Genetic and pharmacological interventions have successfully extended healthspan and lifespan in animals, but their genetic interventions are not appropriate options for human applications and ...pharmacological intervention needs more solid clinical evidence. Consequently, dietary manipulations are the only practical and probable strategies to promote health and longevity in humans. Caloric restriction (CR), reduction of calorie intake to a level that does not compromise overall health, has been considered as being one of the most promising dietary interventions to extend lifespan in humans. Although it is straightforward, continuous reduction of calorie or food intake is not easy to practice in real lives of humans. Recently, fasting-related interventions such as intermittent fasting (IF) and time-restricted feeding (TRF) have emerged as alternatives of CR. Here, we review the history of CR and fasting-related strategies in animal models, discuss the molecular mechanisms underlying these interventions, and propose future directions that can fill the missing gaps in the current understanding of these dietary interventions. CR and fasting appear to extend lifespan by both partially overlapping common mechanisms such as the target of rapamycin (TOR) pathway and circadian clock, and distinct independent mechanisms that remain to be discovered. We propose that a systems approach combining global transcriptomic, metabolomic, and proteomic analyses followed by genetic perturbation studies targeting multiple candidate pathways will allow us to better understand how CR and fasting interact with each other to promote longevity.
This study evaluated the effect of barium titanate (BT) on the dielectricity, radiopacity, and biological properties of tricalcium silicate (C3S). C3S/BT samples were prepared with varying ...proportions of BT (0, 20, 40, and 60 wt%; referred to as BT00, BT20, BT40, and BT60, respectively). Dielectric constant and radiopacity were measured. Cytocompatibility was evaluated on human dental pulp cells. After surgical procedures on rat mandible, immunohistochemistry and Masson’s trichrome staining were performed. The dielectric constant increased with higher proportions of BT (p<0.05). BT40 and BT60 satisfied the clinical guideline of radiopacity. There were no significant differences among groups in the cytocompatibility tests (p>0.05). New bone was observed well, along with the expressions of the dentin matrix protein 1 (DMP1), osteocalcin (OC), and osteonectin (ON) in BT40 and BT60. Conclusively, the contents of 40–60 wt% of BT in C3S provided proper radiopacity, favorable cytocompatibility, and beneficial effect on bone regeneration.
The aim of this study is to evaluate upper airway changes three-dimensionally following rapid maxillary expansion (RME) and compare the changes with matched controls.
Seventeen patients (mean age ...12.6 ± 1.8 years) with maxillary transverse deficiency were treated with RME. Using the propensity score matching method, 17 patients (mean age 12.3 ± 1.5 years) were selected from a non-RME control group of 33. Case-control matching was performed based on 5 covariates: age, gender, CBCT scan interval, sagittal skeletal pattern, and tongue posture. Airway volumes of nasopharynx and oropharynx and minimum cross-sectional areas (MCA) of oropharynx were measured and compared between the case and control groups in CBCT scan images.
In the case group, significant increases from before to after RME were found in all measurements except MCA of the retroglossal segment of oropharynx. Before treatment, there were no significant differences between case group and control group. While comparing the case group with the control group after treatment showed overall greater increases in the case group. In particular, MCA of retropalatal segment showed statistically significant differences.
The results of this study indicate that RME causes an increase in upper airway dimensions.
Muscle‐invasive urothelial carcinoma (MIUC) of the bladder shows highly aggressive tumor behavior, which has prompted the quest for robust biomarkers predicting invasion. To discover such biomarkers, ...we first employed high‐throughput proteomic method and analyzed tissue biopsy cohorts from patients with bladder urothelial carcinoma (BUC), stratifying them according to their pT stage. Candidate biomarkers were selected through bioinformatic analysis, followed by validation. The latter comprised 2D and 3D invasion and migration assays, also a selection of external public datasets to evaluate mRNA expression and an in‐house patient‐derived tissue microarray (TMA) cohort to evaluate protein expression with immunohistochemistry (IHC). Our multilayered platform‐based analysis identified tubulin beta 6 class V (TUBB6) as a promising prognostic biomarker predicting MIUC of the bladder. The in vitro 2D and 3D migration and invasion assays consistently showed that inhibition of TUBB6 mRNA significantly reduced cell migration and invasion ability in two BUC cell lines with aggressive phenotype (TUBB6 migration, P = .0509 and P < .0001; invasion, P = .0002 and P = .0044; TGFBI migration, P = .0214 and P = .0026; invasion, P < .0001 and P = .0001; T24 and J82, respectively). Validation through multiple public datasets, including The Cancer Genome Atlas (TCGA) and selected GSE (Genomic Spatial Event) databases, confirmed TUBB6 as a potential biomarker predicting MIUC. Further protein‐based validation with our TMA cohort revealed concordant results, highlighting the clinical implication of TUBB6 expression in BUC patients (overall survival: P < .001). We propose TUBB6 as a novel IHC biomarker to predict invasion and poor prognosis, also select the optimal treatment in BUC patients.
What's new?
Improvement in the detection of muscle‐invasive urothelial carcinoma (MIUC) depends in part on the discovery of biomarkers with highly accurate predictive capability. In this study, high‐throughput proteomics and bioinformatics analyses were applied to the search for robust biomarkers linked to aggressive features in bladder urothelial carcinoma (BUC) patient‐derived tissue samples. Analyses identified tubulin beta 6 class V (TUBB6) as a promising predictive and prognostic marker in BUC. In phenotypically aggressive BUC cells, TUBB6 mRNA inhibition decreased cell migration and invasion ability. The analyses further cast light on the comprehensive proteomic landscape of BUC and its relationship with tumor stage.
This study explores the implications of the flipped classroom experiment in South Korea as a counter-proposal for the school innovation project based on the Korean educational context. Using ...Dongpyung middle school in South Korea for this case study, this paper focuses on how and why the flipped classroom impacts Korea's education culture. The results of the experiment provide significant insights, such as promoting more active classroom learning and the improvement of student academic achievement. In particular, the narratives of the students and teachers in the flipped classroom experiment show the following positive impacts on learning and teaching: (1) Transformation into a more equal and democratic classroom, (2) restoration of enjoyment in learning and teaching, (3) improvement of self-confidence, and (4) inspiration for the learning and teaching community. Based on these results, this paper discusses possible implications of the flipped classroom as an alternative future class model in Korean society.
When the inverse synthetic aperture radar (ISAR) system has sparse-aperture (SA) dataset along the cross-range axis, it can blur the ISAR image of target having complex motion. To overcome this, we ...propose an improved ISAR imaging method based on dictionary estimation using parametric signal reconstruction (DEPSR) using accelerated meta-heuristic optimization (MHO). The proposed method reconstructs a motion-compensated full-aperture (FA) dataset from an SA dataset using MHO, which can be accelerated by a graphics processing unit. After then, we can obtain the motion-compensated FA dataset and by using this, we can exploit the conventional range-Doppler (R-D) processing. Simulation and real-data-based ISAR imaging results validate the superiority of the proposed method in terms of image quality in comparison with conventional methods, such as simple R-D processing, basis pursuit denoising, and the DEPSR. Particularly, the proposed method exhibits a significantly lower computational burden than that of the traditional DEPSR approach.
Sirtuin is an essential factor that delays cellular senescence and extends the organismal lifespan through the regulation of diverse cellular processes. Suppression of cellular senescence by Sirtuin ...is mainly mediated through delaying the age-related telomere attrition, sustaining genome integrity and promotion of DNA damage repair. In addition, Sirtuin modulates the organismal lifespan by interacting with several lifespan regulating signaling pathways including insulin/IGF-1 signaling pathway, AMP-activated protein kinase, and forkhead box O. Although still controversial, it is suggested that the prolongevity effect of Sirtuin is dependent with the level of and with the tissue expression of Sirtuin. Since Sirtuin is also believed to mediate the prolongevity effect of calorie restriction, activators of Sirtuin have attracted the attention of researchers to develop therapeutics for age-related diseases. Resveratrol, a phytochemical rich in the skin of red grapes and wine, has been actively investigated to activate Sirtuin activity with consequent beneficial effects on aging. This article reviews the evidences and controversies regarding the roles of Sirtuin on cellular senescence and lifespan extension, and summarizes the activators of Sirtuin including Sirtuin-activating compounds and compounds that increase the cellular level of nicotinamide dinucleotide.
Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) small-molecule inhibitors in breast cancer arises through mechanisms that are yet uncharacterized. In this study, we used a ...kinome-wide siRNA screen to identify kinases that, when downregulated, yield sensitivity to the CDK4/6 inhibitor ribociclib. In this manner, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a key modifier of ribociclib sensitivity in estrogen receptor-positive MCF-7 breast cancer cells. Pharmacologic inhibition of PDK1 with GSK2334470 in combination with ribociclib or palbociclib, another CDK4/6 inhibitor, synergistically inhibited proliferation and increased apoptosis in a panel of ER-positive breast cancer cell lines. Ribociclib-resistant breast cancer cells selected by chronic drug exposure displayed a relative increase in the levels of PDK1 and activation of the AKT pathway. Analysis of these cells revealed that CDK4/6 inhibition failed to induce cell-cycle arrest or senescence. Mechanistic investigations showed that resistant cells coordinately upregulated expression of cyclins A, E, and D1, activated phospho-CDK2, and phospho-S477/T479 AKT. Treatment with GSK2334470 or the CDK2 inhibitor dinaciclib was sufficient to reverse these events and to restore the sensitivity of ribociclib-resistant cells to CDK4/6 inhibitors. Ribociclib, in combination with GSK2334470 or the PI3Kα inhibitor alpelisib, decreased xenograft tumor growth more potently than each drug alone. Taken together, our results highlight a role for the PI3K-PDK1 signaling pathway in mediating acquired resistance to CDK4/6 inhibitors.
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Gut dysbiosis is closely associated with the outbreak of inflammatory bowel disease (IBD) and psychiatric disorder. The Enterobacteriaceae population was higher in the feces of patients with ...inflammatory bowel disease (IBD-F) than in those of healthy control volunteers (HC-F). The Enterococcaceae and Lactobacillaceae populations were higher in the feces of IBD patients with depression (IBD/D
-F) vs. the feces of IBD patients without depression (IBD/D
-F). Therefore, we examined the effects of Klebsiella oxytoca, Escherichia coli, Cronobacter sakazakii, Enterococcus faecium, and Pediococcus acidolactici overpopulated in IBD/D
-F and their byproducts LPS and exopolysaccharide (EPS) on the occurrence of depression and colitis in mice. Oral gavages of Klebsiella oxytoca, Escherichia coli, and Cronobacter sakazakii belonging to Enterobacteriaceae, singly or together, caused dose-dependently colitis and depression-like behaviors in germ-free and specific-pathogen-free mice. Although Enterococcus faecium and Pediococcus acidolactici did not significantly cause colitis and depression-like behaviors, they significantly deteriorated Klebsiella oxytoca- or Escherichia coli-induced colitis, neuroinflammation, and anxiety/depression-like behaviors and increased blood LPS, corticosterone, and IL-6 levels. The EPSs from Enterococcus faecium and Pediococcus acidolactici also worsened Klebsiella oxytoca LPS-induced colitis, neuroinflammation, and depression-like behaviors in mice and increased the translocation of fluorescein isothiocyanate-conjugated LPS into the hippocampus. However, Bifidobacterium longum, which was lower in IBD/D
-F vs. IBD/D
-F, or its EPS suppressed them. In conclusion, Enterococcus faecium and Pediococcus acidolactici, known as a probiotic strain, and their EPSs may be a risk factor for the outbreak of depression and IBD.
ABSTRACT
A Rickettsia sp. was isolated from the blood of a patient with an acute febrile illness using the shell vial technique; the isolate was named CN45Kr and was identified by molecular assay as ...Rickettsia monacensis, which was first recognized as a pathogen in Spain. Sequencing analysis showed that the gltA sequence of the isolate was identical to that of Rickettsia sp. IRS3. The ompA‐5mp fragment sequence showed 100% identity to those of R. monacensis and Rickettsia sp. In56 and ompA‐3pA In56 and 100% identity to that of Rickettsia sp. IRS3. The ompB sequence was found to have 99.9% similarity to that of R. monacensis IrR/Munich. This study confirms the pathogenicity of this agent and provides additional information about its geographic distribution.
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