Human herpesvirus 8 (HHV-8) is causally related to human malignancies. HHV-8 latent viral FLICE-inhibitory protein (vFLIP) is a viral oncoprotein that is linked to pathogenesis, but how its ...expression is regulated is largely unknown. In an attempt to understand the role of the mitochondrial antiviral signaling (MAVS) adaptor in HHV-8 infection, we discovered that vFLIP expression was post-translationally up-regulated by the MAVS signaling complex on peroxisomes. Furthermore, we demonstrated that vFLIP could be targeted to the peroxisomes, where it was oncogenically active, in a PEX19-dependent manner. Targeted disruption of vFLIP and MAVS interaction resulted in a decrease in vFLIP expression and selectively promoted death of latently HHV-8-infected cells, providing therapeutic potential for treating HHV-8 diseases. Collectively, our experimental results suggest novel involvement of peroxisomes and MAVS in the stabilization of vFLIP and thereby in the establishment or maintenance of HHV-8 latency and associated pathogenesis.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Even though research on perceiving a calling has been growing, our understanding of its double-edged sword effects and psychological mechanisms remain unclear, especially in terms of work engagement ...and workaholism. Based on the heavy working investment (HWI) and dualistic model of passion (DMP) theories, we established a dual-path structural model to examine the effects of callings on work engagement and workaholism through two types of passion: harmonious (HP) and obsessive (OP) passions. Our results showed that the association between perceiving a calling and work engagement was partially mediated by HP, while the association between perceiving a calling and workaholism was fully mediated by OP. This study contributes to the literature in that it reveals how perceiving a calling has different effects on work engagement and workaholism through the HWI theoretical lens, as well as the mediating roles of HP and OP, based on the DMP theory. Our findings can be practically applied in organizations and counseling.
Culturally held beliefs about the self and its relations with others affect the way individuals view their work. In this study, we examined the associations between individualism-collectivism and the ...three work orientations (i.e., viewing work as a job, a career, or a calling). We also investigated whether the positive effects of a calling orientation can be generalized to a developing eastern country, Mongolia. Using a sample of 352 Mongolian workers, we found that those endorsing horizontal collectivism tended to view their work as a calling more than as a job or a career. Mongolians with a calling orientation reported having better satisfaction with job, salary, and life, more work meaningfulness, and less turnover intention than those viewing work as a job or a career. The results suggest that cultural orientations and work orientations are intertwined, and the positive roles of a calling orientation are generalizable to Mongolia.
Full text
Available for:
NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
We aimed to determine the effect of optic disc tilt on deep learning-based optic disc classification. A total of 2507 fundus photographs were acquired from 2236 eyes of 1809 subjects (mean age of ...46 years; 53% men). Among all photographs, 1010 (40.3%) had tilted optic discs. Image annotation was performed to label pathologic changes of the optic disc (normal, glaucomatous optic disc changes, disc swelling, and disc pallor). Deep learning-based classification modeling was implemented to develop optic-disc appearance classification models with the photographs of all subjects and those with and without tilted optic discs. Regardless of deep learning algorithms, the classification models showed better overall performance when developed based on data from subjects with non-tilted discs (AUC, 0.988 ± 0.002, 0.991 ± 0.003, and 0.986 ± 0.003 for VGG16, VGG19, and DenseNet121, respectively) than when developed based on data with tilted discs (AUC, 0.924 ± 0.046, 0.928 ± 0.017, and 0.935 ± 0.008). In classification of each pathologic change, non-tilted disc models had better sensitivity and specificity than the tilted disc models. The optic disc appearance classification models developed based all-subject data demonstrated lower accuracy in patients with the appearance of tilted discs than in those with non-tilted discs. Our findings suggested the need to identify and adjust for the effect of optic disc tilt on the optic disc classification algorithm in future development.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Biophysical cues can improve the direct reprogramming of fibroblasts into neurons that can be used for therapeutic purposes. However, the effects of a three-dimensional (3D) environment on direct ...neuronal reprogramming remain unexplored. Here, we show that brain extracellular matrix (BEM) decellularized from human brain tissue facilitates the plasmid-transfection-based direct conversion of primary mouse embryonic fibroblasts into induced neuronal (iN) cells. We first show that two-dimensional (2D) surfaces modified with BEM significantly increase the generation efficiency of iN cells and enhance neuronal transdifferentiation and maturation. Moreover, in an animal model of ischaemic stroke, iN cells generated on the BEM substrates and transplanted into the brain led to significant improvements in locomotive behaviours. We also show that compared with the 2D BEM substrates, 3D BEM hydrogels recapitulating brain-like microenvironments further promote neuronal conversion and potentiate the functional recovery of the animals. Our findings suggest that 3D microenvironments can boost nonviral direct reprogramming for the generation of therapeutic neuronal cells.
Abstract
IL-21, a member of four-α-helical bundle type I cytokines, causes many pleiotropic effects, including terminal differentiation of B cells, immunoglobulin production, and the development of ...follicular helper T cells. IL-21 also promotes differentiation of Th17 cells and is implicated in the development of autoimmune disease. IL-21 can be strongly induced in CD4+ T cells by IL-6; however, very little is known about the mechanisms underlying the transcriptional regulation of the Il-21 gene at the chromatin level. Here, we identified insulator elements in the Il-21 locus with enhancer-blocking activity, which constitutively bind CTCF and cohesin. In naïve CD4+ T cells, these upstream and downstream CTCF-binding sites interact with each other to make a DNA loop; however, the Il-21 promoter does not interact with any cis-elements in the Il-21 locus. In contrast, stimulation of CD4+ T cells with IL-6 in the presence of αCD3 and αCD28 leads to recruitment of STAT3 and NFAT transcription factors to the promoter, as well as to novel distal enhancer region. This induces dynamic changes in chromatin configuration, bringing the promoter and the regulatory elements in close spatial proximity, facilitating IL-21 expression. The long-range interaction between the promoter and distal enhancer region was dependent on JAK/STAT3 signaling pathway but was disrupted in regulatory T cells, where IL-21 expression was repressed. In addition, we demonstrated that CTCF was required for optimal IL-21 expression and formation of chromatin looping in the Il-21 locus. Thus, our work uncovers a novel topological chromatin framework underlying proper transcriptional regulation of Il-21 gene.
Citation Format: Yeeun Choi. Dynamic long-range chromatin interaction controls expression of Il-21 in CD4+ T cells. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4531.
Synaptic adhesion molecules regulate diverse aspects of neuronal synapse development, including synapse specificity, formation, and maturation. Neph2, also known as Kirrel3, is an immunoglobulin ...superfamily adhesion molecule implicated in intellectual disability, neurocognitive delay associated with Jacobsen syndrome, and autism spectrum disorders. We here report mice lacking Neph2 (Neph2(-/-) mice) display moderate hyperactivity in a familiar, but not novel, environment and defective novel object recognition with normal performances in Morris water maze spatial learning and memory, contextual fear conditioning and extinction, and pattern separation tests. These mice also show normal levels of anxiety-like behaviors, social interaction, and repetitive behaviors. At the synapse level, Neph2(-/-) dentate gyrus granule cells exhibit unaltered dendritic spine density and spontaneous excitatory synaptic transmission. These results suggest that Neph2 is important for normal locomotor activity and object recognition memory.
Background Langerhans cells (LCs) are skin-resident dendritic cells (DCs) that orchestrate skin immunity. CCCTC-binding factor (CTCF) is a highly conserved DNA-binding protein that regulates ...higher-order chromatin organization and is involved in various gene regulation processes. Objective We sought to clarify a possible role for CTCF in LC homeostasis and function in vivo. Methods We used a conditional gene deletion mouse system to generate DC- and LC-specific CTCF-ablated mice. Short hairpin RNA–mediated RNA interference was used to silence CTCF expression in human monocyte-derived Langerhans cells. DC populations were assessed by using flow cytometry and immunofluorescence. Gene expression arrays were performed to identify genes regulated by CTCF in LCs. Contact hypersensitivity and epicutaneous sensitization responses were measured to examine the functional significance of CTCF ablation. Results DC-specific CTCF deletion led to a reduced pool of systemic DCs, with LCs most severely affected. Decreases in epidermal LC numbers were specifically associated with self-turnover defects. Interestingly, CTCF-deficient LCs demonstrated impaired migration out of the epidermis. Whole-transcriptome analyses revealed that genes that promoted cell adhesion were highly expressed, but CCR7 was downregulated in CTCF-depleted LCs. Hapten-induced contact hypersensitivity responses were more sustained in LC-specific CTCF-deficient mice, whereas epicutaneous sensitization to protein antigen was attenuated, indicating that CTCF-dependent LC homeostasis is required for optimal immune function of LCs in a context-dependent manner. Conclusion Our results show that CTCF positively regulates the homeostatic pool and the efficient emigration of LCs, which are required for modulating the functional immune network of the skin.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background: Moral Growth Mindset (MGM) is a belief about whether one can become a morally better person through efforts. Prior research showed that MGM is positively associated with promotion of ...moral motivation among adolescents and young adults. We developed and tested the English version of the MGM measure in this study with data collected from college student participants.
Methods: In Study 1, we tested the reliability and validity of the MGM measure with two-wave data (
N = 212, Age mean = 24.18 years,
SD = 7.82 years). In Study 2, we retested the construct validity of the MGM measure once again and its association with other moral and positive psychological indicators to test its convergent and discriminant validity (
N = 275, Age mean = 22.02 years,
SD = 6.34 years).
Results: We found that the MGM measure was reliable and valid from Study 1. In Study 2, the results indicated that the MGM was well correlated with other moral and positive psychological indicators as expected.
Conclusions: We developed and validated the English version of the MGM measure in the present study. The results from studies 1 and 2 supported the reliability and validity of the MGM measure. Given this, we found that the English version of the MGM measure can measure one's MGM as we intended.
In semiconductor fabrication (FAB), wafers are placed into carriers known as Front Opening Unified Pods (FOUPs), transported by the Overhead Hoist Transport (OHT). The OHT, a type of Automated Guided ...Vehicle (AGV), moves along a fixed railway network in the FAB. The routes of OHTs on the railway network are typically determined by a Single Source Shortest Path (SSSP) algorithm such as Dijkstra’s. However, the presence of hundreds of operating OHTs often leads to path interruptions, causing congestion or deadlocks that ultimately diminish the overall productivity of the FAB. This research focused on identifying structurally vulnerable links within the OHT railway network in semiconductor FAB and developing a visualization system for enhanced on-site decision-making. We employed betweenness centrality as a quantitative index to evaluate the structural vulnerability of the OHT railway network. Also, to accommodate the unique hierarchical node-port structure of this network, we modified the traditional Brandes algorithm, a widely-used method for calculating betweenness centrality. Our modification of the Brandes algorithm integrated node-port characteristics without increasing computation time while incorporating parallelization to reduce computation time further and improve usability. Ultimately, we developed an end-to-end web-based visualization system that enables users to perform betweenness centrality calculations on specific OHT railway layouts using our algorithm and view the results through a web interface. We validated our approach by comparing our results with historically vulnerable links provided by Samsung Electronics. The study had two main outcomes: the development of a new betweenness centrality calculation algorithm considering the node-port structure and the creation of a visualization system. The study demonstrated that the node-port structure betweenness centrality effectively identified vulnerable links in the OHT railway network. Presenting these findings through a visualization system greatly enhanced their practical applicability and relevance.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
