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Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement. The nonreceptor tyrosine kinase c-Abl has shown a potential role in the progression of PD. As such, c-Abl inhibition is a promising candidate for neuroprotection in PD and α-synucleinopathies. Compound 5 is a newly synthesized blood-brain barrier penetrant c-Abl inhibitor with higher efficacy than existing inhibitors. The objective of the current study was to demonstrate the neuroprotective effects of compound 5 on the α-synuclein preformed fibril (α-syn PFF) mouse model of PD. Compound 5 significantly reduced neurotoxicity, activation of c-Abl, and Lewy body pathology caused by α-syn PFF in cortical neurons. Additionally, compound 5 markedly ameliorated the loss of dopaminergic neurons, c-Abl activation, Lewy body pathology, neuroinflammatory responses, and behavioral deficits induced by α-syn PFF injection in vivo. Taken together, these results suggest that compound 5 could be a pharmaceutical agent to prevent the progression of PD and α-synucleinopathies.

The major suppressive immune cells in tumor sites are myeloid derived suppressor cells (MDSCs), tumor‐associated macrophages (TAMs), and Treg cells, and the major roles of these suppressive immune cells include hindering T‐cell activities and supporting tumor progression and survival. In this study, we analyzed the pattern of circulating MDSC subtypes in patients with non‐small cell lung cancer (NSCLC) whether those suppressive immune cells hinder T‐cell activities leading to poor clinical outcomes. First, we verified PMN‐MDSCs, monocytic‐MDSCs (M‐MDSCs), and Treg cells increased according to the stages of NSCLC, and MDSCs effectively suppressed T‐cell activities and induced T‐cell exhaustion. The analysis of NSCLC patients treated with anti‐PD‐1 immunotherapy demonstrated that low PMN‐MDSCs, M‐MDSCs, and CD39+CD8+ T cells as an individual and all together were associated with longer progression free survival and overall survival, suggesting PMN‐MDSCs, M‐MDSCs, and CD39+CD8+ T cells frequencies in peripheral blood might be useful as potential predictive and prognostic biomarkers., Pre‐existing PMN‐MDSCs, M‐MDSCs, and CD39+CD8+ T cells can be used as predictive biomarkers in anti‐PD‐1 immunotherapy targeting NSCLC. Together with MDSCs, IL‐10 possibly released by suppressive immune cells also leads poor clinical outcomes. Therefore, combinatorial strategies targeting MDSCs or IL‐10 should be investigated to improve outcomes of immune checkpoint inhibitors.

정보의 교류와 더불어 감정의 교류도 진행되는 담화에서 어기조사(modalparticle)의 역할은 매우 중요하다. 어기조사는 명제에 대한 화자의 태도나 감정을 나타내기 때문이다. 그러나 중국어 교수·학습에서는 어기조사가 그리 중요시되고 있지 않다. 특히 ‘嘛(-ma)’는 ‘嗎(-ma)’, ‘吧(-ba)’, ‘呢(-ne)’, ‘啊(-a)‘ 등의 다른 어기조사에 비해 더더욱 그러하다. 중국어교재나 문법서에서는 ‘嘛’에 관한 언급이 전혀 없거나 상당히 적다. 중국어사전에서는 ''嘛''에 관한 설명이 비교적 상세하지만 ''嘛''의 다양한 기능을 설명하기에는 아직도 부족함이 많다. 따라서 이러한 교수매체를 활용하여 체계적인 교수·학습을 진행하기에는 어려움이 있다. ''嘛''는 통사적 분포에 따라 다양한 기능을 가지고 있다. 이에 학자들이 ''嘛''에 대한 연구를 진행하였으나 연구 결과의 접점과 이견이 공존한다. 이에 본고는 선행연구를 고찰하고 그 시시비비를 가려 ''嘛''의 통사적 분포와 그에 따른 화용론적 특징을 전면적으로 고찰하였다. 본고의 연구 결과가 ‘嘛’의 교수·학습에 참고자료로 활용되기를 기대해본다.

Antitumor immune responses induced by immune checkpoint inhibitors anti-PD-1 or anti-PD-L1 have been used as therapeutic strategies in advanced non-small cell lung cancer (NSCLC) patients over the last decade. Favorable antitumor activity to immune checkpoint inhibitors is correlated with high PD-L1 expression, increased tumor-infiltrating lymphocytes, and decreased suppressive immune cells including Treg cells, myeloid-derived suppressor cells, or tumor-associated macrophages in various cancer types. In this study, we investigated the potential correlation between clinical outcomes and peripheral blood immune cell profiles, specifically focused on FoxP3+ Treg cells, collected at baseline and one week after anti-PD-1 therapy in two independent cohorts of patients with NSCLC: a discovery cohort of 83 patients and a validation cohort of 49 patients. High frequencies of circulating Treg cells one week after anti-PD-1 therapy were correlated with a high response rate, longer progression-free survival, and overall survival. Furthermore, high levels of TGF-β and Treg cells were associated with favorable clinical outcomes. Our results suggest that higher levels of FoxP3+ Treg cells and TGF-β can predict a favorable response to anti-PD-1 immunotherapy in patients with advanced NSCLC.

Although immune checkpoint inhibitors have significantly improved clinical outcomes in various malignant cancers, only a small proportion of patients reap benefits, likely due to the low number of T cells and high number of immunosuppressive cells in the tumor microenvironment (TME) of patients with advanced disease. We developed a cancer vaccine adjuvanted with nanoemulsion (NE) loaded with TLR7/8 agonist (R848) and analyzed its therapeutic effect alone or in combination with immune checkpoint inhibitors, on antitumor immune responses and the reprogramming of suppressive immune cells in the TME. NE (R848) demonstrated robust local and systemic antitumor immune responses in both subcutaneous and orthotopic mouse lung cancer models, inducing tumor-specific T cell activation and mitigating T cell exhaustion. Combination with anti-PD-1 antibodies showed synergistic effects with respect to therapeutic efficacy and survival rate. Thus, NE (R848)-based cancer vaccines could prevent tumor recurrence and prolong survival by activating antitumor immunity and reprogramming immunosuppression.

Background: Volume overload results in higher mortality rates in patients on continuous ambulatory peritoneal dialysis (CAPD). The ratio of bioimpedance (RBI) might be a helpful parameter in adjusting dry body weight in CAPD patients. This study examined whether it is possible to distinguish between non-hypervolemic status and hypervolemic status in CAPD patients by using only RBI. Methods: RBI was calculated as follows: RBI = impedance at 50 kHz/impedance at 500 kHz. Based on the experts’ judgements, a total of 64 CAPD patients were divided into two groups, a non-hypervolemic group and a hypervolemic group. The RBI was measured from right wrist to right ankle (rw-raRBI) by bioimpedance spectroscopy (BCM®, Fresenius Medical Care) before and after the peritosol was emptied. Other RBIs were measured from the right side of the anterior superior iliac spine to the ipsilateral ankle (rasis-raRBI) to control for the electro-physiological effects of peritoneal dialysate. Results: The mean rw-raRBI of non-hypervolemic patients was higher than that of hypervolemic patients in the presence (1.141 ± 0.022 vs. 1.121 ± 0.021, P < 0.001) of a peritosol. Likewise, the mean rasis-raRBI of non-hypervolemic patients was higher than that of hypervolemic patients (presence of peritosol: 1.136 ± 0.026 vs. 1.109 ± 0.022, P < 0.001; absence of peritosol: 1.131 ± 0.022 vs. 1.107 ± 0.022, P < 0.001). Conclusion: The volume status of CAPD patients was able to be simply expressed by RBI. Therefore, this study suggests that when patients cannot be analyzed using BCM, RBI could be an alternative.

The factors influencing continuous renal replacement therapy (CRRT) duration for critically ill patients with acute kidney injury (AKI) are unclear. Therefore, we investigated the clinical factors that could influence the duration of CRRT for AKI survivors. In this retrospective observational study, the medical records of all hospital survivors who required CRRT for AKI in intensive care units were analyzed. The CRRT duration (median, 6 days) was categorized as short-duration CRRT (≤ 6 days, n = 65) and long-duration CRRT (> 6 days, n = 59), according to the median CRRT duration. A urine output of less than 0.5 mL/kg/h (adjusted odds ratio [OR], 3.4; P = 0.010), mechanical ventilation use (adjusted OR, 7.9; P = 0.001), and extracorporeal membrane oxygenation (ECMO) use (adjusted OR, 6.5; P = 0.010) were independent predictors of long-duration CRRT, whereas serum creatinine and neutrophil gelatinase-associated lipocalin were not significant predictors. A clinical model demonstrated a good discriminatory ability to predict long-duration CRRT (area under the curve, 0.84; 95% confidence interval, 0.76-0.90). The urine output immediately before CRRT initiation and factors associated with disease severity significantly affected the duration of CRRT. Simultaneously considering the urine output, mechanical ventilation use, and ECMO use predicted CRRT duration in AKI survivors.

Background Evidence suggests that alkaline phosphatase attenuates inflammatory response in sepsis by lipopolysaccharide detoxification and adenosine triphosphate dephosphorylation. We sought to determine changes in alkaline phosphatase (AP) activity during septic acute kidney injury (AKI) and clinical parameters associated with AP activity. Methods In this retrospective study, we investigated baseline (when initiating CRRT) and follow-up AP activity on day 3, and associated outcomes in patients who underwent continuous renal replacement therapy (CRRT) due to septic AKI. Results We analyzed the baseline AP activity of 155 patients and day 3 AP activity in 123 patients. Baseline AP activity was not associated with renal or inflammatory biomarkers, or outcomes. It did not significantly differ between the 75 survivors and 80 non-survivors (p = 0.155). AP activity was higher on day 3 than at baseline (105 U/L [interquartile range, 79–156] vs 90 U/L [interquartile range, 59–133]). In particular, liver and bone isoforms increased significantly (p

The Chinese government has published an official guide specifying the aims for reading in Chinese and the expected comprehension levels for different proficiency learners, with regard to teaching and learning Chinese as a second or foreign language. However, due to lack of teacher training for its implementation, this guide has rarely been used for teaching reading to Chinese language learners and has rarely been used for evaluating their reading ability. Therefore, it appears that teaching and assessing reading comprehension have not been based on a theoretical background of reading ability. The purpose of this study is twofold: (1) to provide validity evidence of a Chinese reading test developed based on a theoretical model of reading ability; and (2) to examine reading test performance of Chinese learners with various reading ability levels. For the purpose of this study, reading ability was defined based on a meaning-based model that included three layers of reading comprehension: literal, intended, and implied meanings of a reading text. A total of 248 Korean university students were divided into three levels, and their test performances were analyzed and compared for the three meaning types using structural equation modeling and regression analysis. The results suggest that the test performance structure represented the meaning-based model in general, thereby providing validity evidence of the test. Further analyses revealed that the three groups differed from one another with respect to their understanding of literal, intended, and implied meanings. The findings provide pedagogical implications for teaching Chinese language learners with different reading proficiency levels. DOI: http://dx.doi.org/10.17576/GEMA-2014-1401-06

Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a serine/threonine kinase and a member of MAP4K. HPK1 is prominently expressed in subsets of hematopoietic cell lineages. HPK1 is a newly identified as a critical negative regulator in the activation of T lymphocytes and dendritic cells. It has been recently demonstrated that the important roles for kinase activity of HPK1 in anti-cancer immunity as a new intracellular checkpoint molecule as well as potential advantages of combination therapy with current checkpoint regimens. HPK1 inhibition is expected to have dual functions, 1. prolonged activation of T cells; 2. enhanced APC functions by dendritic cells. This dual targeting may synergistically work together for efficient immune responses in tumor microenvironment. We have developed a series of small molecule inhibitors of HPK1 with a lead compound of CMPD0431, which are orally available with good physicochemical and pharmacokinetic profiles. CMPD0431 and its series demonstrated good potency for HPK1 with kinase IC50 values of ~20 nM or under. Treatment of T cells with CMPD0431 successfully blocked serine 376 phosphorylation of SLP76, a critical biomarker substrate for HPK1 and also for downstream signaling in T cell activation, leading to sustained activation in human T cells. CMPD0431 was shown to increase the CD3/CD28-induced proliferation of human primary T cells with enhanced production of pro-inflammatory cytokines such as IFN-γ and IL-2. Furthermore, CMPD0431 enhanced the functional activity of antigen presentation with increased level of pro-inflammatory cytokine productions in mouse bone marrow-derived dendritic cells. All together, we have confirmed that HPK1 inhibition indeed play a dual function in T cells and dendritic cells to effectively promote cancer immunity. In the CT-26 syngeneic mouse model, we showed that CMPD0431 inhibited tumor growth with increased intratumoral infiltration of CD3+ lymphocytes and with increased pro-inflammatory cytokine production, demonstrating promoted cancer immunity with a potential for conversion of cold tumor into hot tumor. A subset of mice with high dose treatment of CMPD0431 showed a tumor regression with no further tumor regrowth for 20 days without compound treatment. The cured mouse group did not grow tumor even after re-challenging with CT-26 without compound treatment, demonstrating the effective immunological memory by CMPD0431. Those immune memory mouse group displayed increased secretion of IFN-γ by splenic T lymphocytes with enhanced response to the stimulation by CT-26 specific antigen, AH1 peptide. All together, these results support further development of CMPD0431 and its derivatives, first-in-class and advanced leads of HPK1 inhibitors with novel mechanism of action to be applied as a single-agent or combinational therapy with the current checkpoint inhibitors. Citation Format: Seungmook Lim, A Yeong Park, Misoon Kim, Gyooseung Jung, Suyeon Jo, Keonseung Lim, Gwibin Lee, Heekyoung Yang, Hyonam Kim, Hyeongjun Kim, Minwoo Lee, Jamie Jae Eun Kim, Jinhwa Lee. An HPK1 inhibitor CMPD0431 is a novel immuno-oncology agent that induces anti-tumor effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4150.

Background: The factors in tumor microenvironment hinder T-cell activities against tumor cells. The major immunosuppressive cells in tumor sites are myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T (Treg) cell, and the effector molecules released by those immunosuppressive cells also regulate T-cell activities. Therefore, in this study we examined the pattern of immunosuppressive cells in patients with non-small cell lung cancer. Then, we tested T-cell activities to verify whether the suppressive immune cell populations can influence T-cell activity by monitoring T-cell exhaustion markers. Since CD39 and CD73 expression on cytotoxic T-cell are known to be T-cell exhaustion markers, we analyzed CD39 and CD73 on CD8+ T-cells. Method: Baseline and one week after anti-PD-1 immunotherapy (pembrolizumab and nivolumab) blood samples (n=81) were collected (stage III and IV). For the correlation of suppressive immune cells with disease progression, baseline blood samples from the patients (n=59, stage I~IV) and healthy donors (n=21) were collected. Granulocytic-MDSC, Monocytic-MDSC, TAM, Treg, and CD39+ and CD73+ cytotoxic T-cell population from patients’ PBMC (n=81 and n=59) were analyzed by FACS Verse. For the suppressive assay, isolated T-cells were activated with anti-CD3 and anti-CD28 and then MDSC was co-cultured with T-cells for a week followed by Ki-67, CD39 and CD73 analysis by FACS Verse. Results: G-MDSC (p-value=0.0023), M-MDSC (p-value=0.0032), TAM ((p Citation Format: Jiae Koh, Kyung Young Lee, Boram Kim, Mi Soon Kim, Hee Jin Cho, Jong-Mu Sun, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn. CD39 increase on cytotoxic T-cell induced by myeloid-derived suppressor cell correlated with poor prognosis in patients with non-small cell lung cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A138.

Purpose The optimal timing for the initiation of early continuous renal replacement therapy (CRRT) is uncertain and requires a practically feasible definition with acceptable evidence. Materials and methods We investigated the clinical impacts of 3-time interval parameters on the morbidity and mortality of 177 patients with septic shock–induced acute kidney injury: (1) time from vasopressor initiation to CRRT initiation (T vaso-CRRT ), (2) time from intensive care unit (ICU) admission to CRRT initation (T ICU-CRRT ), and (3) time from endotracheal intubation to CRRT initiation (T endo-CRRT ). Results The proportion of the patients with T vaso-CRRT less than 24 h (median, 14 h, interquartile range [IQR], 5–30 h) was significantly higher in the survival group than in the non-survival group (84.3% vs. 58.5%, p vaso-CRRT less than 24 h and Sequential Organ Failure Assessment score were independent factors associated with 28-day mortality and 90-day mortality. T ICU-CRRT (median, 17 h, IQR, 5–72 h) and T endo-CRRT (median, 13 h, IQR, 4–48 h) were significantly correlated with both the length of ICU stay ( p p Conclusions Considering the possible therapeutic measurement by physician on the basis of the results in this study, early CRRT could be defined by a T vaso-CRRT less than 24 h.

Serotonin antagonist reuptake inhibitor (SARI) drugs that block both 5-HT(2) receptors and the serotonin transporters have been developed. The human 5-HT(2A/2C) receptor has been implicated in several neurological conditions, and potent selective 5-HT(2A/2C) ligands may have therapeutic potential for treatment of CNS diseases such as depression. An imidazole moiety usually provides good pharmacokinetic properties as a drug substance, and thus considerable efforts have been devoted to develop imidazole derivatives into drug candidates. The imidazole series of compounds was evaluated against 5-HT(2A/2C) and serotonin reuptake inhibition. A few of the compounds in the series showed promising IC(50) values and antidepressant-like effect in in vivo forced swimming test (FST). On the basis of these results, further lead optimization studies resulted in identifying promising compounds potentially for therapeutic use.

Numerous research groups have been engaged in searching for novel CB1 receptor antagonists, since SR141716A (rimonabant), a CB1 receptor antagonist, proved to be efficacious in human for the treatment of obesity. In the present study, a series of 1,2,4-triazole-containing diarylpyrazolyl carboxamides based on the 1,5-diarylpyrazole template of rimonabant, was synthesized and tested for CB1 receptor binding affinity. The structure-activity relationship studies demonstrated that incorporation of 1,2,4-triazole ring onto the pyrazole scaffold via a methylene linker led to a significant improvement for CB1 receptor binding affinity. Importantly, these analogues also exhibited excellent selectivity for CB1 receptor over CB2 receptor.

Objectives To determine whether the genotypes of virulent genes in Helicobacter pylori isolates and mucosal biopsy specimens differ in individuals, and to investigate whether different isolates from single hosts show strain differences. Methods Sixty-one Korean patients with H. pylori infection were enrolled. PCR and DNA sequencing for cagA, vacA, iceA, and oipA were performed using DNA extracted from H. pylori isolates cultured (2.6 H. pylori isolates per host) directly from antral mucosal biopsy specimens. Strain diversities were analyzed in 234 H. pylori isolates obtained from 43 hosts with at least two H. pylori isolates from antrum and body, respectively, and random amplified polymorphic DNA fingerprinting was carried out on isolates obtained from patients who showed genotype diversity. Results The patients with inconsistent genotyping results between H. pylori isolates and mucosal biopsies were as follows: 16.4% for cagA, 19.7% for vacA m, 47.5% for vacA s1, 6.6% for vacA i-region, 34.4% for iceA, and 21.3% for oipA. Genotyping of H. pylori isolates from same hosts showed diversity in 58.1% (25/43 patients). When random amplified polymorphic DNA -PCR fingerprinting was carried out on 104 H. pylori isolates from 19 patients who showed genotype diversity among their isolates, 68.4% (13 of 19 patients) of patients were found to be colonized by multiple H. pylori strains. Conclusion This study shows that the genotypes of virulent genes from biopsy samples produced different results when compared with those obtained from H. pylori isolates, especially for vacA s1, and iceA. In addition, about 60% of our patients were infected by multiple H. pylori strains.

pH-sensitive anionic hydrogels composed of poly(vinyl alcohol) (PVA) and poly(γ-glutamic acid) (γ-PGA) were prepared by the freeze drying method and thermally crosslinked to suppress hydrogel deformation in water. The physical properties, swelling, and drug-diffusion behaviors were characterized for the hydrogels. In the equilibrium swelling study, PVA/γ-PGA hydrogels shrunk in pH regions below the pKa (2.27) of γ-PGA, whereas they swelled above the pKa. In the drug-diffusion study, the drug permeation rates of the PVA/γ-PGA hydrogels were directly proportional to their swelling behaviors. The cytocompatibility test showed no cytotoxicity of the PVA/γ-PGA hydrogels for the 3T3 fibroblast cell lines. The results of these studies suggest that hydrogels prepared from PVA and γ-PGA could be used as orally administrable drug-delivery systems. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

Background: Since the cannabinoid receptor 1 (CB1) antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. Discussion: In the present study, biarylpyrazole analogues based on a sulfur-containing pyrazole core coupled with 1,3,4-oxadiazole and 1,3,4-thiadiazole were synthesized and assayed for rat CB1 receptor binding affinity. Results: The structure–activity relationship studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole or 1,3,4-thiadiazole rings led to four novel CB1 antagonists with IC50 values of approximately 1 nM for the rat CB1 receptor binding. Among these derivatives, we identified trifluoromethylcyclobutyl analogues 19e and 19l as promising precandidates for the development as anti-obesity agents.

Streptomyces coelicolor, the model species for morphologically complex actinomycete bacteria, has unique characteristics such as morphological and physiological differentiation, which are controlled by various factors and several protein kinases. From the whole genomic sequence of S. coelicolor A3(2), 44 putative serine/threonine (Ser/Thr) protein kinases were identified, and the pkaF gene was chosen as the best-conserved protein for typical Ser/Thr protein kinases. pkaF encodes a 667-amino acid protein with a predicted N-terminal Ser/Thr kinase domain and four repeated C-terminal penicillin-binding domains and Ser/Thr kinase-associated (PASTA) domains. Based on PCR, a pkaF gene was cloned and heterologously expressed. PkaF expressed in Escherichia coli had the bigger molecular size than the expected value (75 kDa) and was further purified by Ni2+-NTA agarose affinity column chromatography to homogeneity. The purified PkaF was autophosphorylated through the transfer of the γ-phosphate group of ATP. The extent of phosphorylation was proportional to the amount of PkaF, and the phospho-PkaF was dephosphorylated by the addition of the cell lysate of S. coelicolor A3(2). Although no change was observed in the pkaF disruptant, overexpression of pkaF induced severe repression of morphogenesis and actinorhodin production, but not undecylprodigiosin production, implying that PkaF specifically regulates morphogenesis and actinorhodin production in S. coelicolor.

Structure-activity relationship studies in a series of diarylpyrazolyl thiadiazoles identified cannabinoid-1 receptor antagonists with excellent potency and selectivity. Based on its exceptional in vivo efficacy in animal models and its favorable pharmacokinetic and toxicological profiles, 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)-5-tert-butyl-1,3,4-thiadiazole (GCC2680) was selected as a preclinical candidate for the treatment of obesity.

T cells play a pivotal role in the initiation and progression of multiple sclerosis. We have found that 1,4-aryl-2-mercaptoimidazole (KRM-III) inhibited T-cell antigen receptor- and phorbol myristate acetate/ionomycin-induced activation of nuclear factor of activated T cells (NFAT) and T-cell proliferation with an IC(50) of 5 microM. The KRM-III-mediated inhibitory effect was specific for NFAT activation but not for nuclear factor kappaB. Oral administration of 90 mg/kg KRM-III resulted in complete abrogation of anti-CD3 antibody-induced T-cell activation and a 45.8% reduction in footpad swelling in bovine serum albumin-induced delayed-type hypersensitivity. In the murine experimental autoimmune encephalomyelitis (EAE) model, oral administration of KRM-III significantly attenuated the severity of disease when given before or after disease onset. Draining lymph node cells from KRM-III-treated mice showed markedly reduced proliferation in response to myelin oligodendrocyte glycoprotein peptide. Histological analysis indicated that KRM-III reduced the infiltration of inflammatory cells to the white matter of spinal lumbar cords. These results demonstrate that KRM-III efficiently inhibits T-cell activation and inflammatory responses and lessens EAE clinical signs, which suggest KRM-III as a potential lead compound for the treatment of T-cell-driven autoimmune diseases.

Cannabinoid CB1 receptors have been the avenue of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of substituted pyrimidines based on chemical structure of Merck’s taranabant, a cannabinoid CB1 receptor inverse agonist. Noticeably, N4-((2S,3S)-3-(3-bromophenyl)-4-(4-chlorophenyl)butan-2-yl)-N6-butylpyrimidine-4,6-diamine (13b) demonstrated good binding affinity and decent selectivity for CB1 receptor (IC50 = 16.3 nM, CB2/CB1 = 181.6).

The sgtR1 and sgtR2 genes encoding putative regulators similar to the Aha1 and ArsR families, respectively, were identified downstream from the sprT gene. To investigate their function, expression vectors containing various combinations of sprT, sgtR1, and sgtR2 were transformed into Streptomyces lividans and Streptomyces griseus. The trypsin activity levels produced by S. lividans harboring pWHM3-TR2 (sprT and sgtR2) or pWHM3-TR1R2 (sprT, sgtR2, and sgtR2) were, respectively, 6.6 or 8.9 times that of S. lividans transformed with pWHM3-T (sprT). In the pWHM3-TR1R2 transformant, the transcription of sprT consistently occurred during the earlier stages of growth and was maintained at a higher level throughout the 6 days of cultivation. Streptomyces griseus IFO13350 harboring pWHM3-TR1R2 also produced trypsin activity 2.1 times that of the pWHM3-T transformant. However, all S. griseus Delta adpA transformants produced lower SGT activity than the wild-type strain, and none could overcome the deficiency in AdpA transcriptional activator, suggesting that AdpA is an absolute prerequisite for sprT expression. The sprT transcript was detected at a high level only in the wild-type strain, but the sgtR1 and sgtR2 transcript levels were very similar between the S. griseus IFO13350 and Delta adpA strains. This clearly demonstrates that the transcription of the sgtR1 and sgtR2 genes is not dependent on AdpA and that they are therefore not members of the AdpA regulon.

Methylmercury (MeHg) is a ubiquitous environmental toxicant and shows neurotoxicity to central nerve system (CNS) or neuronal cells. It has been known that MeHg has more influence to developing or differentiating CNS/neuronal cells than adult or differentiated CNS/neuronal cells. This study examined the effect of MeHg on differentiation of human neuroblastoma SH-SY5Y cells induced by all-trans-retinoic acid (RA). MeHg caused the impairment of the RA-induced G(1/0) phase arrest; it was induced the reduction of G(1/0) phase and S phase arrest. Extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase C (PKC) are involved in the RA-mediated differentiation and cell cycle progression. Activation of ERK1/2 by RA was increased more in MeHg-treated differentiating cells, comparing with only RA-treated groups. Furthermore, in both cases of inhibition of ERK1/2 with PD98059 or inhibition of PKC with GF109203X, RA/MeHg-induced ERK1/2 phosphorylation was reduced and G(1/0) phase arrest was induced. Thus, it indicates that the neuronal differentiation with RA was mediated by the ERK1/2 and PKC related pathway and MeHg resulted in neurotoxic influences through the disturbance in steps of differentiation by this pathway. These results suggest that MeHg inhibits RA-induced differentiation in SH-SY5Y cells by a pathway dependent ERK1/2 and PKC.

Twelve mecoprop-degrading bacteria were isolated from soil samples, and their genetic and phenotypic characteristics were investigated. Analysis of 16S rDNA sequences indicated that the isolates were related to members of the genus Sphingomonas. Ten different chromosomal DNA patterns were obtained by polymerase-chain-reaction (PCR) amplification of repetitive extragenic palindromic (REP) sequences from the 12 isolates. The isolates were found to be able to utilize the chiral herbicide mecoprop as a sole source of carbon and energy. While seven of the isolates were able to degrade both (R)- and (S)-mecoprop, four isolates exhibited enantioselective degradation of the (S)-type and one isolate could degrade only the (R)-enantiomer. All of the isolates were observed to possess plasmid DNAs. When certain plasmids were removed from isolates MP11, MP15, and MP23, those strains could no longer degrade mecoprop. This compelling result suggests that plasmid DNAs, in this case, conferred the ability to degrade the herbicide. The isolates MP13, MP15, and MP24 were identified as the same strain; however, they exhibited different plasmid profiles. This indicates that these isolates acquired different mecoprop-degradative plasmids in different soils through natural gene transfer.