Role of PemI in the Staphylococcus aureus PemIK toxin-antitoxin complex: PemI controls PemK by acting as a PemK loop mimic.

Staphylococcus aureus is a notorious and globally distributed pathogenic bacterium. New strategies to develop novel antibiotics based on intrinsic bacterial toxin-antitoxin (TA) systems have been recently reported. Because TA systems are present only in bacteria and not in humans, these distinctive systems are attractive targets for developing antibiotics with new modes of action. S. aureus PemIK is a type II TA system, comprising the toxin protein PemK and the labile antitoxin protein PemI. Here, we determined the crystal structures of both PemK and the PemIK complex, in which PemK is neutralized by PemI. Our biochemical approaches, including fluorescence quenching and polarization assays, identified Glu20, Arg25, Thr48, Thr49, and Arg84 of PemK as being important for RNase function. Our study indicates that the active site and RNA-binding residues of PemK are covered by PemI, leading to unique conformational changes in PemK accompanied by repositioning of the loop between ß1 and ß2. These changes can interfere with RNA binding by PemK. Overall, PemK adopts particular open and closed forms for precise neutralization by PemI. This structural and functional information on PemIK will contribute to the discovery and development of novel antibiotics in the form of peptides or small molecules inhibiting direct binding between PemI and PemK.

Role of Serum Pepsinogen II and Helicobacter pylori Status in the Detection of Diffuse-Type Early Gastric Cancer in Young Individuals in South Korea.

Background/Aims: The utility of serum pepsinogen (sPG) I and the sPGI/II ratio as biomarkers for screening individuals with gastric cancer (GC) has not been established in Korea. The aim of this study was to define the role of sPG, especially sPGII, in GC screening. Methods: This study enrolled 2,940 subjects, including patients with GC (n=1,124) or gastric dysplasia (n=353) and controls (n=1,463). Tests to determine sPG levels and Helicobacter pylori (HP) infection status were performed. Area under the curve and receiver operating characteristic curve were calculated to identify the optimal cutoff values for sPG. The usefulness of sPG levels for the detection of GC and gastric dysplasia was validated by multivariate logistic regression. Results: The sPGI/II ratio was associated with the risk of gastric dysplasia and advanced-stage intestinal-type GC (IGC). In contrast, sPGII was associated with the risk of early-stage diffuse-type GC (DGC). Significantly higher risk was indicated by an sPGI/II ratio <3 for gastric dysplasia and advanced-stage IGC and by sPGII levels ≥20 µg/L for early-stage DGC. Positive HP status showed a stronger association with DGC than with IGC. When sPGII level and HP status were combined, the prevalence of DGC was higher in the ≥20 µg/L sPGII and HP-positive group. Age younger than 40 years was strongly related to early-stage DGC, especially in females (odds ratio, 21.00; p=0.006). Conclusions: sPGII ≥20 ng/mL and positive HP status suggest a risk of early-stage DGC, particularly in young adult females in South Korea.

[Development of Koreans Gut Quotient Measurement Scales].

BACKGROUND/AIMS: The aim of this study was to develop 'Koreans Gut Quotient Measurement Scales (GQ)', in which Koreans respond to questionnaires about the subjective feelings and symptoms of their intestinal health status. METHODS: Among 66 items pooled from previous studies and 4 items that were added following a focus group interview, 15 items were chosen using the Delphi survey. The content validity was evaluated using the content validity ratio. Data collected from 1,120 people from the general public in Korea were analyzed to verify the reliability and validity of GQ. RESULTS: The finalized GQ consisted of 17 items (including two exploratory measurement items) that were classified into three independent factors based on exploratory factor analysis (EFA): 'perceived intestine discomfort', 'bowel movement discomfort', and 'bowel movement control discomfort'. The discriminant and convergent validity of GQ were identified using EFA, reliability test, and confirmatory factor analysis. In addition, the criterion-related validity of GQ was identified using correlation and multiple regression analysis. CONCLUSIONS: The GQ, which is a simplified intestinal health index developed based on an easy questionnaire for the public to understand, can be used as a tool for the public to evaluate their own intestinal health and determine when to visit clinics.

The prevalence of histologic atrophy and intestinal metaplasia in the corpus has decreased over 15 years in females in the Korean population.

BACKGROUND: The aim of this study was to investigate the trends of atrophy and intestinal metaplasia (IM) in 2002 subjects without significant gastroduodenal diseases. MATERIALS AND METHODS: A total of 2002 subjects were prospectively enrolled and divided into three periods (2003-2007, 2008-2012, and 2013-2018). Trends of H pylori and atrophy/IM scored by Updated Sydney System were analyzed according to sex, and multivariate logistic analysis was performed for the risk factors for atrophy/IM. RESULTS: H pylori-negative and H pylori-positive subjects were 1220 (61.0%) and 782 (38.0%), respectively. H pylori positivity decreased from 149/303 (49.2%), 207/515 (40.2%) and 426/1184 (36.0%), in the three periods, respectively (P < 0.001). The prevalence of atrophy (P < 0.001) and IM in the corpus (P < 0.001) significantly decreased over 15 years in females, but not in males. The mean grade of atrophy and IM was higher in males (0.36 and 0.51) than in females (0.28 and 0.41) in the corpus (P = 0.027) and in the antrum (P = 0.006), respectively. Similarly, the mean grade of IM in males (0.34) was higher in females (0.19; P < 0.001) in the corpus. Multivariate analysis showed that old age, study period, and H pylori were statistically significant in atrophy of antrum and corpus, and IM in the corpus. In cases of IM of antrum, old age, H pylori, and smoking were statistically significant. CONCLUSION: A significant decrease in atrophy and IM in the corpus in females over 15 years suggests sex- or gender-specific characteristics.

Influence of NK cell count on the survival of patients with diffuse large B-cell lymphoma treated with R-CHOP.

BACKGROUND: Although adding rituximab to the chemotherapy regimen of cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP) has improved clinical outcomes of patients with diffuse large B-cell lymphoma (DLBCL), several recent studies have shown that the effect of rituximab is dominantly in the non-germinal center (non-GC) subtype compared to the germinal center (GC) subtype. Natural killer (NK) cell count, a surrogate marker of immune status, is associated with clinical outcomes in DLBCL patients in the rituximab era. We investigated whether the impact of NK cells on clinical outcomes differed according to the immunophenotype of DLBCL. METHODS: This study analyzed 72 DLBCL patients treated with R-CHOP between January 2010 and January 2014. RESULTS: Low NK cell counts (<100/µL) were associated with poor progression-free survival (PFS) and overall survival (OS) compared to high NK cell counts. In multivariate analysis, low NK cell count was an independent prognostic factor for PFS and OS. However, survival did not significantly differ between the GC and non-GC subtypes. We examined the clinical influence of NK cells according to the immunophenotype and found that low NK cell counts were significantly associated with poor PFS and OS in non-GC cases, but not in GC cases. CONCLUSION: Low NK cell counts at diagnosis are associated with poor clinical outcomes in DLBCL patients treated with R-CHOP therapy. However, the impact is significant only in non-GC subtype DLBCL, not in the GC subtype.

Incidentally detected inoperable malignant pheochromocytoma with hepatic metastasis treated by transcatheter arterial chemoembolization.

Malignant pheochromocytoma (PCC) is a rare condition. Although the liver is the second most frequent site of metastasis in malignant PCC, no definite treatments have been established. Herein, we report a case of liver metastasis of PCC that was successfully treated by transcatheter arterial chemoembolization (TACE). A 69-year-old man was admitted to the Department of Gastroenterology for evaluation of an incidental hepatic mass in August 2013. He had undergone right adrenalectomy in May 2005 and PCC had been confirmed on the basis of histopathological findings. Liver biopsy was performed, and metastatic PCC was diagnosed. The lesion appeared inoperable because of invasion of the portal vein and metastases in the lymph nodes along the hepatoduodenal ligament. Thus, TACE was performed instead. After TACE, symptoms including dizziness and cold sweating improved, and the patient's serum catecholamine levels decreased. On the basis of this case, we believe that TACE may be a useful treatment for liver metastasis in malignant PCC.

Identification of a series of 1,3,4-trisubstituted pyrazoles as novel hepatitis C virus entry inhibitors.

In this report we describe the identification of novel pyrazole analogs as potent hepatitis C virus (HCV) entry inhibitor. The pyrazoles were identified by our phenotypic high-throughput screening using infectious HCV. A series of pyrazole derivatives was synthesized and evaluated for inhibitory activity against HCV in the infectious cell culture system. Through evaluation of selected compounds we observed that the pyrazoles did not interfere with HCV RNA replication but with viral entry as shown by experiments with HCV replicons and HCV pseudo particles, respectively.

Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers.

Parkinson's disease (PD) is characterized by selective and progressive degeneration of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SNpc) and by abnormal aggregation of α-synuclein. Previous studies have suggested that DA can interact with α-synuclein, thus modulating the aggregation process of this protein; this interaction may account for the selective vulnerability of DA neurons in patients with PD. However, the relationship between DA and α-synuclein, and the role in progressive degeneration of DA neurons remains elusive. We have shown that in the presence of DA, recombinant human α-synuclein produces non-fibrillar, SDS-resistant oligomers, while ß-sheet-rich fibril formation is inhibited. Pharmacologic elevation of the cytoplasmic DA level increased the formation of SDS-resistant oligomers in DA-producing neuronal cells. DA promoted α-synuclein oligomerization in intracellular vesicles, but not in the cytosol. Furthermore, elevation of DA levels increased secretion of α-synuclein oligomers to the extracellular space, but the secretion of monomers was not changed. DA-induced secretion of α-synuclein oligomers may contribute to the progressive loss of the dopaminergic neuronal population and the pronounced neuroinflammation observed in the SNpc in patients with PD.