oxide/silver nanoparticles with high dispersion and fused junctions.

Creating stretchable and transparent conductive electrodes for stretchable and transparent electronics is very challenging due to difficulties in obtaining adequate optical and mechanical properties simultaneously. Here, we designed a stretchable and transparent nanofiber-networked electrode (STNNE) based on a networked structure of electrospun stretchable nanofibers made from a mixture of polyurethane (PU)/reduced graphene oxide (rGO)/silver nanoparticles (AgNPs). The STNNE showed a sheet resistance as small as 210 Ω sq-1 at an optical transparency of ∼83%. In addition, the STNNE has up to 40% mechanical stretchability and relatively high electrical stability (i.e., a resistance change of 83% at 40% stretching). The good electrical conductance, mechanical stretchability, and electrical stability under static/dynamic stretching or after cyclic stretching are attributed to the high dispersion of AgNPs in the nanofibers, which creates more electrically conductive pathways and forms fused junctions at the intersections between nanofibers during electrospinning. As a demonstration, an STNNE with a simple selective-patterning process was employed to fabricate a stretchable capacitive touch sensor with a stretchable and transparent dielectric (PU) on a polydimethylsiloxane substrate. The signal output of the touch sensor upon touching under stretched conditions was nearly unchanged. This STNNE has great potential in stretchable and transparent electronics.

Satiety behavior is regulated by ASI/ASH reciprocal antagonism.

Appropriate decision-making is essential for ensuring survival; one such decision is whether to eat. Overall metabolic state and the safety of food are the two factors we examined using C. elegans to ask whether the metabolic state regulates neuronal activities and corresponding feeding behavior. We monitored the activity of sensory neurons that are activated by nutritious (or appetitive) stimuli (ASI) and aversive stimuli (ASH) in starved vs. well-fed worms during stimuli presentation. Starvation reduces ASH activity to aversive stimuli while increasing ASI activity to nutritious stimuli, showing the responsiveness of each neuron is modulated by overall metabolic state. When we monitored satiety quiescence behavior that reflects the overall metabolic state, ablation of ASI and ASH produce the opposite behavior, showing the two neurons interact to control the decision to eat or not. This circuit provides a simple approach to how neurons handle sensory conflict and reach a decision that is translated to behavior.

Photoluminescence profiles and fast/slow annealing effects of Eu(III)/Tb(III)-codoped silica phosphor materials.

A silica (SiO2) nanoparticle matrix was codoped with luminescent Eu(III) and Tb(III) ions using a modified Stöber method. The effects of fast and slow thermal annealing on photoluminescence profile imaging were examined. Slow annealing treatment suppressed more quenching sites than fast thermal annealing to further increase the photoluminescence signals. The photoluminescence signals observed between 450 and 720 nm were assigned to the (5)D(0) → (7)F(J) (J = 0,1,2,3,4) of Eu(III) and the (5)D(4) → (7)F(J) (J = 6,5,4,3) transitions of Tb(III). Photoluminescence was largely sensitized by indirect excitation and was much stronger than that generated by direct excitation. The Eu(III) and Tb(III) ions were doped at lower symmetry sites in the silica matrix.

[The influence of the devotion movement on the health care in North Korea].

Since the early 1960s, North Korea has conducted 'devotion movement' under the directorship of Kim Il Sung across the nation. As a matter of fact, the movement was not a novel invention at all. When North Korean Temporary People's Polity was established in 1946, North Korea emphasized the importance of the devoted care of health personnel. It meant to reform the people's thought and mind along with complementing the lack of human and material resources. Thought reform was not a peculiar phenomenon observed in North Korea only. It was particularly stressed out among communist countries, including the Soviet Union. However any other communist country stresses the importance of thought reform. Devotion movement should be viewed as part of this process. As shown in many cases, the extent and degree of devotion movement and care are beyond our imagination, which does not intend to mean that North Korean health personnel's attitude towards patients is superior to the counterparts in South Korea. Indeed human being's behavior cannot be understood without taking account of society in general. The question can be raised as to whether or not North Korean health personnel's devoted care is really voluntary. To put aside the testimony that the most powerless group in a society can fall prey to victims, if social environment, whether directly or indirectly, is action on the people's thought and mind even in a subtle way and thus influence one's decision power, it is hard to highly evaluate the devoted care in North Korea. Moreover it seems like that the internal conflict exists surrounding devotion. In conclusion, I think that North Korean devotion movement has enforced health personnel to reform their thought and mind to adapt to North Korean regime and has played an important role to accomplish the purpose of North Korean Labor Party to realize essential constituents of its health system, in such a situation in which essential medical supplies are severely lacking. But it seems like that it plays reverse action to develope sound North Korean health system.

Computerized physician order entry and electronic medical record systems in Korean teaching and general hospitals: results of a 2004 survey.

OBJECTIVE: To determine the availability of computerized physician order entry (CPOE) and electronic medical record (EMR) systems in teaching and general hospitals in the Republic of Korea. DESIGN: A combined mail and telephone survey of 283 hospitals. MEASUREMENTS: The surveys assessed the availability of CPOE and EMRs in the hospitals, as well as inducement, participation, and saturation regarding CPOE use by physicians. RESULTS: A total of 122 (43.1%) hospitals responded to the survey. The complete form of CPOE was available in 98 (80.3%) hospitals. The use of CPOE was mandatory in 92 (86.0%) of the 107 hospitals that responded to the questions regarding the requirement of CPOE use. In 85 (79.4%) of the hospitals in which CPOE was in use, more than 90% of physicians used the system. In addition, physicians entered more than 90% of their total orders through CPOE in 87 (81.3%) hospitals. In contrast, a complete EMR system was available in only 11 (9.0%) of the hospitals. CONCLUSION: Of the teaching and general hospitals in the Republic of Korea that responded to the survey, the majority (80.3%) have CPOE systems, and a complete EMR system is available in only 9%.

Pseudophakic residual astigmatism.

We investigated pseudophakic residual astigmatism in order to minimize postoperative refractive astigmatism. We examined 110 eyes of 87 patients who had undergone phacoemulsification with small incision and posterior chamber intraocular lens (IOL) implantation. Corneal astigmatism was measured using an autokeratometer (RK-5, canon), refractive astigmatism by manifest refraction, and residual astigmatism by vector analysis. Mean pseudophakic residual astigmatism was +0.47 x 176 degrees, predominantly against-the-rule. Variations of pseudophakic residual astigmatism according to sex, age and IOL type were not statistically significant. When performing cataract surgery as refractive surgery, we may consider that pseudophakic residual astigmatism is approximately 0.50D against-the-rule.