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Inflammation is a host defense response to harmful agents, such as pathogenic invasion, and is necessary for health. Excessive inflammation may result in the development of inflammatory disorders. Levilactobacillus brevis KU15151 has been reported to exhibit probiotic characteristics and antioxidant activities, but the effect of this strain on inflammatory responses has not been determined. The present study aimed to investigate the anti-inflammatory potential of L. brevis KU15151 in Staphylococcus aureus lipoteichoic acid (aLTA)-induced RAW264.7 macrophages. Treatment with L. brevis KU15151 reduced the production of nitric oxide and prostaglandin E

Probiotics can effectively modulate host immune responses and prevent gastrointestinal diseases. The objective of this study was to investigate the probiotic characteristics of Lactobacillus brevis KU15152 isolated from kimchi and its protective potential against intestinal inflammation induced by Staphylococcus aureus lipoteichoic acid (aLTA). L. brevis KU15152 exhibited a high survival rate in artificial gastric and bile environments. Additionally, the adhesion capability of the strain to HT-29 cells was higher than that of L. rhamnosus GG. L. brevis KU15152 did not produce harmful enzymes, such as β-glucuronidase, indicating that it could be used as a potential probiotic. The anti-inflammatory potential of L. brevis KU15152 was determined in HT-29 cells. Treatment with L. brevis KU15152 suppressed the production of interleukin-8 without inducing significant cytotoxicity. The downregulatory effects of L. brevis KU15152 were involved in the suppression of nuclear factor-kappa B activation mediated by the extracellular signal-regulated kinase and Akt signaling pathways. Collectively, these data suggest that L. brevis KU15152 can be used in developing therapeutic and prophylactic products to manage and treat aLTA-induced intestinal damage.

Introductory paragraphWhile CAR T cells have altered the treatment landscape for B cell malignancies, the risk of on-target, off-tumor toxicity has hampered their development for solid tumors because most target antigens are shared with normal cells1,2. Researchers have attempted to apply Boolean logic gating to CAR T cells to prevent on-target, off-tumor toxicity3–7; however, a truly safe and effective logic-gated CAR has remained elusive8. Here, we describe a novel approach to CAR engineering in which we replace traditional ITAM-containing CD3ζ domains with intracellular proximal T cell signaling molecules. We demonstrate that certain proximal signaling CARs, such as a ZAP-70 CAR, can activate T cells and eradicate tumorsin vivowhile bypassing upstream signaling proteins such as CD3ζ. The primary role of ZAP-70 is to phosphorylate LAT and SLP-76, which form a scaffold for the propagation of T cell signaling. We leveraged the cooperative role of LAT and SLP-76 to engineerLogic-gatedIntracellularNetworK(LINK) CAR, a rapid and reversible Boolean-logic AND-gated CAR T cell platform that outperforms other systems in both efficacy and the prevention of on-target, off-tumor toxicity. LINK CAR will dramatically expand the number and types of molecules that can be targeted with CAR T cells, enabling the deployment of these powerful therapeutics for solid tumors and diverse diseases such as autoimmunity9and fibrosis10. In addition, this work demonstrates that the internal signaling machinery of cells can be repurposed into surface receptors, a finding that could have broad implications for new avenues of cellular engineering.

About 30 years ago, the discovery of CPP improved the therapeutic approach to treat diseases and extended the range of potential targets to intracellular molecules. There are potential drug candidates for FDA approval based on active studies in basic research, preclinical, and clinical trials. Various attempts by CPP application to control the diseases such as allergy, autoimmunity, cancer, and infection demonstrated a strategy to make a new drug pipeline for successful discovery of a biologic drug for immune modulation. However, there are still no CPP-based drug candidates for immune-related diseases in the clinical stage. To control immune responses successfully, not only increasing delivery efficiency of CPPs but also selecting potential target cells and cargoes could be important issues. In particular, as it becomes possible to control intracellular targets, efforts to find various novel potential target are being attempted. In this chapter, we focused on CPP-based approaches to treat diseases through modulation of immune responses and discussed for perspectives on future direction of the research for successful application of CPP technology to immune modulation and disease therapy in clinical trial.

About 30 years ago, the discovery of CPP improved the therapeutic approach to treat diseases and extended the range of potential targets to intracellular molecules. There are potential drug candidates for FDA approval based on active studies in basic research, preclinical, and clinical trials. Various attempts by CPP application to control the diseases such as allergy, autoimmunity, cancer, and infection demonstrated a strategy to make a new drug pipeline for successful discovery of a biologic drug for immune modulation. However, there are still no CPP-based drug candidates for immune-related diseases in the clinical stage. To control immune responses successfully, not only increasing delivery efficiency of CPPs but also selecting potential target cells and cargoes could be important issues. In particular, as it becomes possible to control intracellular targets, efforts to find various novel potential target are being attempted. In this chapter, we focused on CPP-based approaches to treat diseases through modulation of immune responses and discussed for perspectives on future direction of the research for successful application of CPP technology to immune modulation and disease therapy in clinical trial.

Probiotics can effectively modulate host immune responses and prevent gastrointestinal diseases. The objective of this study was to investigate the probiotic characteristics of

Herbs have been of interest to treat diseases, including obesity, owing to their various bioactive constituents that exhibit therapeutic and prophylactic properties. The present study examined the anti-adipogenic effects and mechanisms of Chrysanthemum indicum aqueous extract (CAE) in 3T3-L1 preadipocytes. CAE comprises 1,3-dicaffeoylquinic acid, chlorogenic acid, kaempferol-3-O-glucoside, caffeic acid, and apigenin, which were corresponded with previous reports. CAE inhibited the accumulation of lipid droplets and significantly alleviated the expression of lipogenesis- and adipogenesis-associated biomarkers. Treatment with CAE inhibited the mitotic clonal expansion (MCE), corroborated by cell cycle arrest at the G0 /G1 phase, and mitigated the expression of cell cycle progression-associated proteins and in addition to phosphorylation of MCE-promoting transcription factors. Moreover, CAE downregulated the activation of Akt and extracellular signal-regulated kinase 1/2 signaling pathways. In summary, CAE facilitates adipogenic inhibition during the early phase of differentiation, especially MCE, and its phenolic compounds can contribute to its anti-obesogenic properties. PRACTICAL APPLICATIONS: Chrysanthemum indicum has been mainly used as traditional herbal tea and drinks. Chrysanthemum indicum aqueous extract (CAE) inhibits adipogenesis by suppressing mitotic clonal expansion during the early phase of differentiation in 3T3-L1 preadipocytes. 1,3-Dicaffeoylquinic acid, chlorogenic acid, kaempferol-3-O-glucoside, caffeic acid, and apigenin were detected in CAE. Based on these findings, CAE can be used as nutraceutical agents for prevention and treatment of obesity.

Regulatory T cells play a key role in immune tolerance to self‐antigens, thereby preventing autoimmune diseases. However, no drugs targeting Treg cells have been approved for clinical trials yet. Here, a chimeric peptide is generated by conjugation of the cytoplasmic domain of CTLA‐4 (ctCTLA‐4) with dNP2 for intracellular delivery, dNP2‐ctCTLA‐4, and evaluated Foxp3 expression during Th0, Th1, Treg, and Th17 differentiation dependent on TGF‐β. The lysine motif of ctCTLA‐4, not tyrosine motif, is required for Foxp3 expression for Treg induction and amelioration of experimental autoimmune encephalomyelitis (EAE). Transcriptome analysis reveals that dNP2‐ctCTLA‐4‐treated T cells express Treg transcriptomic patterns with properties of suppressive functions. In addition, the molecular interaction between the lysine motif of ctCTLA‐4 and PKC‐η is critical for Foxp3 expression. Although both CTLA‐4‐Ig and dNP2‐ctCTLA‐4 treatment in vivo ameliorated EAE progression, only dNP2‐ctCTLA‐4 requires Treg cells for inhibition of disease progression and prevention of relapse. Furthermore, the CTLA‐4 signaling peptide is able to induce human Tregs in vitro and in vivo as well as from peripheral blood mononuclear cells (PBMCs) of multiple sclerosis patients. These results collectively suggest that the chimeric CTLA‐4 signaling peptide can be used for successful induction of regulatory T cells in vivo to control autoimmune diseases, such as multiple sclerosis., In this study, it is described how the synthetic peptide dNP2‐ctCTLA‐4 can induce Foxp3+ Tregs in mice and human peripheral blood mononuclear cells (PBMCs), ameliorate experimental autoimmune encephalomyelitis (EAE) progression with long‐term regulation and prevent disease relapse. On the basis of these findings, this peptide is an attractive drug candidate to increase Tregs in autoimmune diseases, such as multiple sclerosis.

The flower of Inula britannica contains various phenolic compounds with prophylactic properties. This study aimed to determine the anti-adipogenic effect of an I. britannica flower aqueous extract (IAE) and its underlying mechanisms in the 3T3-L1 preadipocytes and to identify the phenolic compounds in the extract. Treatment with IAE inhibited the adipogenesis of 3T3-L1 preadipocytes by showing a dose-dependently suppressed intracellular lipid accumulation and significantly mitigated expression levels of lipogenesis- and adipogenesis-associated biomarkers including transcription factors. IAE exerted an anti-adipogenic effect through the modulation of the early phases of adipogenesis including mitotic clonal expansion (MCE). Treatment with IAE inhibited MCE by arresting the cell cycle at the G0/G1 phase and suppressing the activation of MCE-related transcription factors. Furthermore, IAE inhibited adipogenesis by regulating the extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Protocatechuic acid, chlorogenic acid, kaempferol-3-O-glucoside, and 6-methoxyluteolin, which are reported to exhibit anti-adipogenic properties, were detected in IAE. Therefore, modulation of early phases of adipogenesis, especially MCE, is a key mechanism underlying the anti-adipogenic activity of IAE. In summary, the anti-obesity effects of IAE can be attributed to its phenolic compounds, and hence, IAE can be used for the development of anti-obesity products.

In article number 2004973, Je‐Min Choi and co‐workers develop a synthetic peptide dNP2‐ctCTLA‐4 that regulates experimental autoimmune encephalomyelitis progression and relapse in the longterm by inducing Foxp3(+) Treg cells in vivo. This peptide induces Treg cells in human peripheral blood mononuclear cells from multiple sclerosis (MS) patients and in a humanized mouse model, demonstrating that it would be a novel therapeutic agent for MS. [Image: see text]

We have carried out a multi-epoch simultaneous survey of 22 GHz H$_2$O and 44 GHz Class I CH$_3$OH masers toward 103 ultracompact HII regions (UCHIIs) between 2010 and 2017. We detected H$_2$O and CH$_3$OH maser emission in 74 (72%) and 55 (53%) UCHIIs, respectively. Among them, 3 H$_2$O and 27 CH$_3$OH maser sources are new detections. These high detection rates suggest that the occurrence periods of both maser species are significantly overlapped with the UCHII phase of massive star formation. The CH$_3$OH maser lines always have small (< 10 km s$^{-1}$) relative velocities with respect to the natal molecular cores, while H$_2$O maser lines often show larger relative velocities. Twenty four H$_2$O maser-detected sources have maser lines at relative velocities > 30 km s$^{-1}$, and thirteen of them show extremely high-velocity (> 50 km s$^{-1}$) components. The appearance and disappearance of H$_2$O maser lines are quite frequent over six-month or one-year time intervals. In contrast, CH$_3$OH maser lines usually do not exhibit significant variations in the line intensity, velocity, or shape for the same periods. The isotropic luminosities of both masers appear to correlate with the bolometric luminosities of the central stars. This correlation becomes much stronger in the case that data points in the low- and intermediate-mass regimes are added. The maser luminosities also tend to increase with the radio continuum luminosities of UCHIIs and the submillimeter continuum luminosities of the associated dense cores., Accepted for publication in ApJS, 43 pages, 13 figures, and 6 tables

This paper aims to develop the One-In-One web solutions that can work in PC, tablet, notebook, and smart phone depending on the flow of the ICT times to promote the marketing of the technology. The characteristics of this web solutions can be used to a image viewer system of 3D array type for PC, tablet, notebook, and smart phone. It is implemented in the design of 3D display slide show type. And it is developed an image viewer system, which enables users to use by utilizing the links manner ICT base required by each channel of the image. This is the 3D photo viewer PR solution developed in the way that anyone can use easily without the knowledge of programming in various areas such as public relations, business, and education. Key words : Technology Marketing, On-In-One, Web Solution, Image Viewer System, 3D 본 연구는 2015년 교육부와 한국연구재단의 지역혁신창의인력양성사업의 지원을 받아 수행된 연구임(2015_HICIA 1035526)This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

We map 6 massive young stellar objects (YSOs) in the CO J=2–1 line and survey 18 massive YSOs, including the six, in the HCO+ J=1−0, SiO J=2−1, H₂O 6 16 − 5 23 maser, and CH₃OH 7 0 − 6 1 A + maser lines. We detect CO bipolar outflows in all the six mapped sources. Four of them are newly discovered (07299−1651, 21306+5540, 22308+5812, 23133+6050), while 05490+2658 is mapped in the CO J=2–1 line for the first time. The detected outflows are much more massive and energetic than outflows from low-mass YSOs with masses >20 M ⊙ and momenta >300 M⊙ km s −1 . They have mass outflow rates (3−6)×10 −4 M ⊙ yr −1 , which are at least one order of magnitude greater than those observed in low-mass YSOs. We detect HCO+ and SiO line emission in 18 (100%) and 4 (22%) sources, respectively. The HCO + spectra show high-velocity wings in 11 (61%) sources. We detect H₂O maser emission in 13 (72%) sources and 44 GHz CH₃OH maser emission in 8 (44%) sources. Of the detected sources, 5 H₂O and 6 CH₃OH maser sources are new discoveries. 20081+3122 shows high-velocity (>30 km s −1 ) H₂O maser lines. We find good correlations of the bolometric luminosity of the central (proto)star with the mechanical force, mechanical luminosity, and mass outflow rate of molecular outflow in the bolometric luminosity range of 10 −1 −10 6 L ⊙ , and identified 3 intermediate- or high-mass counterparts of Class O objects.

Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates cellular responses such as proteasomal degradation and DNA repair upon interaction with its substrate. We identified a highly cationic region within the PAR-binding motif of Iduna; the region was similar among various species and showed amino acid sequence similarity with that of known cell-penetrating peptides (CPPs). We hypothesized that this Iduna-derived cationic sequence-rich peptide (Iduna) could penetrate the cell membrane and deliver macromolecules into cells. To test this hypothesis, we generated recombinant Iduna-conjugated enhanced green fluorescent protein (Iduna-EGFP) and its tandem-repeat form (d-Iduna-EGFP). Both Iduna-EGFP and d-Iduna-EGFP efficiently penetrated Jurkat cells, with the fluorescence signals increasing dose- and time-dependently. Tandem-repeats of Iduna and other CPPs enhanced intracellular protein delivery efficiency. The delivery mechanism involves lipid-raft-mediated endocytosis following heparan sulfate interaction; d-Iduna-EGFP was localized in the nucleus as well as the cytoplasm, and its residence time was much longer than that of other controls such as TAT and Hph-1. Moreover, following intravenous administration to C57/BL6 mice, d-Iduna-EGFP was efficiently taken up by various tissues, including the liver, spleen, and intestine suggesting that the cell-penetrating function of the human Iduna-derived peptide can be utilized for experimental and therapeutic delivery of macromolecules.

Background Current literatures describe good clinical outcomes of acute displaced fracture of clavicle treated with minimally invasive plate osteosynthesis (MIPO). But, there are little comparative data of the outcomes between open plating and MIPO techniques. We compared the outcomes of open plating and MIPO for treatment of acute displaced clavicular shaft fractures. Materials and methods The author performed a retrospective review on a consecutive series of patients with clavicular shaft fracture who underwent open plating or MIPO. Fourteen patients were treated with open plating with interfragmentary screw fixation, and 19 were treated with the MIPO technique without exposing a fracture site itself. A superior plating method was applied to both groups. Patient demographics, clinical outcomes using Constant score and University of California Los Angeles (UCLA) shoulder score, operation time, union rate, complications, and radiographic evaluation were evaluated. Results There were no statistically significant differences in the demographic data, including patient's variables (age, gender, involved side, smoking, alcohol, and diabetic status) and fracture characteristics (trauma mechanism, distribution of fracture type, presence of polytrauma, and time from trauma to surgery) between the two groups. Mean operation time was 87.5 min in open plating and 77.2 min in MIPO ( p = 0.129). The mean time to union was 15.7 weeks in patients who underwent open plating and 16.8 weeks in patients who underwent MIPO ( p = 0.427). Although there was no significant difference, nonunion developed 1 case in MIPO while none was in open plating. Four patients in open plating had skin numbness (none in MIPO, p = 0.024). There was no significant difference in the Constant score and UCLA score of the two surgical methods. Conclusion This study showed that both open plating with interfragmentary screw fixation (Open plating) and minimally invasive plate osteosynthesis (MIPO) are equally effective and safe treatment methods for acute displaced clavicle shaft fracture.

The aim of this study was to provide a method to assume the value of the continuous and possible management part to investigate the relationship between component of evaluation of Disaster Management and Sustainability Management in enterprise by obtaining Fuzzy Relation Matrix in view of necessity and possibility when there are new data. The index of Disaster Management was yielded from 100 small and medium-sized enterprises for 4 component of evaluations of based on ISO standard, and that of Sustainability Management was obtained from same enterprises for 6 component of evaluations in GRI G4 version of Sustainability Management guideline. The above results suggest that this model is significant by using 80 data as a training data and 20 data as a checking data from the 100 data obtained in this study.

Cytokines are released from the cell, bind to their receptors, and affect cellular responses. The precursor form of interleukin 1 alpha (pIL-1α) has a nuclear localization sequence (NLS) that causes it to be localized to the nucleus and regulate specific gene expression. The amino acids of the NLS are basic amino acid-rich sequences, as is the cell penetrating peptide (CPP), which has been widely studied as a way to deliver macromolecules into cells. Here, we hypothesized that the NLS in pIL-1α (pIL-1αNLS) can penetrate the cell membrane and it could deliver macromolecules such as protein in vivo. We characterized cell membrane penetration ability of pIL-1αNLS or its tandem repeated form (2pIL-1αNLS) to enhance its intracellular delivery efficiency. 2pIL-1αNLS showed comparable protein delivery efficiency to TAT-CPP and it mediates endocytosis following heparan sulfate interaction. 2pIL-1αNLS conjugated enhanced green fluorescence protein was localized to the nucleus and the cytoplasm. Intra-peritoneal administration of 2pIL-1αNLS conjugated dTomato protein showed remarkable in vivo intracellular delivery efficiency in various tissues including spleen, liver, and intestine in mice. Moreover, cytotoxicity of 2pIL-1αNLS was not observed even at 100 μM. Our results demonstrate cell membrane-penetrating function of NLS in pIL-1α, which can be used as a safe therapeutic macromolecular delivery peptide.

Summary Antibacterial activities of ginseng extracts produced from ginseng by-products, stems and leaves, using subcritical water extraction (SWE) at 110, 165 and 190 °C, were evaluated and compared with those of ginseng extracts prepared by hot water and ethanol extraction. The ginseng stems–leaves extract produced by SWE at 190 °C contained the greatest concentration of phenolics (98.4 mg GAE g−1 of extract). All ginseng extracts inhibited the growth of Bacillus cereus, Salmonella enteritidis, Escherichia coli O157:H7 and Listeria monocytogenes. Among four strains, B. cereus was more sensitive to the ginseng extract by SWE at 190 °C than other bacteria. Cell membranes of bacteria were disrupted by the addition of SWE ginseng extract, observed by transmission electron microscopy (TEM), with the release of cellular contents. These findings provided evidence about the potential utilisation of ginseng stems and leaves by using an environmental friendly extraction process, SWE, to produce ginseng extract for the inhibition of bacteria growth.

Biomolecules such as proteins, DNA, and RNA are macromolecules and can not cross the cell membrane. However, cell-penetrating peptide (CPP) has been shown to deliver therapeutic biomolecules successfully into cells. The various and widely used CPPs including TAT, VP22, and Antp are mostly non-human originated CPPs, and are limited by their potential toxicity and immunogenicity. We report here on a newly identified novel cell-penetrating sequence (LPIN; RRKRRRRRK) from the nuclear localization sequence (NLS) of human nuclear phosphatase, LPIN3. LPIN-EGFP recombinant protein was concentration- and time-dependently delivered into cells and localized to the nucleus as well as the cytoplasm. It penetrated the cell membrane by lipid raft-mediated endocytosis by binding to heparan sulfate proteoglycan. LPIN-EGFP was successfully delivered into primary mouse splenocytes in vitro and it could be delivered into various tissues including liver, kidney, and intestine in mice after intra-peritoneal injection. This research suggests that LPIN-CPP could be used in a drug delivery system to deliver therapeutic biomolecules including peptides, proteins, DNA, and RNA and without the limitations of non-human originated CPPs such as TAT-CPP.

We have carried out simultaneous 22 GHz H2O and 44 GHz Class I CH3OH maser line surveys of more than 1500 intermediate- and high-mass YSOs in the Galaxy using newly-constructed KVN 21-m telescopes. As the central (proto)stars evolve, the detection rates of the two masers rapidly decrease for intermediate-mass YSOs while the rates increase for high-mass YSOs. These results suggest that the occurrence of the two masers is closely related both to the evolutionary stage of the central objects and to the circumstellar environments. CH3OH masers always have very similar velocities (−1) to the natal dense cores, whereas H2O masers often have significantly different velocities. The isotropic luminosities of both masers are well correlated with the bolometric luminosities of the central (proto)stars.

We identified the intake pattern and consumption propensity of milk and sought improvements to promote consumption of milk. We targeted 362 preschool children aged 5~7 years old who attended nursery school in the Bucheon area. Questionnaires were distributed and 328 questionnaires were collected. Approximately 36.2% of boys and 31.2% of gorls drank milk six times per week. A total of 32.9% of the preschool children drank more than 2 cups of milk/day. Approximately 72.9% of them currently drink white milk, and 46.0% preferred milk to processed milk. The reasons why they drink milk included 'want to be tall'(66.5%) and 'good health'(52.4%). Mothers(54.6%)and preschool children(39.3%) were the purchasers with the greatest impact on product purchases. Consumer propensity to buy milk was shown in the order of expiration date(4.80 points), and nutrition facts(4.01 points). (4.88 points) and enhanced nutrients(4.59 points) should be promoted for milk consumption. Therefore, it is thought that continuous nutrition education should be made together in order to increase consumption of milk of children and education targeting teachers and school parents should be conducted as well. And in order for children to drink milk without repulsion, the development of various products satisfying both symbolic aspects and nutritional aspects should continue to be made.

In this study, the antimicrobial effects of an onion peel extract prepared using subcritical water extraction (SWE) were assessed for possible development into new bio-functional materials. The extraction temperatures were controlled to 110 and 160°C. At 0.15, 0.3, 0.6, and 1.2 mg extract/mL of broth, the growth inhibition and bactericidal activity of SWE extracts against Bacillus cereus KCCM 40935 and KCCM 11341 were compared with those of ethanol and hot-water extracts. In the case of B. cereus KCCM 40935, it appeared that over 0.6 mg/mL of SWE (110°C) extract exerted a bactericidal effect, and 1.2 mg/mL of SWE (160°C) extract exerted a bacteriostatic effect during culturing, and also that B. cereus KCCM 11341 was more resistant than B. cereus KCCM 40935. Furthermore, our results demonstrated that the death time of 107 CFU/mL of B. cereus KCCM 40935 treated with SWE (110°C) extract at 1.2 mg/mL was 60 min at maximum in 0.8% NaCl. Additionally, the cells damaged by SWE extract were observed with a SEM. It was suggested that an extract of onion peels prepared via SWE (110°C) could be used as a functional biomaterial for the food or pharmaceutical industries.

Atopic dermatitis and psoriasis are the two most common chronic inflammatory skin diseases with unmet needs. There are still no effective and safe topical therapeutics for inflammatory skin diseases and current developing biologics have limitation of administration methods. Here, we identified a novel transdermal delivery peptide (AP) and generated engineered immunomodulatory protein to inhibit dermatitis. AP-conjugated proteins exhibited significant intracellular transduction efficacy in keratinocytes, fibroblasts, and immune cells. Transdermal delivery of AP-dTomato protein showed localization into the dermis and epidermis in both mouse and human skin. Next, we generated AP-conjugated phosphatase domain of TC-PTP protein (AP-rPTP) for regulating cytokine and T cell receptor signaling. AP-rPTP inhibited pSTAT1, pSTAT3, pSTAT5 and pSTAT6 upon cytokine stimulation in mouse splenocytes. AP-rPTP also regulated T cell activation, proliferation and Th1, Th2 differentiation upon CD3/28 stimulation. The transdermal paper-patch of the AP-rPTP protein significantly ameliorated ear thickness, tissue inflammation, and cytokine expression in allergic dermatitis as well as in psoriasis-like mice models. These results collectively demonstrate the feasibility of utilizing AP peptide for biologic drug delivery via paper-patch and suggest AP-rPTP as a novel immune modulatory drug candidate for inflammatory skin diseases.

Central nervous system (CNS)-infiltrating effector T cells play critical roles in the development and progression of multiple sclerosis (MS). However, current drugs for MS are very limited due to the difficulty of delivering drugs into the CNS. Here we identify a cell-permeable peptide, dNP2, which efficiently delivers proteins into mouse and human T cells, as well as various tissues. Moreover, it enters the brain tissue and resident cells through blood vessels by penetrating the tightly organized blood–brain barrier. The dNP2-conjugated cytoplasmic domain of cytotoxic T-lymphocyte antigen 4 (dNP2-ctCTLA-4) negatively regulates activated T cells and shows inhibitory effects on experimental autoimmune encephalomyelitis in both preventive and therapeutic mouse models, resulting in the reduction of demyelination and CNS-infiltrating T helper 1 and T helper 17 cells. Thus, this study demonstrates that dNP2 is a blood–brain barrier-permeable peptide and dNP2-ctCTLA-4 could be an effective agent for treating CNS inflammatory diseases such as MS., Most of the cell penetrating peptides can transport therapeutic agents across plasma membranes but barely across the blood-brain barrier. Here the authors develop a peptide that can enter the brain, and show that its fusion to immunomodulatory protein ctCTLA-4 is effective in a mouse model of multiple sclerosis.

Background:Arthroscopic partial repair is a treatment option in irreparable large-to-massive rotator cuff tears without arthritic changes. However, there are indications that arthroscopic partial repair does not yield satisfactory outcomes.Purpose:To report the clinical and radiographic results of arthroscopic partial repairs in patients with irreparable large-to-massive cuff tears. In addition, an analysis was performed regarding preoperative factors that may influence patient outcomes and patient-rated satisfaction over time.Study Design:Case series; Level of evidence, 4.Methods:From 2005 to 2011, a total of 31 patients who underwent arthroscopic partial repair for irreparable large-to-massive cuff tears were retrospectively evaluated. Partial repair was defined as posterior cuff tissue repair with or without subscapularis tendon repair to restore the transverse force couple of the cuff. Pain visual analog scale (PVAS), questionnaire results (American Shoulder and Elbow Surgeons [ASES] and Simple Shoulder Test [SST]), and radiographic changes (acromiohumeral distance and degenerative change) were assessed preoperatively, at first follow-up (roughly 1 year postoperatively), and at final follow-up (>2 years postoperatively). Patients rated their satisfaction level at each postoperative follow-up as well. Preoperative factors that might influence outcomes, such as patient demographics, tear size, and fatty infiltration, were investigated.Results:The preoperative, first follow-up, and final follow-up results for mean PVAS (5.13, 2.13, and 3.16, respectively) and questionnaires (ASES: 41.97, 76.37, and 73.78; SST: 3.61, 6.33, and 6.07, respectively) improved significantly (all P < .05). Radiographic evaluation showed no difference compared with preoperative status. Nevertheless, patient-rated satisfaction at final evaluation was inferior: 16 good responses (“very satisfied” and “satisfied”) and 15 poor responses (“rather the same” and “dissatisfied”). Despite initial improvements in both groups ( P < .05), patients with poor satisfaction demonstrated statistically significant deterioration in mean PVAS (from 2.07 to 4.67), questionnaire scores (ASES: from 74.56 to 59.80; SST: from 5.11 to 3.81), and acromiohumeral distance (from 7.19 to 5.06 mm) between the first and final follow-up (all P < .05). Patients with good satisfaction showed no significant difference or they improved ( P > .05) from the first to the final follow-up. Among preoperative factors, fatty infiltration of the teres minor was identified as the only statistically significant factor affecting patient-rated satisfaction ( P = .007).Conclusion:This study showed that arthroscopic partial repair may produce initial improvement in selected outcomes at 2-year follow-up. However, about half of the patients in the study were not satisfied with their outcomes, which had deteriorated over time. Preoperative fatty infiltration of the teres minor was the only factor that correlated with worse final outcomes and poor satisfaction after arthroscopic partial repair.

In this paper, we consider fuzzy number-valued func- tions and fuzzy number-valued Choquet integrals. And we also discuss positively homogeneous and monotonicity of Choquet inte- grals of fuzzy number-valued functions(simply, fuzzy number-valued Choquet integrals). Furthermore, we prove convergence theorems for fuzzy number-valued Choquet integrals.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates lipid and glucose metabolism. Although studies of PPARγ ligands have demonstrated its regulatory functions in inflammation and adaptive immunity, its intrinsic role in T cells and autoimmunity has yet to be fully elucidated. Here we used CD4-PPARγKO mice to investigate PPARγ-deficient T cells, which were hyper-reactive to produce higher levels of cytokines and exhibited greater proliferation than wild type T cells with increased ERK and AKT phosphorylation. Diminished expression of IκBα, Sirt1, and Foxo1, which are inhibitors of NF-κB, was observed in PPARγ-deficient T cells that were prone to produce all the signature cytokines under Th1, Th2, Th17, and Th9 skewing condition. Interestingly, 1-year-old CD4-PPARγKO mice spontaneously developed moderate autoimmune phenotype by increased activated T cells, follicular helper T cells (TFH cells) and germinal center B cells with glomerular inflammation and enhanced autoantibody production. Sheep red blood cell immunization more induced TFH cells and germinal centers in CD4-PPARγKO mice and the T cells showed increased of Bcl-6 and IL-21 expression suggesting its regulatory role in germinal center reaction. Collectively, these results suggest that PPARγ has a regulatory role for TFH cells and germinal center reaction to prevent autoimmunity.

Post-translational phosphorylation plays critical roles in the assembly of signaling and repair proteins in the DNA damage response pathway. RAP80, a component of the BRCA1-A complex, is crucial in cell cycle checkpoint activation and DNA damage repair. However, its molecular mechanism is unclear. In this study, we identified Cdk1 as a new RAP80-binding protein and demonstrated that the Cdk1-cyclin B1 complex phosphorylates RAP80 at Ser-677 using an in vitro kinase assay and a phosphopeptide-specific antibody against phospho-Ser-677 of RAP80. RAP80 Ser-677 phosphorylation occurred in the M phase of the cell cycle when Cdk1 was in an active state. In addition, ionizing radiation (IR) induced RAP80 phosphorylation at Ser-677. Mutation of Ser-677 to alanine sensitized cells to IR and functioned in G2/M checkpoint control. These results suggest that post-translational phosphorylation of RAP80 by the Cdk1-cyclin B1 complex is important for RAP80 functional sensitivity to IR and G2/M checkpoint control. Background: RAP80, a component of the BRCA1-A complex, is crucial in the cell cycle checkpoint and DNA damage repair. Results: RAP80 phosphorylation by Cdk1 is important for sensitivity to ionizing radiation and G2/M checkpoint control. Conclusion: Cdk1-mediated RAP80 phosphorylation is important for the DNA damage response. Significance: The findings provide new implications for the interplay of the DNA damage signaling pathway and RAP80 phosphorylation.

Transcutaneous delivery of therapeutic drugs has many advantages of topical treatment over the systemic administration for inflammatory skin diseases such as atopic dermatitis or psoriasis. However, the greatest challenge for transcutaneous drug delivery limits clinical applications due to the skin tissue barrier. Here, we identified a novel transcutaneous delivery peptide, AP, from human neuronal adhesion protein (Astrotactin 1) which could deliver a macromolecule such as a protein into skin tissue. AP-conjugated EGFP protein exhibited significantly higher intracellular transduction efficacy in HaCaT (keratinocyte), NIH3T3 (fibroblast) and Jurkat (T cell) cells compared with control proteins. In addition, AP-EGFP and –dTomato protein was efficiently localized into the dermis as well as epidermis in mouse skin tissue following transcutaneous administration. Next, we generated AP-rPTP protein, which is chimeric protein of AP and phosphatase domain of TC-PTP. AP-rPTP inhibited phosphorylation of STAT1, 3, 5 in mouse splenocytes and T cells and reduced cytokines production by activated splenocyets. To confirm its in vivo relevance, we transcutaneously applied it to dermatitis mouse models. Multiple skin patch administrations of AP-rPTP protein significantly ameliorated tissue inflammation in oxazolone-induced contact dermatitis and imiquimod-induced psoriasis mouse model. Our results collectively demonstrate that AP is a novel human derived transcutaneous delivery peptide and AP-rPTP protein could be a therapeutic biomolecule in inflammatory skin diseases such as allergic dermatitis and psoriasis.

Multiple sclerosis (MS) is one of the most severe autoimmune disease, which cause severe inflammation in central nervous system (CNS). In the MS, CNS-infiltrating effector T cells are regarded that play critical roles. However, current drugs for MS could not targeting infiltrated T cells due to the limitations of drug delivery, which cannot penetrate blood-brain barrier (BBB) and deliver into the CNS. Here, we identified a novel BBB-permeable peptide, dNP2, which effectively delivered proteins into the CNS in vivo. It transduced cargo proteins into the cells with higher efficiency than other cargo delivery peptides. Moreover, it localized in resident neuron, astrocytes and microglia of the mouse brain through blood vessels by penetrating the BBB. Also, we found that dNP2 can deliver its cargo protein into the infiltrated T cells in the CNS of MOG35-55 immunized MS model mice. When we treated the dNP2-conjugated cytoplasmic domain of cytotoxic T lymphocyte antigen 4 (dNP2-ctCTLA-4), it efficiently downregulated cytokine production in activated T cells, and showed inhibitory impact on experimental autoimmune encephalomyelitis (EAE) in both preventive and therapeutic schemes. This was accompanied with reductions of demyelination and infiltration of T helper 1 (Th1) and T helper 17 (Th17) cells in the CNS. This study suggests that dNP2 is a novel BBB-permeable peptide and that dNP2-ctCTLA-4 could be an effective agent for treating CNS inflammatory diseases such as MS.

We report a multi-epoch, simultaneous 22 GHz H2O and 44 GHz class I CH3OH maser line survey towards 180 intermediate-mass young stellar objects, including 14 Class 0, 19 Class I objects, and 147 Herbig Ae/Be stars. We detected H2O and CH3OH maser emission towards 16 (9%) and 10 (6%) sources with one new H2O and six new CH3OH maser sources. The detection rates of both masers rapidly decrease as the central (proto)stars evolve, which is contrary to the trends in high-mass star-forming regions. This suggests that the excitations of the two masers are closely related to the evolutionary stage of the central (proto)stars and the circumstellar environments. H2O maser velocities deviate on average 9 km s^-1 from the ambient gas velocities whereas CH3OH maser velocities match quite well with the ambient gas velocities. For both maser emissions, large velocity differences (|v_{H2O} - v_{sys} | > 10 km s^-1 and |v_{CH3OH} - v_{sys}| > 1 km s^-1) are mostly confined to Class 0 objects. The formation and disappearance of H2O masers is frequent and their integrated intensities change by up to two orders of magnitude. In contrast, CH3OH maser lines usually show no significant change in intensity, shape, or velocity. This is consistent with the previous suggestion that H2O maser emission originates from the base of an outflow while 44 GHz class I CH3OH maser emission arises from the interaction region of the outflow with the ambient gas. The isotropic maser luminosities are well correlated with the bolometric luminosities of the central objects. The fitted relations are L_{H2O} = 1.71 * 10^{-9} (L_{bol})^{0.97} and L_{CH3OH} = 1.71 * 10^{-10} (L_{bol})^{1.22}., Accepted to ApJS, 40 pages, 9 figures, 9 tables

We report simultaneous multi-frequency observing performance at 22 and 43 GHz of the 21-m shaped-Cassegrain radio telescopes of the Korean VLBI Network (KVN). KVN is the first millimeter-dedicated VLBI network in Korea having a maximum baseline length of 480 km. It currently operates at 22 and 43 GHz and planed to operate in four frequency bands, 22, 43, 86, and 129 GHz. The unique quasioptics of KVN enable simultaneous multi-frequency observations based on efficient beam filtering and accuarate antenna-beam alignment at 22 and 43 GHz. We found that the offset of the beams is within 20 degrees., 33 pages, 10 figures, 9 tables, Accepted for publication in PASP

C/SiC composites were prepared via isothermal chemical vapor infiltration (ICVI). A novel process of in situ whisker growing and matrix filling during ICVI was devised to reduce the porosity of the C/SiC composites, by alternating the dilute-gas species. C/SiC composites with increased density were prepared successfully using this novel process, in comparison with those obtained from the conventional ICVI process. The whiskers seem to have grown into the large pores and modified the pore structure that is filled by the SiC matrix.

Follicular helper T (TFH) cells are recently highlighted as their crucial role for humoral immunity to infection as well as their abnormal control to induce autoimmune disease. During an infection, naïve T cells are differentiating into TFH cells which mediate memory B cells and long-lived plasma cells in germinal center (GC). TFH cells are characterized by their expression of master regulator, Bcl-6, and chemokine receptor, CXCR5, which are essential for the migration of T cells into the B cell follicle. Within the follicle, crosstalk occurs between B cells and TFH cells, leading to class switch recombination and affinity maturation. Various signaling molecules, including cytokines, surface molecules, and transcription factors are involved in TFH cell differentiation. IL-6 and IL-21 cytokine-mediated STAT signaling pathways, including STAT1 and STAT3, are crucial for inducing Bcl-6 expression and TFH cell differentiation. TFH cells express important surface molecules such as ICOS, PD-1, IL-21, BTLA, SAP and CD40L for mediating the interaction between T and B cells. Recently, two types of microRNA (miRNA) were found to be involved in the regulation of TFH cells. The miR-17-92 cluster induces Bcl-6 and TFH cell differentiation, whereas miR-10a negatively regulates Bcl-6 expression in T cells. In addition, follicular regulatory T (TFR) cells are studied as thymus-derived CXCR5(+)PD-1(+)Foxp3(+) Treg cells that play a significant role in limiting the GC response. Regulation of TFH cell differentiation and the GC reaction via miRNA and TFR cells could be important regulatory mechanisms for maintaining immune tolerance and preventing autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we review recent studies on the various factors that affect TFH cell differentiation, and the role of TFH cells in autoimmune diseases.

Background: Early pain control after gastrectomy is essential to minimize complication. We have compared the analgesic efficacy and side effects of sufentanil versus morphine for postoperative epidural analgesia. And we investigated the optimal dosage of sufentanil. Methods: Sixty of seventy-five patients underwent gastrectomy were randomly allocated into three groups to receive ropivacaine 0.15%+sufentanil 0.5/hour (group S1), or ropivacaine 0.15%+sufentanil 1.0/hour (group S2) or ropivacaine 0.15% morphine+32/hour (group M). Before surgery, an epidural catheter was inserted at T 7-9 level and sufentanil 20 in group S1 and S2 or morphine 2 mg in group M were injected via the epidural catheter. After completion of surgery, continuous epidural infusion was started using PCEA device. Basal infusion rate, lock out time, bolus dose were 4 ml/hour, 20 minutes and 4 ml, respectively. Resting VAS, coughing VAS and side effects were recorded : immediate after awakening, 6, 12, 24, 48 hours after surgery. Forced vital capacity was assessed before and at 6, 24, 48 hours after surgery. Results: There were no significant differences in resting VAS, coughing VAS and FVC among three groups. The number of side effects, especially pruritus and sedation were significantly more in group M than group S1 and S2 (P /hour.

Background: The use of intraoperative brainstem auditory evoked potential (BAEP) has reduced the incidence of sensorineural hearing loss (SNHL) after microvascular decompression (MVD). This complication occurs due to direct compressive and/or stretching injury of the cochlear nerve or to indirect compression of the perineural vasculature during cerebellar retraction. The aim of this study was to evaluate the effect of thiopental sodium on SNHL after MVD for hemifacial spasm. Methods: 94 hemifacial spasm patients with normal hearing function preoperatively and who underwent MVD under intraoperative BAEP monitoring were enrolled in this study. Patients were randomly divided into two groups. 52 patients were administered placebo (control group) and 42 patients were administered thiopental sodium 5 mg/kg intravenously 5 minutes before cerebellar retraction (thiopental group). The effects of thiopental on intraoperative BAEP changes and postoperative hearing functional outcomes were sought. Incidence and degree of postoperative SNHL were evaluated by pure tone audiometry threshold analysis. Results: Maximal changes in intraoperative BAEP parameters did not differ between the two groups, and neither did the incidence nor degree of SNHL. In the control group, 4 transient and 4 permanent postoperative SNHL, including 2 deaf patients, occurred with an overall incidence of 15.4%. In the thiopental group, 2 transient and 1 permanent postoperative SNHL occurred, with an overall incidence of 7.1%. Conclusions: Thiopental sodium administered prior to cerebellar retraction might reduce the incidence of postoperative hearing loss.