Intact Recognition Memory and Altered Hippocampal Glucocorticoid Receptor Signaling in Fkbp5-deficient Mice Following Acute Uncontrollable Stress.

The FK506 binding protein 5 (FKBP5) is a co-chaperone that regulates the activity of the glucocorticoid receptor (GR) and has been reported to mediate stress resilience. This study aimed to determine the effects of Fkbp5 deletion on acute stress-induced recognition memory impairment and hippocampal GR signaling. Wild-type and Fkbp5-knockout mice were subjected to acute uncontrollable stress induced by restraint and electrical tail shock. First, we assessed the cognitive status of mice using a novel object recognition task. Next, we measured plasma corticosterone, GR levels, and the levels of GR phosphorylation at serine 211 in the hippocampus. Wild-type mice exhibited stress-induced memory impairments, whereas Fkbp5-knockout mice did not. Plasma corticosterone and GR levels did not differ between the non-stressed wild-type and Fkbp5-knockout mice, but the levels of phosphorylated GR were lower in Fkbp5-knockout mice than in wild-type mice. Wild-type and Fkbp5-knockout mice showed increased nuclear GR levels following stress, indicating GR translocation. However, cytosolic phosphorylated GR levels were lower in the hippocampi of Fkbp5-knockout mice following stress than in those of wild-type mice. These results suggest that FKBP5 deficiency increases resilience to acute stress by altering GR signaling.

Chemogenetic modulation of the medial prefrontal cortex regulates resistance to acute stress-induced cognitive impairments.

The medial prefrontal cortex (mPFC) has been implicated in regulating resistance to the effects of acute uncontrollable stress. We previously showed that mPFC-lesioned animals exhibit impaired object recognition memory after acute exposure to a brief stress that had no effect in normal animals. Here, we used designer receptors exclusively activated by designer drugs to determine how modulating mPFC activity affects recognition-memory performance under stressful conditions. Specifically, animals with chemogenetic excitation or inhibition of the mPFC underwent either a brief ineffective stress (20-min restraint + 20 tail shocks) or a prolonged effective stress (60-min restraint + 60 tail shocks). Subsequent recognition memory tests showed that animals with chemogenetic mPFC inhibition exposed to brief stress showed impairment in an object recognition memory task, whereas those with chemogenetic mPFC excitation exposed to prolonged stress did not. Thus, the present findings the decreased mPFC activity exacerbates acute stress effects on memory function whereas increased mPFC activity counters these stress effects provide evidence that the mPFC bidirectionally modulates stress resistance.

Peroxiredoxin 2 deletion impairs hippocampal-dependent memory via exacerbating transient ischemia-induced oxidative damage.

Peroxiredoxin 2 (Prx2) regulates oxidative stress response in neuronal injury. The present study examined the effects of Prx2 deletion on transient global ischemia-induced hippocampal-dependent memory impairment. First, 20-min bilateral common carotid artery occlusion (BCCAO)-reperfusion and sham-operated control procedures were conducted in 6- or 7-month-old Prx2 knockout and wild-type mice. The cognitive status of these mice was assessed using the Morris water maze task with a hidden platform and a novel object recognition task 7 days after the 20-min BCCAO. Next, to evaluate neuronal degeneration and oxidative stress in the CA1 subregion of the hippocampus critical for learning and memory, we measured immunoreactive Fluoro-jade C (FJC)-positive signals and 4-hydroxy-2-trans-nonenal (4-HNE) levels, respectively. The 20-min BCCAO induced cognitive impairments and increased the intensity of FJC-positive signals and 4-HNE levels of CA1 in Prx2 knockout mice but not in wild-type mice. These results suggest that Prx2 deficiency reduces resilience to transient global ischemia.

Surface-Modifying Effect of Zwitterionic Polyurethane Oligomers Complexed with Metal Ions on Blood Compatibility.

BACKGROUND: To prevent unsolved problems of medical devices, we hypothesized that combinatorial effects of zwitterionic functional group and anti-bacterial metal ions can reduce effectively the thrombosis and bacterial infection of polymeric biomaterials. In this research, we designed a novel series of zwitterionic polyurethane (zPU) additives to impart anti-thrombotic properties to a polyvinyl chloride (PVC) matrix. METHODS: We have synthesized zPUs by combination of various components and zPUs complexed with metal ions. Zwitterion group was prepared by reaction with 1,3-propane sultone and Nmethyldiethanolamine and metal ions were incorporated into sulfobetaine chains via molecular complexation. These zPU additives were characterized using FT-IR, 1H-NMR, elemental analysis, and thermal analysis. The PVC film blended with zPU additives were prepared by utilizing a solvent casting and hot melting process. RESULTS: Water contact angle demonstrated that the introduction of zwitterion group has improved hydrophilicity of polyurethanes dramatically. Protein adsorption test resulted in improved anti-fouling effects dependent on additive concentration and decreases in their effects by metal complexation. Platelet adhesion test revealed anti-fouling effects by additive blending but not significant as compared to protein resistance results. CONCLUSION: With further studies, the synthesized zPUs and zPUs complexed with metal ions are expected to be used as good biomaterials in biomedical fields. Based on our results, we can carefully estimate that the enhanced anti-fouling effect contributed to reduced platelet adhesion. Schematic explanation of the effect of zwitterionic polyurethane additives for blood-compatible and anti-bacterial bulk modification.

Optimal application of compressive palatal stents following mesiodens removal in pediatric patients: A Randomized Controlled Trial / Aplicación óptima de stents palatinos de compresión después de la extracción del mesiodens en pacientes pediátricos: un ensayo controlado aleatorio

Background: There is no scientific evidence supporting the choice of a palatal stent in patients who underwentremoval of an impacted supernumerary tooth. We aimed to investigate the effects of palatal stents in patients whounderwent supernumerary tooth removal through a palatal approach and to suggest the optimal stent thicknessand material.Material and Methods: We recruited 144 patients who underwent extraction of a supernumerary tooth between themaxillary anterior teeth. Subjects were assigned to a control group (CG) or one of four compressive palatal stentgroups (CPSGs) classified by the thickness and material of the thermoplastic acrylic stent used. Palatal gingivalswelling and objective indices (healing, oral hygiene, gingival, and plaque) were evaluated before surgery and onpostoperative days (PODs) 3, 7, and 14; pain/discomfort and the Child Oral Health Impact Profile (COHIP) wereassessed as subjective indices of the effects of the stent.Results: The CPSGs showed faster healing than did the CG on PODs 7 (P<0.001) and 14 (P=0.043); swelling wasmeasured by 1.64±0.88 mm and 4.52±0.39 mm, respectively. Although swelling was least in the 4-mm hard group(0.92±0.33 mm), the difference compared with that in the 2-mm hard group (1.01±0.18 mm) was not significant(P=0.077). The CPSGs showed better COHIP (P<0.001-0.036) and pain scores (P<0.001) than did the CG onPODs 1-3. Conclusions: Compressive palatal stents reduce discomfort by decreasing pain and alleviating swelling. Althougha stent is effective regardless of its thickness and material, 2-mm hard stents maximized such positive effects withminimal discomfort.(AU)

Engagement of lateral habenula in the extinction of the appetitive conditioned responses.

Following the association of a neutral stimulus (conditioned stimulus, CS) with a biologically significant stimulus (unconditioned stimulus, US), CS-alone presentations generate extinction: a decline in the conditioned response. Many studies have revealed the neural substrates of fear extinction; however, a few have identified the brain regions responsible for appetitive extinction. Midbrain dopamine neurons are activated by presenting a reward or predictable reward cue, whereas the cue signaling the absence of reward activates the lateral habenula (LHb) neurons. We examined the engagement of the LHb in appetitive extinction. In the first phase, rats first received pairings of a CS (light) with US delivery (food pellets). In the second phase, rats in the CS-alone group underwent four CS-alone presentations, whereas those in the paired group received four pairings of light with food pellets. We also included a comparison group for CS-alone presentations: rats were placed in the training box without CS or US exposures in the first phase and received four CS-alone presentations in the second phase. Thirty minutes after the second phase, c-Fos levels in the ventral tegmental area (VTA), substantia nigra pars compacta (SNc), and LHb in these groups were measured. c-Fos levels in the LHb were higher in the paired-CS-alone group than in the paired-paired and comparison groups, while those in the VTA and SNc were significantly higher in the paired-paired group than in the other groups. On examination of LHb neurotoxic lesion effects on the decline of conditioned food-cup responses when a CS was repeatedly presented with no US, LHb lesions decelerated the decline in conditioned food-cup responses, suggesting a crucial role of LHb in appetitive extinction.

SGK1 knockdown in the medial prefrontal cortex reduces resistance to stress-induced memory impairment.

Down-regulation of serum and glucocorticoid-regulated kinase1 (SGK1) expression has been reported in the postmortem prefrontal cortex (PFC) of subjects with post-traumatic stress disorder. Furthermore, experimental treatments that reduce SGK1 function in the medial prefrontal cortex (mPFC) cause depressive-like behaviors and synaptic dysfunction. Therefore, we examined the effect of SGK1 down-regulation in the mPFC on resistance to stress-induced cognitive impairment. Rats with viral-mediated knockdown of SGK1 in the mPFC were subjected to either a brief 20-min restraint plus 20 intermittent tail shocks or a prolonged 60-min restraint plus 60 intermittent tail shocks, after which their performance in an object recognition task was assessed. Recognition memory remained intact in control rats following the brief stress, but was impaired in rats with SGK1 knockdown in the mPFC. Prolonged stress impaired recognition memory in both control rats and rats with SGK1 knockdown. Our findings indicate that altered mPFC SGK1 signaling is a potential mechanism for resistance to stress-induced cognitive impairment.

Pedagogy, Partnership, and Collaboration: A Longitudinal, Empirical Study of Serious Educational Gameplay in Secondary Biology Classrooms.

The use of serious educational games has the potential to increase student learning outcomes in science education by providing students with opportunities to explore phenomena in ways that vary from traditional instruction; yet, empirical research to support this assertion is limited. This study aimed to explore deeply what learning gains were associated with the use of three serious educational games (SEGs) created for use in secondary biology classrooms that partner teachers implemented during a 2-week curriculum unit. This longitudinal, mixed method study includes a control year, in which we examined how six highly qualified teachers taught students (n = 407) a 2-week curriculum unit addressing cellular biology without the SEGs, followed by 2 years in which the teachers integrated the SEGs into the curriculum unit with students (n =871). Data were collected from multiple sources, including a validated content pre- and post-test measure, embedded gameplay data, participant observation, teacher interviews, and focus groups. Quantitative findings showed significant learning gains associated with students who experienced the game condition during year 2, when compared with the control condition. During the replication year (year 3), learning gains increased again, compared with year two. Although the SEGs did not change between years 2 and 3, teachers were provided real-time access to students' performance during gameplay. Thematic analysis of observation notes, teacher interviews, and student performance in-game identified four affordances teachers identified related to the use of serious educational games in their classrooms and the extended partnership model employed. Implications for researchers and game designers are discussed.

The Impact of Markov Chain Convergence on Estimation of Mixture IRT Model Parameters.

A nonconverged Markov chain can potentially lead to invalid inferences about model parameters. The purpose of this study was to assess the effect of a nonconverged Markov chain on the estimation of parameters for mixture item response theory models using a Markov chain Monte Carlo algorithm. A simulation study was conducted to investigate the accuracy of model parameters estimated with different degree of convergence. Results indicated the accuracy of the estimated model parameters for the mixture item response theory models decreased as the number of iterations of the Markov chain decreased. In particular, increasing the number of burn-in iterations resulted in more accurate estimation of mixture IRT model parameters. In addition, the different methods for monitoring convergence of a Markov chain resulted in different degrees of convergence despite almost identical accuracy of estimation.

Dexmedetomidine modulates transient receptor potential vanilloid subtype 1.

Dexmedetomidine, a highly selective alpha-2 adrenergic receptor agonist and novel sedative drug with minimal respiratory suppression, have shown anti-nociceptive activity in various pain models by poorly understood mechanisms. Because alpha-2 adrenergic receptor is co-localized with TRPV1 polymodal nociceptive receptor in dorsal root ganglion neurons and up-regulated in neuropathic pain animal models, the analgesic activity might be mediated through inhibition of TRPV1 in the peripheral nervous system. In an effort to elucidate whether modulatory effect of dexmedetomidine on TRPV1 activity could be the potential peripheral mechanism underlying the antinociceptive effect of dexmedetomidine, intracellular calcium concentration after capsaicin application was investigated in mice dorsal root ganglion (DRG) neurons, with and without pretreatment of dexmedetomidine. Dexmedetomidine (10 µM) reduced capsaicin-induced calcium responses by 29.7 ± 7.39% (n = 34, p < 0.0001), in dose-dependent manner. Higher level of inhibition was observed with increased dose of dexmedetomidine (50 µM, 45.1 ± 8.58%, n = 15, p = 0.0002), and lower inhibition by decreased dose (1 µM, 18.8 ± 1.48%, n = 148, p = 0.004). RT-PCR analysis revealed expression of TRPV1 and alpha-2A, alpha-2B and alpha-2C subtypes of adrenergic receptor in mice DRG neurons, and immunocytochemical analysis revealed co-expression of TRPV1 and alpha-2A receptors in primary cultured DRG neurons. In summary, these results suggested the inhibition of TRPV1 expressed in the primary sensory neurons as a potential mechanism that contributes to the anti-nociceptive action of dexmedetomidine.

Assessment of Cognitive Phenotyping in Inbred, Genetically Modified Mice, and Transgenic Mouse Models of Alzheimer's Disease.

Genetically modified mouse models are being used predominantly to understand brain functions and diseases. Well-designed and controlled behavioral analyses of genetically modified mice have successfully led to the identification of gene functions, understanding of brain diseases, and development of treatments. Recently, complex and higher cognitive functions have been examined in mice with genetic mutations. Therefore, research strategies for cognitive phenotyping should be sophisticated and evolve to convey the exact meaning of the findings and provide robust translational tools for testing hypotheses and developing treatments. This review addresses issues of experimental design and discusses studies that have examined cognitive function using mouse strain differences, genetically modified mice, and transgenic mice for Alzheimer's disease.

Synthesis and Electroresponse Activity of Porous Polypyrrole/Silica-Titania Core/Shell Nanoparticles.

Inverted conducting polymer/metal oxide core/shell structured pPPy/SiO2-TiO2 nanoparticles were prepared as electrorheological (ER) materials using sequential experimental methods. The core was synthesized via the low-temperature self-assembly of PPy and SiO2 materials, and the outer TiO2 shell was easily coated onto the core part using a sol-gel method and a titanium isopropoxide precursor. Sonication-mediated etching and redeposition were employed to etch out SiO2 portions from the core part to blend with TiO2 shells. Each step in nanoparticle synthesis involved morphological and physical changes to the surface area and porosity, with subsequent changes in the intrinsic properties of the materials. Specifically, the electrical conductivity and dielectric properties were successfully altered. The final pPPy/SiO2-TiO2 nanoparticle configuration was optimized for ER applications, offering low electrical conductivity, high dielectric properties, and increased dispersion stability. pPPy/SiO2-TiO2 nanoparticles exhibited 24.7- and 2.7-fold enhancements in ER performance compared to that of PPy-SiO2 and PPy-SiO2/TiO2 precursor nanoparticles, respectively. The versatile method proposed in this study for the synthesis of inverted conducting polymer/metal oxide core/shell nanoparticles shows great potential for the development of custom-designed ER materials.

Enhanced Electrorheological Performance of Mixed Silica Nanomaterial Geometry.

The mixed geometrical effect on the electrorheological (ER) activity of bimodal ER fluids was investigated by mixing SiO2 spheres and rods of different dimensions. To gain an in-depth understanding of the mixed geometrical effect, 12 bimodal ER fluids were prepared from 4 sizes of SiO2 spheres (50, 100, 150, and 350 nm) and 3 types of SiO2 rods with different aspect ratios (L/D = 2, 3, and 5). Five concentrations of SiO2 spheres and rods were created for each bimodal ER fluid, resulting in a total of 60 sets of comprehensive ER measurements. Some bimodal ER fluids exhibited enhanced ER performance, as high as 23.0%, compared to single SiO2 rod-based ER fluids to reveal the mixed geometrical effect of bimodal ER fluids. This interesting experimental result is based on the structural reinforcement provided by spheres to fibrillated rod materials, demonstrating the mixed geometrical effect on ER activity.

Smart Fluid System Dually Responsive to Light and Electric Fields: An Electrophotorheological Fluid.

Electrophotorheological (EPR) fluids, whose rheological activity is dually responsive to light and electric fields (E fields), is formulated by mixing photosensitive spiropyran-decorated silica (SP-sSiO2) nanoparticles with zwitterionic lecithin and mineral oil. A reversible photorheological (PR) activity of the EPR fluid is developed via the binding and releasing mechanism of lecithin and merocyanine (MC, a photoisomerized form of SP) under ultraviolet (UV) and visible (VIS) light applications. Moreover, the EPR fluid exhibits an 8-fold higher electrorheological (ER) performance compared to the SP-sSiO2 nanoparticle-based ER fluid (without lecithin) under an E field, which is attributed to the enhanced dielectric properties facilitated by the binding of the lecithin and SP molecules. Upon dual application of UV light and an E field, the EPR fluid exhibits high EPR performance (ca. 115.3 Pa) that far exceeds its separate PR (ca. 0.8 Pa) and ER (ca. 57.5 Pa) activities, because of the synergistic contributions of the PR and ER effects through rigid and fully connected fibril-like structures. Consequently, this study offers a strategy on formulation of dual-stimuli responsive smart fluid systems.

Graphene Oxide Wrapped SiO2 /TiO2 Hollow Nanoparticles Loaded with Photosensitizer for Photothermal and Photodynamic Combination Therapy.

Graphene oxide (GO) enwrapped SiO2 /TiO2 hollow nanoparticles (GO-HNP) are synthesized by the Stöber method and used as a nanocarrier for loading protoporphyrin IX (PpIX). The synthesized nanoparticle has high dispersibility and high uniformity in diameter (ca. 50 nm). Furthermore, this nanoparticle shows λ=808 nm laser induced PpIX release properties (photoinduced "on-off" drug-release system). GO-HNP-PpIX is employed for inducing both photothermal therapy (PTT) and photodynamic therapy (PDT). The synergic effect of PTT and PDT exhibits powerful anticancer properties. When cancer cells are treated with GO-HNP-PpIX and irradiated with both visible light and a NIR laser, the cell viability drops dramatically to 2.5 %, which is an anticancer effect approximately 13 times higher than that obtained in a previous study. Moreover, no significant cell damage has been observed under λ=808 nm laser irradiation. The GO-HNP-PpIX system suggests an external stimuli-responsive efficient anticancer treatment effect toward human breast cancer cells.

A folic acid conjugated silica-titania porous hollow nanosphere for improved topical photodynamic therapy.

The folic acid conjugated hollow nanosphere is used to encapsulate protoporphyrin IX and is utilized for photodynamic therapy. This system represents a 3.33 times higher photodynamic efficiency than previous protoporphyrin IX-based systems. The result proposes a new opportunity for effective photodynamic therapy of folate receptor positive tumor cells.

Highly fluorescent amidine/schiff base dual-modified polyacrylonitrile nanoparticles for selective and sensitive detection of copper ions in living cells.

Highly fluorescent surface modified polyacrylonitrile nanoparticles (PAN NPs) of 50 nm diameter were fabricated for selective Cu(2+) sensing. After surface modification, the PAN NPs were converted to amidine/Schiff base dual-modified PAN nanoparticles (tPAN NPs) with a Cu(2+) sensing property and high QY (0.19). The selectivity of tPAN NPs for Cu(2+) is much higher than that of other metal ions due to the fact that amidine group on the surface of tPAN NPs has a higher binding affinity with Cu(2+). The effect of other metal ions on the fluorescence intensity of the tPAN NPs was also studied, and other metal ions showed a low interference response in the detection of Cu(2+). Furthermore, as a metal ion chelator, ethylenediaminetetraacetate can competitively interact with Cu(2+) to recover the quenched fluorescence of tPAN NPs. The tPAN NPs are easily introduced into cells and exhibit low toxicity, enabling their use as a fluorescence sensor for Cu(2+) in living cells. The tPAN NPs provide a new direction for the development of copper ion sensors in living cells.

Fabrication of barium- and strontium-doped silica/titania hollow nanoparticles and their synergetic effects on promoting neuronal differentiation by activating ERK and p38 pathways.

Pristine, barium-doped, and strontium-doped hollow nanoparticles (p-HNPs, Ba-HNP, and Sr-HNP; HNPs) are prepared by sonication-mediated etching and redeposition (SMER) method and alkali-earth-metal hydroxide solution treatment. The HNPs are investigated to facilitate synergetic neuronal differentiation through alkali-earth-metal doping and in conjunction with nerve growth factor (NGF). PC12 cells are used as model cells for neuronal differentiation. The differentiation efficiency is improved in the presence of the HNPs+NGF, and the neurite length is in the order of Sr-HNP+NGF > Ba-HNP+NGF > p-HNP+NGF > NGF. Silica/titania have increasing effect on both differentiation efficiency and neurite length, and doped barium/strontium influences additional elongation of the average neurite length. Take advantage of hollow structure, NGF is encapsulated into HNPs, and they are further applied for directly inducing differentiation. The maximum differentiation efficiency is 67% in presence of the NGF-encapsulated Sr-HNP, which was 1.3 times higher than previous research. Furthermore, the neurite length is also 2.7 times higher than MnO2 decorated poly(3,4-ethylenedioxythiophene) nanoellipsoids. Ba- and Sr-HNP may offer a possibility for novel application of metal-hybrid nanomaterials for cell differentiation, and can be expanded to other cellular applications.

Enhanced antibacterial activity of silver/polyrhodanine-composite-decorated silica nanoparticles.

This work describes the synthesis of silver/polyrhodanine-composite-decorated silica nanoparticles and their antibacterial activity. Polymerization of polyrhodanine proceeded preferentially on the surface of the silica nanoparticles where Ag(+) ions were located. In addition, the embedded Ag(+) ions were reduced to form metallic Ag nanoparticles; consequently, silver/polyrhodanine-composite nanoparticles (approximately 7 nm in diameter) were formed on the surface of the silica nanoparticles. The resulting nanostructure was investigated using electron microscopy, Fourier-transform infrared spectroscopy, ultraviolet-visible spectroscopy, and X-ray photoelectron spectroscopy. The silver/polyrhodanine-nanocomposite-decorated silica nanoparticles exhibited excellent antimicrobial activity toward gram-negative Escherichia coli and gram-positive Staphylococcus aureus because of the antibacterial effects of the silver nanoparticles and the polyrhodanine. The silver/polyrhodanine-composite nanoparticles may therefore have potential for use as a long-term antibacterial agent.