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Background: Chronic kidney disease (CKD) is a common disease, affecting about 10% of the general population. The genetic component about CKD incidence in Asian population is not well known. The aim of the study is to find the genetic loci associated with incident CKD and to figure out the effect of genetic variation on the development of CKD. Methods: We conducted a genome-wide association (GWA) study regarding the development of CKD based on two population-based cohorts of Korean Genome Epidemiology Study. 3617 Koreans from two different cohorts, aged 40–49 years without CKD at initial visit, were included in our analysis. We used 2510 individuals in Ansan as the discovery set and another 1107 individuals from Ansung as the replication set. At baseline, members of both cohorts provided information on creatinine, and DNA samples were collected for genotyping. Single nucleotide polymorphisms that surpassed a significance threshold of P < 5 × 10−3 were selected. Results: A total of 281 among 3617 developed CKD during the follow-up period. Incident CKD group was older (P < 0.001), included more female (P < 0.001), and had more hypertension and diabetes (P < 0.001). We identified 12 SNPs that are associated with incident CKD in the GWA study and made genetic risk score using these SNPs. In multiple Cox regression analysis, genetic risk score was still a significant associated factor (HR 1.311, CI 1.201, 1.431, P < 0.001). Conclusions: We identified several loci highly associated with incident CKD. The findings suggest the need for further investigations on the genetic propensity for incident CKD. [ABSTRACT FROM AUTHOR]

Problem Trophoblasts are known to decrease natural killer ( NK) cell cytotoxicity. However, little is known about the interaction between trophoblasts and NK cells during pregnancy. Interleukin-15 ( IL-15) is essential for priming NK cells and maximizing their effector functions. We investigated whether trophoblasts regulate NK cell activation via IL-15/ IL-2 receptor and its signaling pathways. Method of study Natural killer-92 cells were primed with human first-trimester trophoblast cells (Sw.71) conditioned medium ( CM) and co-cultured with K562 cells. Flow cytometry, Western blot analysis, and real-time PCR were performed to assess NK cell cytotoxicity, IL-15/ IL-2 receptor expression, phosphorylation of STAT5 and MAPKs, and mRNA expression of IL-15-related genes. Results Natural killer-92 cells incubated with Sw.71 CM showed reduced cytotoxicity and IL-15-mediated proliferation, and expression of IL-15/ IL-2 receptor subunits. STAT5 phosphorylation, EOMES and T-bet mRNA expressions, and ERK/ JNK pathways of NK 92 cells were suppressed by Sw.71 CM. Productions of perforin, granzyme B, and IFN-γ were also downregulated. Conclusion Trophoblasts regulate human NK cell functions via suppression of IL-15/ IL-2 receptor expression, transcription factors, and ERK/ JNK pathways. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are innate immune effector cells that protect against cancer and some viral infections. Until recently, most studies have investigated the molecular signatures of human or mouse NK cells to identify genes that are specifically expressed during NK cell development. However, the mechanism regulating NK cell development remains unclear. Here, we report a regulatory network of potential interactions during in vitro differentiation of human NK cells, identified using genome-wide mRNA and miRNA databases through hierarchical clustering analysis, gene ontology analysis and a miRNA target prediction program. The microRNA (miR)-583, which demonstrated the largest ratio change in mature NK cells, was highly correlated with IL2 receptor gamma (IL2Rγ) expression. The overexpression of miR-583 had an inhibitory effect on NK cell differentiation. In a reporter assay, the suppressive effect of miR-583 was ablated by mutating the putative miR-583 binding site of the IL2Rγ 3′ UTR. Therefore, we show that miR-583 acts as a negative regulator of NK cell differentiation by silencing IL2Rγ. Additionally, we provide a comprehensive database of genome-wide mRNA and miRNA expression during human NK cell differentiation, offering a better understanding of basic human NK cell biology for the application of human NK cells in immunotherapy. [ABSTRACT FROM AUTHOR]

Highlights: [•] TXNIP interacts with hEcd. [•] TXNIP enhances p53 stability in the presence of hEcd. [•] TXNIP increases cell death in the presence of hEcd. [ABSTRACT FROM AUTHOR]

Abstract: Natural killer (NK) cells are differentiated from hematopoietic stem cells (HSCs) which are located at the lowest end of an oxygen gradient within the bone marrow (BM). In this report, we investigated whether oxygen tension could affect NK cell differentiation from hematopoietic cells in vitro. We found that hypoxia led to an inhibition of differentiation in NK cells, and increased oxygen supply alleviated this inhibition and restored NK cell differentiation under hypoxic condition. Hypoxia-treated cells demonstrated reduced mRNA expression of transcription factors (TFs) that have important roles in NK cell differentiation, such as EOMES, T-bet, GATA-3 and ETS-1. Moreover, hypoxia-pretreated cells recovered mRNA expression of TFs when the oxygen tension was changed to normoxia. Our findings suggest that oxygen tension modulates in vitro differentiation of NK cells through the regulation of TF expression. [Copyright &y& Elsevier]

Abstract: Natural killer (NK) cells act important roles in innate immunity and adaptive immunity. However, the mechanisms governing NK cell development have not been clearly elucidated. Previous studies have shown that an HMG (high-mobility group) protein, TOX, is important for regulating the differentiation program of developing T cells in mice. In this study, we examined the role of TOX in differentiation of human NK cells. Knockdown of TOX in differentiating cells decreased the NK cell population identified by expression of NK surface markers and receptors. In addition, over-expression of TOX enhanced the differentiation of NK cells which give rise to a population showing effector functions of mature NK cells. Moreover, TOX influenced expression of T-bet (T-box expressed in T cells, also as known as Tbx21) during NK cell development. Overall, these results suggest that TOX is required for IL-15-mediated NK cell differentiation and affected expression of T-bet that plays critical roles in NK differentiation and maturation. [Copyright &y& Elsevier]

Abstract: NK cells play crucial roles in innate immunity and adaptive immunity. The detailed mechanisms, however, governing NK cell development remains unclear. In this study, we report that YC-1 significantly enhances NK cell populations differentiated from human umbilical cord blood hematopoietic stem cells (HSCs). NK cells increased by YC-1 display both phenotypic and functional features of fully mature NK (mNK) cells, but YC-1 does not affect the activation of mNK cells. YC-1 did not affect cGMP production and phosphorylation of STAT-5 which is essential for IL-15R signaling. On the other hand, YC-1 increased p38 MAPK phosphorylation during NK cell differentiation. Furthermore, p38 inhibitor SB203580 inhibited the differentiation of NK cells enhanced by YC-1. Taken together, these data suggest that YC-1 enhances NK cell differentiation through the activation of p38 MAPK which is involved in NK cell differentiation. [Copyright &y& Elsevier]

Automatic guided vehicles (AGVs) have been successfully applied to cargo terminals to reduce operating costs and improve productivity. However, the focus was on container terminal operations. Ports with roll-on/roll-off (RORO) terminals still heavily depend on human resources for the loading/unloading processes. Work operations are affected by human errors and safety issues. In particular, terminals where vehicles cannot be stacked pressure workers to handle cargo more rapidly, which induces more errors. In this study, we propose automating RORO terminal operations by using AGVs. We assessed the impact of AGVs on the productivity, cost efficiency, and environment. A series of simulation models was developed on the basis of the current loading system at an actual port to test the impact of AGVs. Then, we developed a cost model to analyze the economic benefit of AGVs compared with the current loading system. The environmental benefits were also analyzed. Results revealed that a system using 29 AGVs matched the productivity of the current loading system, and using more AGVs increased the productivity. For a given productivity level, the total operating cost of the AGV system was three times less than that of the current system over a 15-year period. The AGV system also showed great potential for improving the environmental friendliness of terminal operations. This is the first study to propose automating RORO terminal operations to improve productivity and sustainability through AGV technology rather than human factors. AGVs are expected to become a good option in the future to address labor shortages and the "untact" era. [ABSTRACT FROM AUTHOR]

Hereditary Spastic Paraplegias (HSP) are a group of rare inherited neurological disorders characterized by progressive loss of corticospinal motor-tract function. Numerous patients with HSP remain undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel genetic variations related to HSP is needed. In this study, we identified 88 genetic variants in 54 genes from whole-exome data of 82 clinically well-defined Korean HSP families. Fifty-six percent were known HSP genes, and 44% were composed of putative candidate HSP genes involved in the HSPome and originally reported neuron-related genes, not previously diagnosed in HSP patients. Their inheritance modes were 39, de novo ; 33, autosomal dominant; and 10, autosomal recessive. Notably, ALDH18A1 showed the second highest frequency. Fourteen known HSP genes were firstly reported in Koreans, with some of their variants being predictive of HSP-causing protein malfunction. SPAST and REEP1 mutants with unknown function induced neurite abnormality. Further, 54 HSP-related genes were closely linked to the HSP progression-related network. Additionally, the genetic spectrum and variation of known HSP genes differed across ethnic groups. These results expand the genetic spectrum for HSP and may contribute to the accurate diagnosis and treatment for rare HSP. • In 104 clinically defined Korean HSP families, 54 HSP-related genes were identified. • This first report of 14 HSP genes in Koreans revealed a high ALDH18A1 frequency. • 54 HSP-related genes were linked to the HSP progression-related network. • Genetic HSP variants in Korean subjects differed from those in other ethnic groups. • The genetic diversity of Korean HSP expands the genetic spectrum for HSP diagnosis. [ABSTRACT FROM AUTHOR]

Perforin (Prf1) and granzyme B (GzmB) are essential effector molecules for natural killer (NK)-cell cytotoxicity, but how Prf1 and GzmB expression is regulated during arming of NK cells is poorly defined. We show that human microRNA (miR)-27a* is a negative regulator of NK-cell cytotoxicity by silencing Prf1 and GzmB expression. Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells, and it functioned as a fine-tuner for homeostasis of the net amount of the effector proteins. Consistent with miR-27a* having an inhibitory role, knockdown of miR-27a* in NK cells dramatically increased cytotoxicity in vitro and decreased tumor growth in a human tumor xenograft model. Thus, NK-cell cytotoxicity is regulated, in part, by microRNA, and modulating endogenous miR-27a* levels in NK cells represents a potential immunotherapeutic strategy. [ABSTRACT FROM AUTHOR]

Abstract Cisplatin causes acute kidney injury (AKI) through proximal tubular injury. We investigated the protective effect of the adenosine monophosphate protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) against cisplatin-induced AKI. We investigated whether the AMP-kinase activator AICAR ameliorates cisplatin-induced AKI through the JAK/STAT/SOCS pathway. Male Sprague-Dawley (SD) rats were randomly divided into four groups: control, AICAR, cisplatin, and cisplatin + AICAR. As appropriate to their treatment group, the rats were injected with a single dose of cisplatin (7 mg/kg, i.p.). AICAR was administered to the rats at 100 mg/kg i.p. daily. Blood urea nitrogen (BUN) and serum creatinine were measured. Renal damage was analyzed in sections stained with hematoxylin and eosin (H&E). Renal tissues were also examined by immunohistochemistry and western blot for p-AMPK, Kim-1, cleaved caspase 3, and JAK/STAT/SOCS. For in vitro studies, NRK-52E normal rat kidney cells were treated with cisplatin and/or AICAR. By western blot, we confirmed the expression of p-AMPK and the JAK/STAT/SOCS pathway in NRK-52E cells. AICAR was protective against cisplatin-induced acute tubular injury by up-regulating p-AMPK expression in NRK-52E cells. Protein expression levels of JAK2/STAT1 were markedly ameliorated in NRK-52E cells by AICAR. The protective mechanism of AICAR may be associated with suppression of the JAK2/STAT1 pathway and up-regulation of SOCS1, an inhibitor of the JAK2/STAT1 pathway. The present study demonstrates the protective effects of AICAR against cisplatin-induced AKI and shows a new renoprotective mechanism through the JAK2/STAT1/SOCS1 pathway and apoptosis inhibition. This study suggests that activation of the AMPK activator AICAR might ameliorate cisplatin-induced AKI. Highlights • AICAR, AMPK activator ameliorated cisplatin induced acute kidney injury. • Serum creatinine and BUN levels decreased in cisplatin-treated rats after treatment with AICAR. • AICAR with cisplatin treatment decreased p-STAT1 and p-JAK2, inhibitor of SOCS1 expression was decreased after cisplatin treatment group. • AICAR treatment improved AKI index, down-regulated KIM-1 expression in association with p-AMPK up-regulation. • AICAR ameliorated cisplatin-induced AKI, which may be associated with suppression of the JAK2/STAT1 pathway. [ABSTRACT FROM AUTHOR]

Decidual stromal cells ( DSCs) are known to regulate trophoblast invasion via unveiled mechanism yet. And nucleotide-binding oligomerization domain-containing protein 1 ( NOD1) may influence on this DSC-trophoblast interaction. We investigated the mechanism underlying the DSC-mediated regulation of trophoblast invasion and the effect of NOD1 on their cross talk. Using human primary DSCs, BeWo cell invasion was measured. Cytokine secretion and MAP kinase signaling were examined in DSCs following treatment with NOD1 agonist, Tri- DAP. DSCs secreted IL-8 and increased trophoblast invasion. Tri- DAP further increased IL-8 secretion from DSCs via JNK pathway and facilitated both MMP-2 production and trophoblast invasion compared with control. Upon cotreatment of IL-8 and anti- IL-8 antibody to BeWo cells, the number of invading trophoblasts and MMP-2 production decreased significantly. These results suggest that IL-8 from DSCs may play a role to increase the invasiveness of trophoblast cells into the decidua via NOD1/ JNK pathway. [ABSTRACT FROM AUTHOR]

Abstract: Vitamin-D3 upregulated protein-1 (VDUP1) is a stress response protein. Pseudomonas aeruginosa (P. aeruginosa) infection is a leading cause of death. Mice infected with live P. aeruginosa exhibit significantly decreased VDUP1 expression. However, the function of VDUP1 during P. aeruginosa-induced mouse bacteremic shock is unknown. To address the function of VDUP1 in P. aeruginosa-infected mice, we constructed a bacteremic shock model wherein both wild-type and VDUP1-deficient mice were infected intra-peritoneally with live P. aeruginosa. We found that VDUP1-deficient mice were more resistant to P. aeruginosa-induced bacteremic shock than wild-type mice, as shown by the increased survival, accelerated bacterial clearance and suppression of cytokine overproduction of the VDUP1-deficient mice. VDUP1 promoted the recruitment of neutrophils into the peritoneal cavities of infected mice. VDUP1 impeded the phagocytosis of non-opsonized P. aeruginosa via phosphatidylinositide 3-kinase (PI3K) pathway in macrophages. P. aeruginosa infection induced the generation of reactive oxygen species (ROS), and the increased production of ROS by the peritoneal cells of VDUP1-deficient mice was advantageous in clearing the bacteria. Overall, VDUP1 aggravates bacteremic shock; thus, VDUP1 can be considered a target molecule for the inhibition of P. aeruginosa-induced bacteremic shock. [Copyright &y& Elsevier]

Abstract: The IL-22 NKp46+ innate lymphoid cells, NCR22 cells, are very important for the early host defense against microbial pathogens. We show here that NCR22 cells were differentiated from Lin−CD127+CD117+ cells that were derived from hematopoietic precursor cells (HPCs) of mouse bone marrow cells. The combination of low concentrations of IL-23 and IL-15 induced differentiation of NCR22 cells from Lin−CD127+CD117+ cells. NCR22 cells expressed a large amount of IL-22 and RORγt, and they had poor cytolytic activity and produced little IFN-γ. Lin−CD127+CD117+ cells were very similar to intestinal lamina propria LTi-like cells; both cells dominantly expressed RORγt and IL-22. Meanwhile, Lin−CD127−CD117+ cells that were also derived from HPCs did not express RORγt and IL-22, and they developed into conventional NK cells, not into NCR22 cells. These findings revealed that NCR22 cells can be differentiated from Lin−CD127+CD117+ cells which are derived from HPCs. [Copyright &y& Elsevier]