We propose a highly scalable cluster-based hierarchical trust management protocol for wireless sensor networks (WSNs) to effectively deal with selfish or malicious nodes. Unlike prior work, we ...consider multidimensional trust attributes derived from communication and social networks to evaluate the overall trust of a sensor node. By means of a novel probability model, we describe a heterogeneous WSN comprising a large number of sensor nodes with vastly different social and quality of service (QoS) behaviors with the objective to yield "ground truth" node status. This serves as a basis for validating our protocol design by comparing subjective trust generated as a result of protocol execution at runtime against objective trust obtained from actual node status. To demonstrate the utility of our hierarchical trust management protocol, we apply it to trust-based geographic routing and trust-based intrusion detection. For each application, we identify the best trust composition and formation to maximize application performance. Our results indicate that trust-based geographic routing approaches the ideal performance level achievable by flooding-based routing in message delivery ratio and message delay without incurring substantial message overhead. For trust-based intrusion detection, we discover that there exists an optimal trust threshold for minimizing false positives and false negatives. Furthermore, trust-based intrusion detection outperforms traditional anomaly-based intrusion detection approaches in both the detection probability and the false positive probability.
We aimed to investigate the association between nonalcoholic fatty liver disease (NAFLD) and cerebral small vessel disease (CSVD) burden, especially according to the NAFLD severity. A total of 1,260 ...participants were included. The CSVD burden was assessed with white matter hyperintensities (WMH), lacunes, and microbleeds (MBs) on brain MRI. An ultrasound diagnosis of fatty liver was made based on standard criteria, and the Fibrosis-4 (FIB-4) index was used to classify participants with NAFLD with having a high-intermediate (FIB-4 ≥1.45) or low (FIB-4 < 1.45) probability of advanced fibrosis. A multivariable logistic regression analysis was used to assess the association between NAFLD and the presence of moderate to severe WMH, lacunes, and MBs. NAFLD had a significant association only with moderate to severe WMH (OR: 1.64, 95% CI: 1.10-2.42), even after controlling for cardiometabolic risk factors. A linear trend test showed a significant association between the severity of NAFLD fibrosis and the presence of moderate to severe WMH (p for trend <0.001). Our findings suggest that NAFLD, especially NAFLD with fibrosis, has a significant association with the presence of moderate to severe WMH in cognitively normal individuals, and NAFLD severity predicted more frequent moderate to severe WMH.
Rheumatoid arthritis (RA) is a systemic inflammatory disease that mainly affects the synovial joints. Although involvement of the fibroblast growth factor (FGF) signaling pathway has been suggested ...as an important modulator in RA development, no clear evidence has been provided. In this study, we found that synovial fluid basic FGF (bFGF) concentration was significantly higher in RA than in osteoarthritis (OA) patients. bFGF stimulates proliferation and migration of human fibroblast-like synoviocytes (FLSs) by activation of the bFGF-FGF receptor 3 (FGFR3)-ribosomal S6 kinase 2 (RSK2) signaling axis. Moreover, a molecular docking study revealed that kaempferol inhibited FGFR3 activity by binding to the active pocket of the FGFR3 kinase domain. Kaempferol forms hydrogen bonds with the FGFR3 backbone oxygen of Glu555 and Ala558 and the side chain of Lys508. Notably, the inhibition of bFGF-FGFR3-RSK2 signaling by kaempferol suppresses the proliferation and migration of RA FLSs and the release of activated T-cell-mediated inflammatory cytokines, such as IL-17, IL-21, and TNF-α. We further found that activated phospho-FGFR3 and -RSK2 were more highly observed in RA than in OA synovium. The hyperplastic lining and sublining lymphoid aggregate layers of RA synovium showed p-RSK2-expressing CD68
macrophages with high frequency, while pRSK2-expressing CD4
T-cells was observed at a lower frequency. Notably, kaempferol administration in collagen-induced arthritis mice relieved the frequency and severity of arthritis. Kaempferol reduced osteoclast differentiation in vitro and in vivo relative to the controls and was associated with the inhibition of osteoclast markers, such as tartrate-resistant acid phosphatase, integrin β3, and MMP9. Conclusively, our data suggest that bFGF-induced FGFR3-RSK2 signaling may play a critical role during the initiation and progression of RA in terms of FLS proliferation and enhanced osteoclastogenesis, and that kaempferol may be effective as a new treatment for RA.
Aim
This cross‐sectional study aimed to examine the diagnostic ability of salivary matrix metalloproteinase (MMP)‐9 lateral flow test (LFT) point‐of‐care (POC) kit and develop an algorithm for ...diagnosis of periodontitis.
Materials and Methods
Through Seoul National Dental Hospital, 137 participants (46 LFT negatives, 91 LFT positives) were recruited. For salivary diagnostics, 150 μl of the unstimulated saliva was applied to LFT‐POC kit. To make a diagnosis of periodontitis, stage II‐IV in modified new international classification system was used. Covariates encompassing age, sex, smoking and obesity were evaluated through face‐to‐face interview. Enzyme‐linked immunosorbent assay was used for quantification of salivary MMP‐9. To develop a diagnostic algorithm, multivariable logistic regression analysis was used. Receiver operating characteristic curve was applied for evaluating diagnostic ability.
Results
Diagnostic ability of salivary MMP‐9 LFT‐POC test was 0.82 (sensitivity of 0.92, specificity of 0.72) in total participants. Diagnostic algorithm using POC test resulted in a response equation, that is algorithm score = −3.675 + 2.877*LFT + 0.034*age + 0.121*sex + 0.372*smoking + 0.192*obesity. Diagnostic ability of the algorithm was 0.88 (sensitivity of 0.92, specificity of 0.85) with cut‐off score of 0.589.
Conclusions
Salivary MMP‐9 LFT‐POC kit showed appropriate diagnostic ability for periodontitis and would be an efficient tool for screening of periodontitis.
Little is known about the principles of surface structure design for orthopedic and dental implants. To find topographical groove patterns that could enhance osteoblast differentiation according to ...cell type, groove patterns are fabricated with ridges (0.35−7 µm) and grooves (0.65−6 µm) of various widths and explored their mechanisms in improving osteoblast differentiation. This study finds that a groove pattern enhancing osteoblast differentiation is associated with the ability of the cell to extend its length and that it is able to overcome the inhibition of osteoblast differentiation that takes place under inflammatory conditions. The groove pattern suppresses the generation of reactive oxygen species, a reaction that is increased in inflammatory conditions. It also modulates the expression of osteogenic factors according to differentiation time. Importantly, specific groove patterns AZ‐2 and AZ‐4, with ridge width of 2 µm and groove width of 2 or 4 µm, respectively, effectively promote bone regeneration in critical‐sized calvarial defects without additional factors. This knowledge of groove patterns can be applied to the development of orthopedic and dental devices.
A groove pattern enhancing osteoblast differentiation is associated with the ability of the cell to extend its length and that it is able to overcome the inhibition of osteoblast differentiation and effectively promotes bone regeneration in calvarial defects. This knowledge of groove patterns can be applied to the development of orthopedic and dental devices.
We evaluated the prognostic implications of the circulating tumor cell (CTC) count in non-metastatic, HER2-negative breast cancer patients who failed to achieve pathologic complete response (pCR) ...after neoadjuvant chemotherapy (NCT). A total of 173, non-metastatic breast cancer patients treated with NCT were prospectively enrolled. CTCs were obtained from blood drawn pre-NCT and post-NCT using a SMART BIOPSY SYSTEM isolation kit (Cytogen Inc., Seoul, Korea) with immunofluorescence staining. Excluding 26 HER2-positive patients, Relapse-free survival (RFS) and overall survival (OS) related to the CTC count and the association of the CTC count with the treatment response to given therapy were analyzed in 147 HER2-negative patients. Among 147 HER2-negative patients, 28 relapses (19.0%) and 13 deaths (8.8%, all breast cancer-specific) were observed during a median follow-up of 37.3 months. One hundred and seven patients (72.8%) were hormone receptor-positive, and 40 patients (27.2%) had triple-negative breast cancer (TNBC). One or more CTCs were identified in 88 of the 147 patients (59.9%) before NCT and 77 of the 134 patients (52.4%) after NCT. In the entire HER2-negative patient cohort, the initial nodal status was the most significant factor influencing RFS and OS. In TNBC, 11 patients (27.5%) achieved pCR and patients that failed to achieve pCR with ≥ 5 CTCs after NCT, showed worse RFS (HR, 10.66; 95% CI, 1.80-63.07; p = 0.009) and OS (HR, 14.00; 95% CI, 1.26-155.53; p = 0.032). The patients with residual tumor and a high number of the CTCs after NCT displayed the worse outcome. These findings could provide justification to launch a future, well designed trial with longer follow-up data to obtain regulatory approval for clinical use of the assay, especially for the ER-positive, HER2-negative breast cancer subset.
Ginseng has been shown to produce a cognitive improvement effect. The key molecular components in ginseng that produce pharmacological effects are ginsenosides. Previous studies reported a memory ...improvement effect of a few major ginsenosides. However, the identity of specific minor ginsenosides mediating such function remains unknown. Here, we report that a minor ginsenoside F1 improves memory function in APPswe/PSEN1dE9 (APP/PS1) double-transgenic Alzheimer's disease (AD) model mice. After 8-wk oral administration of F1 jelly, we observed that spatial working memory, but not context-dependent fear memory, was restored in AD mice. To search for a possible underlying molecular and cellular mechanism, we investigated the effect of F1 on Aβ plaque. We observed F1 administration reduced the Aβ plaque area and density in the cortex, but not in the hippocampus of AD mice. Next, we tested for the effect of F1 on the expression level of key molecules involved in learning and memory. Results from Western blot assay revealed that an abnormally reduced level of a phosphorylated form of CREB in the hippocampus of AD mice was restored to a normal level by F1 administration. Moreover, in the same animals, BDNF level was augmented in the cortex. Our results, therefore, suggest that minor ginsenoside F1 constitutes a promising target to develop therapeutic agents for AD.
Monogononta is the most speciose class of rotifers, with more than 2,000 species. The monogonont genus Brachionus is widely distributed at a global scale, and a few of its species are commonly used ...as ecological and evolutionary models to address questions related to aquatic ecology, cryptic speciation, evolutionary ecology, the evolution of sex and ecotoxicology. With the importance of Brachionus species in many areas of research, it is remarkable that the genome has not been characterized. This study aims to address this lacuna by presenting, for the first time, the whole‐genome assembly of the freshwater species Brachionus calyciflorus. The total length of the assembled genome was 129.6 Mb, with 1,041 scaffolds. The N50 value was 786.6 kb, and the GC content was 24%. A total of 16,114 genes were annotated with repeat sequences, accounting for 21% of the assembled genome. This assembled genome may form a basis for future studies addressing key questions on the evolution of monogonont rotifers. It will also provide the necessary molecular resources to mechanistically investigate ecophysiological and ecotoxicological responses.
Progranulin (PGRN) haploinsufficiency due to progranulin gene (GRN) variants can cause frontotemporal dementia (FTD) with aberrant TAR DNA-binding protein 43 (TDP-43) accumulation. Despite microglial ...burden with TDP-43-related pathophysiology, direct microglial TDP-43 pathology has not been clarified yet, only emphasized in neuronal pathology. Thus, the objective of this study was to investigate TDP-43 pathology in microglia of patients with PGRN haploinsufficiency.
To design a human microglial cell model with PGRN haploinsufficiency, monocyte-derived microglia (iMGs) were generated from FTD-GRN patients carrying pathogenic or likely pathogenic variants (p.M1? and p.W147*) and three healthy controls.
iMGs from FTD-GRN patients with PGRN deficiency exhibited severe neuroinflammation phenotype and failure to maintain their homeostatic molecular signatures, along with impaired phagocytosis. In FTD-GRN patients-derived iMGs, significant cytoplasmic TDP-43 aggregation and accumulation of lipid droplets with profound lysosomal abnormalities were observed. These pathomechanisms were mediated by complement C1q activation and upregulation of pro-inflammatory cytokines.
Our study provides considerable cellular and molecular evidence that loss-of-function variants of GRN in human microglia can cause microglial dysfunction with abnormal TDP-43 aggregation induced by inflammatory milieu as well as the impaired lysosome. Elucidating the role of microglial TDP-43 pathology in intensifying neuroinflammation in individuals with FTD due to PGRN deficiency and examining consequential effects on microglial dysfunction might yield novel insights into the mechanisms underlying FTD and neurodegenerative disorders.
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