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Abstract Background Mouse definitive neural stem cells (NSCs) are derived from a population of LIF-responsive primitive neural stem cells (pNSCs) within the neurectoderm, yet details on the early signaling and transcriptional mechanisms that control this lineage transition are lacking. Here we tested whether FGF and Wnt signaling pathways can regulate Zfhx1b expression to control early neural stem cell development. Results By microinjecting FGF8b into the pro-amniotic cavity ex vivo at 7.0 days post-coitum (dpc) and culturing whole embryos, we demonstrate that neurectoderm-specific gene expression (for example, Sox2, Nestin, Zfhx1b) is increased, whereas Wnt3a represses neurectoderm gene expression. To determine whether FGF signaling also mediates the lineage transition from a pNSC to a NSC, 7.0-dpc embryos were microinjected with either FGF8b or inhibitors of the FGF receptor-MAP kinase signaling pathway ex vivo, cultured as whole embryos to approximately 8.5 dpc and assayed for clonal NSC colony formation. We show that pre-activation of FGF signaling in the anterior neurectoderm causes an increase in the number of colony forming NSCs derived later from the anterior neural plate, whereas inhibition of FGF signaling significantly reduces the number of NSC colonies. Interestingly, inhibition of FGF signaling causes the persistence of LIF-responsive pNSCs within the anterior neural plate and over-expression of Zfhx1b in these cells is sufficient to rescue the transition from a LIF-responsive pNSC to an FGF-responsive NSC. Conclusion Our data suggest that definitive NSC fate specification in the mouse neurectoderm is facilitated by FGF activation of Zfhx1b.

Objective: To explore the effects of Huxin formula (HXF) in curtailing atherosclerosis and its underlying mechanism., Methods: According to random number table method, 24 specific pathogen free male ApoE -/- mice were randomly divided into model group, HXF low-dose (HXF-L) group (8.4 g/kg daily), HXF high-dose (HXF-H) group (16.8 g/kg daily), and pravastatin (8 mg/kg daily) group in Experiment I (n=6 per group). C57BL/6J mice served as the control group (n=6). ApoE -/- mice in HXF-L, HXF-H, pravastatin groups were fed a Western diet and administered continuously by gavage for 12 weeks, while C57BL/6J mice in the control group were fed conventional lab mouse chow for 12 weeks. Further, Tregs were depleted by weekly intraperitoneal injection of purified anti-mouse CD25 antibody (PC61, 250 µg per mouse) for 4 weeks in Experiment II (n=6 per group). Oil Red O and Masson staining were used to evaluate the plaque area and aortic root fibrosis. The CD4 + CD25 + Foxp3 + Treg counts in the lymph nodes and spleen cells were detected using flow cytometric analysis. The transforming growth factor-β1 (TGF-β1), interleukin (IL)-10, and IL-6 serum levels were examined by MILLIPLEX® MAP technology. Quantitative real-time reverse transcription PCR (qRT-PCR) and Western blot were utilized to assess the expression of TGF-β mRNA and protein in the aorta. The expression of CD4 + T lymphocytes, macrophages and smooth muscle cells in the aortic root were detected by immunofluorescence staining., Results: HXF reduced plaque area in ApoE -/- mice (P<0.01). HXF increased the Treg counts in the lymph nodes and spleen cells (P<0.05 or P<0.01). Moreover, HXF alleviated inflammatory response via elevating IL-10 and TGF-β 1 serum levels (P<0.05), while decreasing the IL-6 serum levels in ApoE -/- mice (P>0.05). Also, HXF upregulated the expression of TGF-β mRNA and protein in the aorta (P<0.05). Additionally, HXF attenuated CD4 + T lymphocytes, macrophages and smooth muscle cells in aortic root plaque (P<0.01). Furthermore, the depletion of Tregs with CD25 antibody (PC61) curtailed the reduction in plaque area and aortic root fibrosis by HXF (P<0.01)., Conclusion: HXF relieved atherosclerosis, probably by restraining inflammatory response, reducing inflammatory cell infiltration and attenuating aortic root fibrosis by increasing Treg counts., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/purpose: The preciseness of detecting periodontal bone loss is examiners dependent, and this leads to low reliability. The need for automated assistance systems on dental radiographic images has been increased. To the best of our knowledge, no studies have quantitatively and automatically staged periodontitis using dental periapical radiographs. The purpose of this study was to evaluate periodontal bone loss and periodontitis stage on dental periapical radiographs using deep convolutional neural networks (CNNs)., Materials and Methods: 336 periapical radiographic images (teeth: 390) between January 2017 and December 2019 were collected and de-identified. All periapical radiographic image datasets were divided into training dataset (n = 82, teeth: 123) and test dataset (n = 336, teeth: 390). For creating an optimal deep CNN algorithm model, the training datasets were directly used for the segmentation and individual tooth detection. To evaluate the diagnostic power, we calculated the degree of alveolar bone loss deviation between our proposed method and ground truth, the Pearson correlation coefficients (PCC), and the diagnostic accuracy of the proposed method in the test datasets., Results: The periodontal bone loss degree deviation between our proposed method and the ground truth drawn by the three periodontists was 6.5 %. In addition, the overall PCC value of our proposed system and the periodontists' diagnoses was 0.828 ( P  < 0.01). The total diagnostic accuracy of our proposed method was 72.8 %. The diagnostic accuracy was highest for stage III (97.0 %)., Conclusion: This tool helps with diagnosis and prevents omission, and this may be especially helpful for inexperienced younger doctors and doctors in underdeveloped countries. It could also dramatically reduce the workload of clinicians and timely access to periodontist care for people requiring advanced periodontal treatment., Competing Interests: The authors declare no conflicts of interest with respective to the research and publication of this article., (© 2023 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background/purpose: The accuracy of a full-arch scan by using an intraoral scanner should be validated under clinical conditions. This study aimed to compare the accuracy of full-arch digital impressions in the maxilla and mandible using two intra oral scanners with three different scan segmental sequential ranges., Materials and Methods: A dental model with 28 teeth in their normal positions served as the reference. Sixty full-arch scans were performed using Trios 3 and Trios 4, employing scanning strategy O (manufacturer's original method), OH (segmental sequential ranges one half), and TQ (segmental sequential ranges third quarter). Trueness was evaluated by comparing digital impressions with a reference dataset using specialized software. One-way ANOVA and Tukey tests assessed differences between the groups., Results: For Trios 3 on the maxilla, no significant difference was found among the groups of trueness; in the mandible, strategy O exhibited a significant difference ( P  = 0.008) with the highest deviation. For Trios 4 on the maxilla, strategy TQ demonstrated the lowest deviation with a significant difference ( P  = 0.006); in the mandible, no significant difference was found among the groups of trueness., Conclusion: Strategy TQ exhibited the best trueness for Trios 3 and Trios 4, suggesting it may be preferred for higher accuracy. Clinicians should consider these findings when selecting scanning strategies and intraoral scanners for specific cases., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2023 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background/purpose: As science and technology continue to advance, the utilization of intraoral scanners (IOSs) has become increasingly popular in the orthodontic workflow. The aim of this study was to discuss whether the degree of crowded arches affects scan accuracy., Materials and Methods: Three different crowding levels of dental models (model MI: mild, model MO: moderate, and model SE: severe) were scanned using both an IOS and desktop scanner. Stereolithographic files were obtained and superimposed via CAD software to calculate differences between each measuring point of a model and the farthest corresponding point. The deviations from three models were compared with statistical analysis., Results: The trueness of different crowding arches showed that the deviation value of model SE was the maximum, followed by model MI, and model MO in the maxillary arch. In the mandibular arch, the order of the deviation from greatest to least was firstly model SE, then model MO, and model MI. Significant differences were observed among the maxillary models ( P  < 0.001), but there was no significant difference between models in the mandible ( P  = 0.669)., Conclusion: The trueness of the three crowded arches is in the clinically acceptable range. The degree of crowding increases, the trueness of scanning at each position decreases. In the maxillary arch, more severe crowding corresponds to higher deviations. In the mandible, the degree of crowding is not explicitly related to the maximum deviation; therefore, the clinician should notice the deviation when using IOSs for crowding cases., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2023 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Bladder cancer is the leading urinary tract malignancy. Epidemiological evidence has linked lower cancer incidence in schizophrenia patients to long-term medication, highlighting the anticancer potential of antipsychotics. Sertindole is an atypical antipsychotic agent with reported anticancer action on breast and gastric cancers. Yet, sertindole's effect on bladder cancer remains unaddressed. We herein present the first evidence of sertindole's antiproliferative effect and mechanisms of action on human bladder cancer cells. Sertindole was cytotoxic against bladder cancer cells while less cytotoxic to normal urothelial cells. Apoptosis was a primary cause of sertindole's cytotoxicity, as the pan-caspase inhibitor z-VAD-fmk rescued cells from sertindole-induced killing. Mechanistically, sertindole inhibited the activation of signal transducer and activator of transcription 3 (STAT3), an oncogenic driver of bladder cancer, as sertindole lowered the levels of tyrosine 705-phosphorylated STAT3 along with that of STAT3's target gene BCL-xL. Notably, ectopic expression of the dominant-active STAT3 mutant impaired sertindole-induced apoptosis in addition to restoring BCL-xL expression. Moreover, bladder cancer cells overexpressing BCL-xL were refractory to sertindole's proapoptotic action, arguing that sertindole represses STAT3 to downregulate BCL-xL, culminating in the induction of apoptosis. Overall, the current study indicated sertindole exerts bladder cancer cytotoxicity by provoking apoptosis through targeted inhibition of the antiapoptotic STAT3/BCL-xL signaling axis. These findings implicate the potential to repurpose sertindole as a therapeutic strategy for bladder cancer.

Indoleamine 2,3-dioxygenase (IDO1) is a heme-containing enzyme mainly responsible for the metabolism of tryptophan to kynurenine. To date, the IDO1 inhibitors have been developed intensively for the re-activation of the anticancer immune response. In this report, we designed, and synthesized novel 1,3-dimethyl-6-amino indazole derivatives as IDO1 inhibitors based on the structure of IDO1 active site. We further examined their anticancer activity on hypopharyngeal carcinoma cells (FaDu), squamous cell carcinoma of the oral tongue (YD-15), breast cancer cells (MCF7), and human dental pulp stem cells (HDPSC). Of them, compound N-(4-bromobenzyl)-1,3-dimethyl-1H-indazol-6-amine (7) remarkably suppressed IDO1 expression in a concentration - dependent manner. In addition, 7 was the most potential anticancer compound with inducing apoptosis activity as well as selectively activated extracellular signal-regulated kinases (ERK) in mitogen-activated protein kinase (MAPK) pathways on FaDu cells. Finally, compound 7 suppressed cell mobility in wound healing assay with the reduced expression of matrix metalloproteinase MMP9. Taken together, we believe that 7 is the most promising compound, which may be applied to treatment of hypopharyngeal carcinoma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background/purpose: Immediate implant placement (IIP) with and without immediate provisionalization (Ipro) may yield satisfactory results in appropriate indications and treatment, especially in the esthetic zone. The aim of this study was to compare implant stability, marginal bone loss (MBL), survival rates, and patient satisfaction between IIP with Ipro and IIP without Ipro., Materials and Methods: Seventy patients, each with a failed maxillary anterior tooth, were randomly assigned to IIP with Ipro (Group A: n = 35) or IIP without Ipro (Group B: n = 35). Implant stability quotient (ISQ) and standardized periapical radiographs were performed at surgery and at 3, 6, 9, and 12 months postoperatively to investigate implant stability and MBL, respectively. Survival was assessed 1 year after surgery. Patient satisfaction was evaluated with a visual analogue scale (VAS)., Results: Primary ISQ and MBL were not significantly different between groups A and B immediately after surgery ( P ＞ 0.05). Implant survival was 100% in both groups, and only one mechanical complication was observed. Patient satisfaction was good at definitive crown delivery and postoperatively 1-year in both groups. However, the immediate postoperative VAS score in Group A was significantly higher than that in Group B ( P  < 0.05)., Conclusion: Group A revealed significantly higher secondary ISQ than Group B at postoperatively 3, 6, 9, and 12 months. There were no significant differences between groups A and B in terms of MBL and survival. Notably, patient satisfaction in Group A was significantly higher than in Group B immediately after surgery., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2023 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background/purpose: Implant stability is crucial for successful osseointegration. Marginal bone level is considered an important indicator of long-term implant success and stability. The purposes of this study were to investigate 1) the effect of age, gender, bone density, implant length, and implant diameter on insertion torque (IT), primary implant stability quotient (ISQ), and secondary ISQ, 2) the impact of age, gender, bone density, implant length, implant diameter, IT, and ISQ on marginal bone loss (MBL)., Materials and Methods: Ninety patients who needed implant therapy were enrolled and overall 156 implants were installed to support single crowns. IT and ISQ were recorded for all implants during surgery and ISQ measurements were performed at follow-up visits. Age, gender, bone density, implant length and diameter were also registered. Radiographic evaluation of MBL was performed postoperative immediate (baseline), 3, 6, 9, 12, 18, and 24 months using digital periapical radiographs., Results: Age had little effect on IT and primary ISQ ( P  > 0.05). Generally, males had higher IT and primary ISQ, but no significant differences between genders were detected. Bone density showed significant effects on IT and primary ISQ. Correlation analysis revealed high positive correlations between IT/bone density and primary ISQ/implant diameter. Significant impacts of bone density and IT on MBL were found., Conclusion: Implant diameter had a more profound impact than length on IT/primary ISQ. Bone density played a considerable role in IT/primary ISQ determination. Bone density and IT had more impacts than primary ISQ on MBL., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2023 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background/purpose: The simulated color of restorations plays an important role in improving patient satisfaction. The aim of this study was to test a new intelligent colorimetric solution using the Advanced Reflectionless Technology (ART) monitor and compare them using commercially available shade systems., Materials and Methods: Six participants' right maxillary central incisors were tested with three devices, including the AUO Display Plus (Group A), a Canon single-lens reflex camera with eLAB's polar eyes filter (Group E), and the VITA Easyshade V (Group V). Each porcelain tooth was divided into three areas, and was assigned a CIELAB L∗a∗b∗ value by using the VITA Easyshade V. The original data were compared with the CIELAB L∗a∗b∗ obtained using the VITA Easyshade V. A prosthodontist compared the color of the porcelain veneers by eyes and gave the scores from 1 to 3., Results: For the ΔE, the three areas of Group A had the smallest differences between the color of the fabricated teeth and that of the original teeth. Colorimetric analysis indicated that Groups A and V did not differ much in the color of the three areas of the tooth. Groups E and A exhibited significant differences between the cervical third and middle third of the tooth, and Groups E and V exhibited significant differences between the middle third and incisal third of the tooth., Conclusion: Compared with traditional monitors, ART is closer to real images in terms of color, contrast, and detail grayscale. Technicians are able to produce realistic and pleasing colors., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2023 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background: XinLi formula (XLF) is a traditional Chinese medicine used in clinical practice to treat chronic heart failure (CHF) in humans, with remarkable curative effect. However, the mechanism remains unknown., Purpose: The goal of the current investigation was to determine how XLF affected CHF in a rat model of the condition brought on by ligation of the left anterior descending coronary artery, and to investigate the underlying mechanism., Study Design and Methods: Cardiac function was detected by echocardiography. The contents of myocardial enzymes, Ang II, ALD, TGF-β1, and inflammatory factors were measured by ELISA. Myocardial injury and myocardial fibrosis were evaluated by HE and Masson staining. Myocardial edema was assessed by cardiac mass index and transmission electron microscopy. Using Western blot and immunohistochemistry to examining the protein expression of inflammasome, TGF-β1, AGTR1, and AQP1 in the left ventricle. Furthermore, the interaction of AGTR1 and AQP1 was evaluated by co-immunoprecipitation., Results: XLF attenuated myocardial enzymes and myocardial injury, and improved cardiac function in rats with CHF after myocardial infarction. It also reduced Ang II and ALD levels in CHF rats, and suppressed the expression of AGTR1 and TGF-β1, finally alleviated myocardial fibrosis. By mechanism, XLF inhibited the expression of NLRP3 inflammasome proteins, reduced the plasma contents of IL-1β, IL-18, IL-6 and TNF-α. Additionally, XLF inhibited the expression of AQP1 and the interaction of AGTR1 and AQP1, alleviating myocardial edema. The common structure of the main chemical constituents of XLF were glycoside compounds with glycosyl., Conclusion: XLF ameliorated CHF, which was evidenced by the alleviation of myocardial fibrosis by inhibiting AGTR1/NLRP3 signal, as well as the attenuation of myocardial edema by suppressing the interaction of AGTR1 and AQP1., Competing Interests: Conflict of interest No potential conflict of interest was reported by the authors., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background/purpose: The optimal strategy for scanning removable partial dentures remains unknown. This study investigated scanning strategies for patients with a maxillary Kennedy Class I arch as well as the measurement deviations of three scanning strategies., Materials and Methods: A standard maxilla model was positioned with a holder in a dental chair to simulate a natural patient position and posture. Standard Tessellation Language files for reference models were formatted with a desktop scanner, and model operation files were obtained with a TRIOS 3 Pod intraoral scanner and superimposed using Exocad computer-aided design software. The three scanning strategies evaluated in this study (Strategy M, T-R, and R-T) were used for nine scans each, and the resulting data were recorded. The deviation of the three strategies was statistically analyzed through one-way ANOVA and Tukey post hoc testing., Results: The trueness of Strategy M, T-R, and R-T was 52.6 ± 31.0, 54.9 ± 27.6, and 50.1 ± 22.3 μm, respectively. No statistically significant differences in trueness were detected among the three groups ( P  > 0.05). However, Strategy T-R had the evenest distribution of all measuring points. The deviations of the measurements obtained by three scanning strategies were mostly between 30 and 70 μm. The precision of the three strategies was similar as well., Conclusion: Trueness did not differ significantly among the three strategies. However, Strategy T-R is recommended for use with a TRIOS 3 Pod scanner because of its reduction of the seesaw effect and high stabilization of the RPD framework., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2022 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier.)

Background/purpose: Palladium-silver (Pd-Ag) alloys are important as an alternative to gold-based alloys. The purpose of this study was to investigate the effect of an argon-arc vacuum pressure casting process on the recasting of the Pd-Ag alloy., Materials and Methods: The recasting Pd-Ag alloys were compared with conventional horizontal centrifugal (HC) casting to an argon (Ar)-arc vacuum pressure (Ar-arc/VP) casting. The first-generation castings were made from a Pd-Ag alloy purchased from a supplier. Next-generation castings were made from 50 wt% Pd-Ag alloy before casting and 50 wt% from previous castings. This sequence was repeated over three generations to form the 2nd, 3rd and 4th recasting ingots. The ingots were then measured for marginal accuracy, interfacial oxidation, hardness and phase identification., Results: The recasting success rate of recastibility reached 100%. Compared with the HC group, the Ar-arc/VP group had better edge precision, smaller oxide layer thickness and lower hardness. The comparison of X-ray diffraction intensity showed that the relative intensities of Pd and Ag in the first, second and third generations recasting of the Ar-arc/VP group were significantly higher than those of the HC group. Phase analysis showed that the trace elements of indium and tin contents in the Pd-Ag recasting ingots of the Ar-arc/VP group were higher than those of the HC group., Conclusion: The results showed that the casting process used for recasting affected the quality of the Pd-Ag alloy. Therefore, Ar-arc/VP casting process could improve the effect of Pd-Ag recasting and maintain the alloy properties in comparison with HC casting., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2022 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background/purpose: The SimEx is dental training system that applies new technology in a computerized dental simulator. The purpose of this study was to understand the usability satisfaction of the SimEx dental education and evaluation system by dental students and dentists at Tohoku University., Materials and Methods: In this study, the Tohoku University IRB execution number was 2020-3-33. The number of subjects accepted was 59 at Tohoku University and divided into 4 groups based on years of clinical experience (Group A: 0 years; Group B: 1-2 years; Group C: 2-5 years; Group D: at least 5 years), and a total of 58 usability questionnaires were collected. Subjects completed the SimEx Usability Satisfaction Questionnaire after operating the SimEx (EPED Inc., Kaohsiung, Taiwan) course, which contained 16 questions., Results: Among the 58 questionnaires collected by Tohoku University, there were 19 undergraduate students (4th∼6th grade), 12 post-graduate students, 14 residents, and 13 dentists. Significant differences between Group A and Group B, and between Group A and Group D were found ( P  < 0.05). The same results were obtained for the "experience satisfaction index". In the items where significant differences were found, longer clinical experience tended to result in lower scores., Conclusion: From these results, we can conclude that the SimEx education and evaluation system facilitates students' self-learning, and this system is very useful for continued study and clinical skill training for dentists, especially for students and junior dentists with high usability satisfaction., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2023 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background/purpose: Clenching is a dental parafunctional disorder that jeopardizes the life of teeth and/or dental prostheses. Computer-aided design and computer-aided manufacturing (CAD/CAM)-fabricated or 3-dimensional-printed dental prostheses are aesthetic, strong, and of good quality, but noticeable damage can still be observed after clenching. Stress analysis of synthetic ceramic assemblies with various parameters was conducted to provide data that may be used to improve the fabrication of CAD/CAM-fabricated dental prostheses., Materials and Methods: Abaqus software was used to run the simulations. A total of 96 axisymmetric finite element ceramic assembly models were simulated under 800 N vertical loading and different contact radii (0.25, 0.5, 0.75, 1.0 mm), materials (IPS e.max CAD and Vita Enamic), layer thicknesses and combinations., Results: Four-layered ceramic assembly models produced promising results with the following parameters: contact radius of at least 0.5 mm, total thickness of at least 0.5 mm, and use of IPS e.max CAD as the first layer and Vita Enamic as the second layer without cement., Conclusion: The ideal four-layered assembly model design uses 0.25-mm-thick IPS e.max CAD as its outer layer to simulate enamel binding and 0.25-mm-thick Vita Enamic as its inner layer to imitate the natural tooth. This design may be used as reference for prosthodontic treatment., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2023 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Manoalide provides preferential antiproliferation of oral cancer but is non-cytotoxic to normal cells by modulating reactive oxygen species (ROS) and apoptosis. Although ROS interplays with endoplasmic reticulum (ER) stress and apoptosis, the influence of ER stress on manoalide-triggered apoptosis has not been reported. The role of ER stress in manoalide-induced preferential antiproliferation and apoptosis was assessed in this study. Manoalide induces a higher ER expansion and aggresome accumulation of oral cancer than normal cells. Generally, manoalide differentially influences higher mRNA and protein expressions of ER-stress-associated genes ( PERK , IRE1α , ATF6 , and BIP ) in oral cancer cells than in normal cells. Subsequently, the contribution of ER stress on manoalide-treated oral cancer cells was further examined. ER stress inducer, thapsigargin, enhances the manoalide-induced antiproliferation, caspase 3/7 activation, and autophagy of oral cancer cells rather than normal cells. Moreover, N -acetylcysteine, an ROS inhibitor, reverses the responses of ER stress, aggresome formation, and the antiproliferation of oral cancer cells. Consequently, the preferential ER stress of manoalide-treated oral cancer cells is crucial for its antiproliferative effect.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) have recently been identified to be closely related to the occurrence and development of atherosclerosis (AS). A growing body of evidence has suggested Chinese medicine takes unique advantages in preventing and treating AS. In this review, the related research progress of AS and LOX-1 has been summarized. And the anti-AS effects of 10 active components of herbal medicine through LOX-1 regulation have been further reviewed. As a potential biomarker and target for intervention in AS, LOX-1 targeted therapy might provide a promising and novel approach to atherosclerotic prevention and treatment., (© 2022. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Optogenetics combines genetics and biophotonics to enable noninvasive control of biological processes with high spatiotemporal precision. When engineered into protein machineries that govern the cellular information flow as depicted in the central dogma, multiple genetically encoded non-opsin photosensory modules have been harnessed to modulate gene transcription, DNA or RNA modifications, DNA recombination, and genome engineering by utilizing photons emitting in the wide range of 200-1000 nm. We present herein generally applicable modular strategies for optogenetic engineering and highlight latest advances in the broad applications of opsin-free optogenetics to program transcriptional outputs and precisely manipulate the mammalian genome, epigenome, and epitranscriptome. We also discuss current challenges and future trends in opsin-free optogenetics, which has been rapidly evolving to meet the growing needs in synthetic biology and genetics research., Competing Interests: Declaration of interests The authors have no conflict of interest to disclose., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Physapruin A (PHA), a Physalis peruviana -derived withanolide, exhibits antiproliferation activity against oral and breast cancer cells. However, its potential antitumor effects in combined treatments remain unclear. This investigation focused on evaluating the impact of the combined treatment of ultraviolet-C with PHA (UVC/PHA) on the proliferation of oral cancer cells. The UVC-caused antiproliferation was enhanced by combination with PHA in oral cancer (Ca9-22 and CAL 27) but not normal cells (SG), as evidenced by ATP detection, compared with UVC or PHA alone. UVC/PHA showed a greater extent of subG1 increase, G2/M arrest, annexin-V-assessed apoptosis, caspase 3/7 activation, and reactive oxygen species (ROS) in the UVC or PHA treatment of oral cancer compared to normal cells. Moreover, the mitochondrial functions, such as mitochondrial superoxide bursts and mitochondrial membrane potential destruction, of oral cancer cells were also enhanced by UVC/PHA compared to UVC or PHA alone. These oxidative stresses triggered γH2AX and 8-hydroxyl-2'-deoxyguanosine-assessed DNA damage to a greater extent under UVC/PHA treatment than under UVC or PHA treatment alone. The ROS inhibitor N -acetylcysteine reversed all these UVC/PHA-promoted changes. In conclusion, UVC/PHA is a promising strategy for decreasing the proliferation of oral cancer cells but shows no inhibitory effect on normal cells.

Natural RNA modifications diversify the structures and functions of existing nucleic acid building blocks. Geranyl is one of the most hydrophobic groups recently identified in bacterial tRNAs. Selenouridine synthase (SelU, also called mnmH) is an enzyme with a dual activity which catalyzes selenation and geranylation in tRNAs containing 2-thiouridine using selenophosphate or geranyl-pyrophosphate as cofactors. In this study, we explored the in vitro geranylation process of tRNA anticodon stem loops (ASL) mediated by SelU and showed that the geranylation activity was abolished when U 35 was mutated to A 35 (ASL-tRNA Lys (s2U)UU to ASL-tRNA Ile (s2U)AU ). By examining the SelU cofactor geranyl-pyrophosphate (gePP) and its analogues, we found that only the geranyl group, but not dimethylallyl- and farnesyl-pyrophosphate with either shorter or longer terpene chains, could be incorporated into ASL. The degree of tRNA geranylation in the end-point analysis for SelU follows the order of ASL Lys (s2UUU) ≃ ASL Gln (s2UUG) >ASL Glu (s2UUC) . These findings suggest a putative mechanism for substrate discrimination by SelU and reveal key factors that might influence its enzymatic activity. Given that SelU plays an important role in bacterial translation systems, inhibiting this enzyme and targeting its geranylation and selenation pathways could be exploited as a promising strategy to develop SelU-based antibiotics., (© 2022 Wiley-VCH GmbH.)

Competing Interests: Conflicts of interest None disclosed.

Background/purpose: Cone beam computed tomography (CBCT) is frequently used in dental diagnosis and treatment. Comparative studies of the effects of CBCT on implant navigation, however, are still limited. The objective of this study was to evaluate whether the computed tomography images of the four commercial brands will affect the accuracy of the new version of IRIS implant navigation system., Materials and Methods: In the first part, the accuracy of the IRIS implant navigation system was evaluated by a precision confirmation jig whose position is confirmed. In the second part, the IRIS implant navigation system was used in conjunction with 4 brands of CBCT scans analyzed by its effect on accuracy., Results: The results showed that the mean deviation of the new version of IRIS-100 system accuracy was less than 1 mm. Among the four groups, the overall average deviation caused by CBCT images showed that the 3D eXam group had the smallest error of approximately 0.94 ± 0.12 mm and the AZ 3000 CT group had the largest error of approximately 1.34 ± 0.10 mm., Conclusion: Based on the study, the accuracy of the IRIS implant navigation system will vary with the CBCT image resolution and the status of the CBCT machine., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2022 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

It is known that anxiety has a lot of comorbidity such as depression and may cause older subjects to be more prone to anxiety. Animal studies have also observed that older rats have lower movement in different situations, somewhat like anxiety symptoms (avoidance and freezing). The anxiety level of rodents is commonly evaluated using the elevated plus maze test, and videos are often used to record and quantify the activities of animals during the test. Furthermore, aging can reduce the frequency and activity of locomotion-induced hippocampal theta rhythm, and these reductions are also reflected in sensory-motor integration and cognition. Thus, directly analyzing the hippocampal theta rhythm and the quantity and quality of physical activity (PA) during the anxiety test can help elucidate the mechanisms underlying the anxiety-like behaviour. We explored alterations in the hippocampal theta rhythm, PA, and behavioural consistency (cross-correlation with 8-s window length) from triaxial acceleration vectors and subsequently examined the effects of age during the elevated plus maze test. We hypothesized that middle-aged rats would exhibit more anxiety, which is correlated with a reduction in behavioural consistency and hippocampal theta frequency during the elevated plus maze test. The middle-aged rats had a lower open-arm frequency and more low-frequency theta oscillations. The middle-aged rats had a lower mean power frequency (Frq) of the hippocampal theta rhythm, PA, and behavioural consistency. The Frq of the middle-aged rats was positively correlated with behavioural consistency. The results indicated that behavioural consistency could distinguish age-related anxiety-like behaviour. Behavioural consistency can serve as an index for the quality of movement and be used to distinguish age-related anxiety., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Oral cancer is one of the highest-incidence malignancies worldwide, with the occurrence of oral squamous cell carcinoma (OSCC) being the most frequently diagnosed form. A barrier for oral cancer management may arise from tumor cells that possess properties of cancer stemness, which has been recognized as a crucial factor in tumor recurrence and metastasis. As such, understanding the molecular mechanisms underlying these tumor cells may provide insights for improving cancer treatment. MRE11 is the core protein of the RAD50/MRE11/NBS1 complex with a primary role in DNA damage repair, and it has been diversely associated with tumor development including OSCC. In this study, we aimed to investigate the engagement of CD44, a cancer stemness marker functioning in the control of cell growth and motility, in OSCC malignancy under the influence of MRE11. We found that overexpression of MRE11 enhanced CD44 expression and tumorsphere formation in OSCC cells, whereas knockdown of MRE11 reduced these phenomena. In addition, the MRE11-promoted tumorsphere formation or cell migration ability was compromised in OSCC cells carrying siRNA that targets CD44, as was the MRE11-promoted AKT phosphorylation. These were further supported by analyzing clinical samples, where higher CD44 expression was associated with lymph node metastasis. Additionally, a positive correlation between the expression of MRE11 and CD44, or that of CD44 and phosphorylated AKT, was observed in OSCC tumor tissues. Finally, the expression of CD44 was found to be higher in the metastatic lung nodules from mice receiving tail vein-injection with MRE11-overexpressing OSCC cells compared with control mice, and a positive correlation between CD44 and phosphorylated AKT was also observed in these metastatic lung nodules. Altogether, our current study revealed a previously unidentified mechanism linking CD44 and AKT in MRE11-promoted OSCC malignancy, which may shed light to the development of novel therapeutic strategies in consideration of this new pathway in OSCC.

Letter fluency task (LFT) is a tool that measures memory, executive function, and language function but lacks a definite cutoff value to define abnormalities. We used the optical signals of functional near-infrared spectroscopy (fNIRS) to study the differences in power and connectivity between the high-functioning and low-functioning participants while performing three successive LFTs, as well as the relationships between the brain network/power and LFT performance. We found that the most differentiating factor between these two groups was network topology rather than activation power. The high-functional group (7 men and 10 women) displayed higher left intra-hemispheric global efficiency, nodal strength, and shorter characteristic path length in the first section. They then demonstrated a higher power over the left Broca's area than the right corresponding area in the latter two sections. The low-LFT group (9 men and 11 women) displayed less left-lateralized connectivity and activation power. LFT performance was only related to the network topology rather than the power values, which was only presented in the low-functioning group in the second section. The direct correlation between power and connectivity primarily existed in the inter-hemispheric network, with the timing relationship also seeming to be present. In conclusion, the high-functioning group presented more prominent left-lateralized intra-hemispheric network connectivity and power activation, particularly in the Broca's area. The low-functioning group seemed to prefer using other networks, like the inter-hemispheric, rather than having a single focus on left intra-hemispheric connectivity. The network topology seemed to better reflect the LFT performance than did the power values., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tung, Lin, Hsieh, Lan, Chiang, Lin and Peng.)

The nervous and endocrine systems coordinate with each other to closely influence physiological and behavioural responses in animals. Here we show that WAKE (encoded by wide awake, also known as wake) modulates membrane levels of GABA A receptor Resistance to Dieldrin (Rdl), in insulin-producing cells of adult male Drosophila melanogaster. This results in changes to secretion of insulin-like peptides which is associated with changes in juvenile hormone biosynthesis in the corpus allatum, which in turn leads to a decrease in 20-hydroxyecdysone levels. A reduction in ecdysone signalling changes neural architecture and lowers the perception of the male-specific sex pheromone 11-cis-vaccenyl acetate by odorant receptor 67d olfactory neurons. These finding explain why WAKE-deficient in Drosophila elicits significant male-male courtship behaviour., (© 2022. The Author(s).)

Study Objectives: Lemborexant (LEM) is a dual orexin receptor antagonist approved for treating adults with insomnia. We analyzed the efficacy (subjective sleep outcomes) and safety of LEM over 12 months in the subgroup of Asian subjects from Study E2006-G000-303 (Study 303)., Methods: Study 303 was a 12-month, randomized, placebo-controlled (first 6 months), double-blind, parallel-group, phase 3 study of adults with insomnia disorder. During the 6-month Period 1, subjects were randomized (1:1:1) to placebo, LEM 5 mg (LEM5), or LEM 10 mg (LEM10); LEM subjects continued treatment in the following 6-month Period 2. Outcome measures included subject-reported (subjective) sleep onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), total sleep time (sTST), Insomnia Severity Index (ISI), and Patient Global Impression-Insomnia version (PGI-I). Treatment-emergent adverse events (TEAEs) were assessed., Results: Overall, 178 Asian subjects (Japanese, n  = 161; Chinese, n  = 4; other Asian, n  = 13) were included. Greater decreases in sSOL and sWASO and increases in sSE and sTST from baseline were observed with LEM vs placebo at 6 months; LEM benefits were sustained through 12 months. Greater decreases in ISI total score were seen with LEM vs placebo at 6 months; improvements from baseline with LEM continued through 12 months. For each PGI-I item, LEM-treated subjects had more positive medication effects than placebo-treated subjects at 6 months; these effects were maintained with LEM in Period 2. TEAEs were generally mild to moderate., Conclusions: LEM improved subjective sleep parameters and was well-tolerated in Asian subjects with insomnia disorder over 12 months., Clinical Trial Registration: ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39., Competing Interests: Financial disclosure: AD is an employee of Eisai Singapore Pte Ltd. KP and JY are employees of Eisai Ltd. YI has received grants and/or personal fees from Eisai Inc., Eisai Ltd., Merck Sharp & Dohme, and Takeda in relation to the submitted work; has received grants or personal fees from Alfresa Pharma, Philips, and Koike Medical; and has received funding for clinical trials from Astellas and Janssen outside of the submitted work. KH has received grants/personal fees and consultant/speaker fees from Eisai Inc.; has received funding for clinical trials from Eisai Inc.; and has received personal fees from and Eisai Ltd., and Merck Sharp & Dohme. SCL has received grants/personal fees from Eisai Inc. CHY has no conflict of interests relevant to this study. THL and CLH have received funding for clinical trials from Eisai Inc. and have no conflicts of interests relevant to this study. NK is an employee of Eisai Co., Ltd. MM is an employee of Eisai Inc.; she has been issued a patent and has pending and planned patents broadly related to this work. Nonfinancial disclosure: None. The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: https://doi.org/10.1016/j.sleepx.2022.100044., (© 2022 The Authors.)

Background: Obesity is a common health problem among patients with schizophrenia, but the precise mechanisms are not fully understood. There has been much interest in the relationship between gut microbiome and development of obesity. Gender-dependent microbial alteration has been reported in previous studies. However, the gender factor in gut microbiome composition of schizophrenia patients has been less investigated. Our study aimed to identify differences in gut microbiota between schizophrenia patients with normal weight and central obesity and investigate the gender specific features., Method: Twenty participants (10 males, 10 females) with central obesity (CO) and 20 participants (10 males, 10 females) with normal weight (NW) were recruited from two rehabilitation wards in a psychiatric hospital in central Taiwan. Fecal samples from 40 participants were processed for microbiota analysis. The intestinal microbiota composition was analyzed using next-generation sequencing and QIIME software., Results: Significantly higher richness of gut microbiota at the class level (measured by the number of observed OTUs) was observed in female NW subjects than in female CO subjects ( P = 0.033). Furthermore, female NW subjects showed higher alpha diversity at both phylum and class levels (measured by the Shannon, Simpson, and Inverse-Simpson indexes) compared with female CO subjects. Males showed no significant difference in alpha diversity between groups. Taxonomic analysis showed that female CO subjects had significantly lower abundance of Verrucomicrobia ( P = 0.004) at the phylum level, reduced abundance of Akkermansia ( P = 0.003) and elevated level of Prevotella ( P = 0.038) and Roseburia ( P = 0.005) at the genus level., Conclusions: The present results evidenced altered microbiome composition in schizophrenia patients with central obesity and further suggested the role of the gender factor in the process of gut dysbiosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tsai, Liu, Wang, Lin and Lan.)

Introduction: Brain cortico-subcortical connectivity has been investigated in epilepsy using the functional MRI (MRI). Although structural images cannot demonstrate dynamic changes, they provide higher spatial resolution, which allows exploration of the organization of brain in greater detail., Methods: We used high-resolution brain MRI to study the hippocampal-thalamic-cortical networks in temporal lobe epilepsy (TLE) using a volume-based morphometric method. We enrolled 22 right-TLE, 33 left-TLE, and 28 age/gender-matched controls retrospectively. FreeSurfer software was used for the thalamus segmentation., Results: Among the 50 subfields, ipsilateral anterior, lateral, and parts of the intralaminar and medial nuclei, as well as the contralateral parts of lateral nuclei had significant volume loss in both TLE. The anteroventral nucleus was most vulnerable. Most thalamic subfields were susceptible to seizure burden, especially the left-TLE. SPM12 was used to conduct an analysis of the gray matter density (GMD) maps. Decreased extratemporal GMD occurred bilaterally. Both TLE demonstrated significant GMD loss over the ipsilateral inferior frontal gyrus, precentral gyrus, and medial orbital cortices., Significance: Thalamic subfield atrophy was related to the ipsilateral inferior frontal GMD changes, which presented positively in left-TLE and negatively in right-TLE. These findings suggest prefrontal-thalamo-hippocampal network disruption in TLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tung, Pan, Lan, Lin and Peng.)

Background: Walking is the fundamental component of taking steps and is the main form of physical activity among individuals with schizophrenia; it also offers a range of health benefits. This study aimed to examine the associations between daily steps and cognitive function and further explored how many steps were related to better cognitive function among inpatients with schizophrenia., Methods: Inpatients with schizophrenia were recruited from long-stay psychiatric wards across two hospitals (n=199 at site 1 and n=195 at site 2). Daily steps were collected with an accelerometer for 7 days. Four cognitive domains (attention, processing speed, reaction time, and motor speed) were tested at site 1, and two cognitive domains (attention and processing speed) were tested at site 2. The associations of daily steps and levels of steps/day with cognitive function were tested using multivariable linear regressions separated by site. Covariates included demographic variables, weight status, metabolic parameters, and clinical state., Results: Participants took an average of 7445 (±3442) steps/day. More steps were related to better attention, processing speed, reaction time, and motor speed after multivariable adjustments. Compared with participants taking <5000 steps/day, those taking ≥5000 steps/day showed significantly better processing speed. Participants taking ≥7500 steps/day were associated with better attention, better reaction time, and better motor speed than those taking <5000 steps/day., Conclusion: Daily steps are associated with better cognitive function among inpatients with schizophrenia. The optimal benefit for cognitive function among this clinical population is achieving 7500 steps/day or more., (© 2022. The Author(s).)

Objectives: To determine the minimum thickness required for a monolithic hybrid ceramic crown on different substrates (soft vs stiff) used in posterior dentition for bruxism., Methods: 80 polymer-infiltrated ceramic networks Vita Enamic (PICN VE) disc specimens with four different occlusal thicknesses (0.8, 1.2, 1.6 and 2.0 mm), were produced using a computer-aided design/manufacturing system, and cemented on a stiff (zirconia) or soft (polyamide) substrate of 4-mm thickness. The ten specimens, in soft or stiff groups, were subjected to compressive loading by a MTS machine until fracture or maximum load (4500 N) was reached. The unbroken specimens were examined using optical coherence tomography. Eight axisymmetric finite element models and eight 3D models comprising the four different occlusal thicknesses and two substrates under different vertical loads and sliding movements were constructed. The maximum principal stress was selected to evaluate the stress distribution in this study., Results: The fracture resistance of the specimens was significantly different between the two substrates (P < 0.001). Fracture resistance was positively associated with specimen thickness (r = 0.597 and 0.896 for the soft and stiff substrate respectively). Specimens on the soft substrate had lower fracture loads, whilst cone cracks were observed in unbroken samples on different soft/stiff substrate prior to final fracture. The finite element analysis confirmed that samples on the stiff substrate had lower maximum principal stress values than those on the soft substrate. For the maximum principal stress not to exceed the flexural strength of PICN VE, a stiff substrate and minimum thickness of 2.0 mm are required for the prostheses., Significance: A minimum 2.0 mm thick, stiff substrate was needed for bruxism as shown by the effect of high/large chewing force on the posterior dentition of monolithic PICN VE crowns., Competing Interests: Conflict of interest statement The authors have stated explicitly that there is no conflict of interest with this article., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Increased serum levels of pro-inflammatory biomarkers are consistently associated with cognitive decline. The omega-3 unsaturated fatty acids (n-3 PUFAs) had been linked to slowing cognitive decline due to their potential anti-inflammatory effects. To our knowledge, the different regiments of pure DHA, pure EPA, and their combination on various associated symptoms of dementia, including a mild form of cognitive impairment (MCI) and Alzheimer's disease (AD), have never been studied., Methods: This multisite, randomized, double-blind, placebo-controlled trial was conducted at two veteran's retirement centers and one medical center in central Taiwan between 2013 and 2015. 163 MCI or AD patients were randomly assigned to placebo (n = 40), docosahexaenoic acid (DHA, 0.7 g/day, n = 41), eicosapentaenoic acid (EPA, 1.6 g/day, n = 40), or EPA (0.8 g/day) + DHA (0.35 g/day) (n = 42) group for 24 months. The results were measured as the cognitive and functional abilities, biochemical, and inflammatory cytokines profiles. Chi-square tests, two-sample t-test, ANOVA, and linear mixedeffects models were conducted with p < 0.05., Results: 131 (80%) participants had completed the trial with all cognitive, functional, and mood status assessments. The statistically significant difference between the placebo and treatment groups was not determined, concerning the changes in cognitive, functional, and mood status scores, the biochemical profiles, and inflammatory cytokines levels. However, EPA was found to reduce the C-C motif ligands 4 (CCL4) level (p < 0.001). Additionally, EPA could reduce the constructional praxis (p < 0.05) and spoken language ability scores (p < 0.01), and DHA also reduced the spoken language ability score (p < 0.05)., Conclusion: Overall, n-3 PUFAs supplements did not reduce cognitive, functional, and depressive symptom outcomes, but spoken language ability and constructional praxis subitems of ADAS-cog. These findings show that attention to clinical heterogeneity in dementia is crucial when studying nutrients interventions, such as n-3 PUFAs. In addition, with small effect size CCL4 is a better indicator than other inflammatory cytokines for EPA treatment response., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: A controversial issue of the need to protect human rights and ensure public safety still remains a conflict in Taiwan. The purpose of this study was to translate the Crisis Triage Rating Scale to Chinese Mandarin (CMCTRS)., Method: A cross-sectional design with convenient sampling was employed in this study. The CMCTRS was tested on 302 Taiwanese individuals with mental illness who were admitted to the emergency room (ER) of a psychiatric center. A higher score indicated a greater need for mandatory psychiatric admission. Psychiatrists rated the patients' status according to three scale criteria and six action plans of recommendations., Results: Five specialists evaluated the content validity index to be 0.8. A total of 210 participants (69.5%) were deemed suitable for compulsory hospitalization or admission for observation in ER. The optimal cut-off score was 8, with a Youden Index of 1.46, a sensitivity of 0.748, and a specificity of 0.712 in deciding the need for hospitalization or observation., Conclusions: The CMCTRS exhibited an acceptable criterion validity with psychiatrists in a population of 302 patients at the ER of a psychiatric center. A cut-off point of 8 is recommended for determining hospitalization or a minimum 24 h stay at emergency for observation.

Objective: The TREVIDA study aimed to evaluate vortioxetine for the treatment of major depressive disorder (MDD) in Taiwanese adults., Methods: Patients with active depressive episode were recruited in this non-interventional, prospective, multi-site study conducted between June 2019 and August 2020 in Taiwan. Patient eligibility was independent of the physician's decision to prescribe vortioxetine for an MDD episode. Vortioxetine was initiated on the first visit. Depression severity, cognitive function, work productivity, functioning and safety were evaluated over 3 months., Results: Overall, 242 patients were analyzed. At baseline, 70.7% and 90.4% of patients had moderately severe-to-severe depression based on PHQ-9 (Patient Health Questionnaire-9) and TDQ (Taiwanese Depression Questionnaire), respectively. By Month 3, significant improvements from baseline in depression severity (mean [SD] changes in PHQ-9, TDQ and CGI-S [Clinical Global Impression-Severity]: -6.3 [7.3]; -13.2 [14.0]; -1.5 [1.3], respectively), cognitive function (mean [SD] change in PDQ-D: -8.0 [17.5]), functioning (mean [SD] change in SDS: -5.4 [7.6]), and presenteeism (38.9% from 56.3%), work productivity loss (40.9% from 58.7%) and activity impairment (43.2% from 61.0%) were observed ( p  < .001 for all). By month 3, patient-reported (PHQ-9) response and remission rates were 43.4% and 52.9%, respectively; physician-reported (CGI-S) response and remission rates were 29.0% and 31.6%, respectively. Vortioxetine was well-tolerated and no unexpected side effects were reported., Conclusions: Vortioxetine reduced depression severity and improved cognitive function, work productivity, and functioning in Taiwanese patients with MDD in the real-world setting. Vortioxetine was well-tolerated in this Taiwanese population.

Background: The Pay-for-performance (P4P) program of diabetes care has demonstrated successful outcomes in patients with type 2 diabetes. However, the effectiveness of this multidisciplinary care model for psychiatric patients has never been evaluated. The objective of this study is to examine the effectiveness of P4P program of diabetes for psychiatric patients with diabetes., Methods: This study utilized a retrospective cohort design to examine the effectiveness of P4P program of diabetes care for psychiatric patients with diabetes. The participants' HbA1c (hemoglobin A1c) data of the fourth quarter in 2018 were used as baseline value, while P4P program was not applied yet. HbA1c data of every quarter in 2019 were collected. Generalized estimating equations (GEE) was used to analyze the change of HbA1c level., Results: The HbA1c level increased slightly in the first quarter, and then decreased gradually since the second quarter. The HbA1c level was significantly lower in the fourth quarter after P4P program intervention ( p < 0.05)., Conclusion: P4P program of diabetes care is also effective on psychiatric patients with diabetes, and this multidisciplinary care model could be encouraged and promoted for psychiatric patients with diabetes.

Inflammation and immune disorders are integral to the occurrence and progression of atherosclerosis (AS). With the role of regulatory T cells (Tregs) in immune regulation attracting attention, it has been widely accepted that Treg decrease and dysfunction are involved in AS pathogenesis. Chinese medicine (CM) has the advantages of being dual-directional, multi-targeted, and having minimal side effects in immune regulation. The anti-atherosclerosis effects of CM via Treg modulation have been revealed in clinical and animal studies. Therefore, this article reviews existing research on Tregs, the relationship between Tregs and AS, and the progress of CM for treating and prevention of atherosclerotic cardio-cerebrovascular diseases by regulating Tregs. Although the underlying mechanisms remain to be elucidated, CM treatment targeting Treg cells might provide a promising and novel future approach for prevention and treatment of AS., (© 2021. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/purpose: Among the ceramic materials used for all-ceramic crowns, zirconia has high biocompatibility and favorable mechanical properties, but its main drawbacks include low translucency and stress-induced phase transformation. To stabilize high-strength tetragonal zirconia polycrystal (TZP), 3-5 mol% yttria is usually added to prepare yttria-stabilized TZP (Y-TZP). In this study, the optical properties of three commercial Y-TZP ceramics were compared with those of the clinically available glass-ceramic material of lithium disilicate, and the relationship between translucency and crystal properties was analyzed in vitro., Materials and Methods: Twelve 5-mm-thick standardized disks were prepared from three Y-TZP ceramics and one lithium disilicate block. Absolute translucency was measured using a spectrophotometer with an integrating sphere. X-ray diffraction was used to quantify the main structural parameters (i.e., preferred plane, quantitative phase, and grain size) of Y-TZP crystals., Results: The product-dominated phase of Y-TZP exhibited a tetragonal lattice pattern, and the preferred planes had minor variations. The diffraction patterns of the three Y-TZP ceramics demonstrated minor effects on translucency, without significant differences ( p > 0.05). The grain size of 54-70 nm was negatively related to translucency in Y-TZP. Lithium disilicate specimens had significantly higher translucency than the three Y-TZP specimens ( p < 0.001)., Conclusion: Grain size reduction played an essential role in developing highly translucent Y-TZP ceramics. The three Y-TZP ceramics were essentially opaque but exhibited poorer translucency than lithium disilicate in terms of esthetics., Competing Interests: All authors declare no conflicts of interest., (© 2021 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background: Gamma-aminobutyric acid type A (GABAA) receptors mainly mediate the effects of gamma-aminobutyric acid, which is the primary inhibitory neurotransmitter in the central nervous system. Abundant evidence suggests that GABAA receptors play a key role in sleep-regulating processes. No genetic association study has explored the relationships between GABAA receptor genes and sleep duration, sleep quality, and sleep timing in humans., Methods: We determined the association between single-nucleotide polymorphisms (SNPs) in the GABAA receptor genes GABRA1, GABRA2, GABRB3, GABRA5, and GABRG3 and sleep duration, sleep quality, and sleep timing in the Taiwan Biobank with a sample of 10,127 Taiwanese subjects. There were 10,142 subjects in the original study cohort. We excluded 15 subjects with a medication history of sedative-hypnotics., Results: Our data revealed an association of the GABRB3-GABRA5-GABRG3 gene cluster with sleep duration, which has not been previously identified: rs79333046 (beta = - 0.07; P = 1.21 × 10 -3 ) in GABRB3, rs189790076 (beta = 0.92; P = 1.04 × 10 -3 ) in GABRA5, and rs147619342 (beta = - 0.72; P = 3.97 × 10 -3 ) in GABRG3. The association between rs189790076 in GABRA5 and sleep duration remained significant after Bonferroni correction. A variant (rs12438141) in GABRB3 was also found to act as a potential expression quantitative trait locus. Additionally, we discovered interactions between variants in the GABRB3-GABRA5-GABRG3 gene cluster and lifestyle factors, such as tea and coffee consumption, smoking, and physical activity, that influenced sleep duration, although some interactions became nonsignificant after Bonferroni correction. We also found interactions among GABRB3, GABRA5, and GABRG3 that affected sleep duration. Furthermore, we identified an association of rs7165524 (beta = - 0.06; P = 2.20 × 10 -3 ) in GABRA5 with sleep quality and an association of rs79465949 (beta = - 0.12; P = 3.95 × 10 -3 ) in GABRB3 with sleep timing, although these associations became nonsignificant after Bonferroni correction. However, we detected no evidence of an association of individual SNPs in GABRA1 and GABRA2., Conclusions: Our results indicate that rs189790076 in GABRA5 and gene-gene interactions among GABRB3, GABRA5, and GABRG3 may contribute to sleep duration in the Taiwanese population., (© 2021. The Author(s).)

The computer-aided design/computer-aided manufacturing (CAD/CAM) fabrication technique has become one of the hottest topics in the dental field. This technology can be applied to fixed partial dentures, removable dentures, and implant prostheses. This study aimed to evaluate the feasibility of NaCaPO 4 -blended zirconia as a new CAD/CAM material. Eleven different proportional samples of zirconia and NaCaPO 4 ( x Z y N) were prepared and characterized by X-ray diffractometry (XRD) and Vickers microhardness, and the milling property of these new samples was tested via a digital optical microscope. After calcination at 950 °C for 4 h, XRD results showed that the intensity of tetragonal ZrO 2 gradually decreased with an increase in the content of NaCaPO 4 . Furthermore, with the increase in NaCaPO 4 content, the sintering became more obvious, which improved the densification of the sintered body and reduced its porosity. Specimens went through milling by a computer numerical control (CNC) machine, and the marginal integrity revealed that being sintered at 1350 °C was better than being sintered at 950 °C. Moreover, 7Z3N showed better marginal fit than that of 6Z4N among thirty-six samples when sintered at 1350 °C ( p < 0.05). The milling test results revealed that 7Z3N could be a new CAD/CAM material for dental restoration use in the future.

Betel quid (BQ), a group I human carcinogen, strongly contributes to an increased risk of oral potentially malignant disorders (OPMD) and cancers of the oral cavity and pharynx. This study was conducted to discover whether monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) variants play a potential role in the risk assessment of oral cavity and pharynx cancers and OPMD, particularly among BQ users. We applied a case-control study to confirm the polymorphism of MAO and COMT using single-nucleotide polymorphisms. We used qRT-PCR, Western blotting, and immunohistochemistry (IHC) to determine MAO and COMT expression. Carriers of the MAOA rs6323 G-allele, MAOB rs6324 G-allele, and COMT rs4633 C/C-genotype had a prominently increased risk of oral cavity and pharynx cancers (AOR = 56.99; p < 0.001). Compared to adjacent noncancerous tissues, a significant downregulation of MAO and COMT expression was exhibited in cancerous tissues ( p < 0.01). Furthermore, in different cell models, MAO and COMT expression was significantly downregulated with an increased dose of arecoline ( p < 0.01). In personalized preventive medicine for oral and pharyngeal cancers, our findings are the first to demonstrate the potential role of lower MAO and COMT expression levels, with the risk polymorphisms utilized as clinical biomarkers.

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease, which has elevated autophagosome levels regulated by autophagy-related gene (ATG) expression. We investigated the associations of ATG polymorphisms with AOSD susceptibility, clinical manifestations, and disease course. The six-candidate single-nucleotide polymorphisms (SNPs) involved in autophagy were genotyped using direct sequencing on samples from 129 AOSD patients and 129 healthy participants. The differentially expressed gene products were quantified using PCR and ELISA. Significant linkage disequilibrium was noted in three SNPs of autophagy-related 16-like 1 ( ATG16L1 ) gene (rs10210302, rs2241880, and rs1045100). Although the AA/CC/TT haplotype of ATG16L1 was not associated with the susceptibility of our AOSD patients compared with other haplotypes, those carrying this haplotype had lower mRNA expression levels of LC3-II, reflecting by autophagosome formation ( p = 0.026). Patients carrying AA/CC/TT haplotype also have a significantly higher proportion of skin rash and a lower proportion of arthritis compared with other haplotypes. The AA/CC/TT haplotype was significantly associated with systemic pattern (odds ratio, 3.25; 95% confidence interval, 1.15-9.14; p = 0.026). In summary, the AA/CC/TT haplotype encoded lower levels of autophagosome formation and was associated with a higher proportion of skin rash and systemic pattern of AOSD compared with other haplotypes.

Background: Polycystic kidney disease (PKD) is a common renal disorder affecting approximately 1 in 1000 live births. Tuberculosis (TB) is an infectious disease worldwide. This study investigated the risk of TB infection in patients with PKD., Methods: A nationwide population-based cohort study was performed using Taiwan's National Health Insurance Research Database. We used patients' hospitalization files for the entire analysis during 2000-2012. As per diagnosis, we divided patients into PKD and non-PKD cohorts and the major outcome was TB infection., Results: A total of 13,540 participants with 6770 patients in each cohort were enrolled. The PKD cohort had a higher risk of TB infection than did the non-PKD cohort after adjusting for age, sex, and comorbidities (adjusted hazard ratio (aHR) = 1.91, 95% confidence interval [CI] = 1.51-2.43). When classifying by sites of pulmonary TB (PTB) and extrapulmonary TB (EPTB), the PKD cohort demonstrated a significantly higher risk of EPTB (aHR = 2.44, 95% CI = 1.46-4.08) as well as a risk of PTB (aHR = 1.69, 95% CI = 1.29-2.22). When stratified by the presence or absence of a comorbidity, high TB infection risk was noted in the PKD patients without any comorbidity (HR = 2.69, 95% CI = 1.69-4.30)., Conclusions: Taken together, our findings suggest that PKD is associated with a 1.91-fold increased risk of TB infection. Medical professionls should maintain a high index of suspicion in daily practice for patients with PKD, particularly those with EPTB infection.

This is the first study to use functional near-infrared spectroscopy (fNIRS) to investigate how the lateralization of the epileptogenic zone affects the reconfiguration of task-related network patterns. Eleven left fronto-temporal epilepsy (L-FTE) and 11 right fronto-temporal epilepsy (R-FTE), as well as 22 age- and gender-matched controls, were enrolled. Signals from 52-channel fNIRS were recorded while the subject was undertaking verbal fluency tasks (VFTs), which included categorical (CFT) and letter (LFT) fluency tasks. Three analytic methods were used to study the network topology: network-based analysis, hub identification, and proportional threshold to select the top 20% strongest connections for both graph theory parameters and clinical correlation. Performance of CFT is accomplished primarily using the ventral pathway, and bilateral ventral pathways are augmented in fronto-temporal epilepsy patients by strengthening the inter-hemispheric connections, especially for R-FTE. LFT mainly employed the dorsal pathway, and further prioritized the left dorsal pathway in strengthening intra-hemispheric connections in fronto-temporal epilepsy, especially L-FTE. The top 20% of the strongest connections only present differences in CFT network compared with the controls. R-FTE increased inter-hemispheric network density, while L-FTE decreased inter-hemispheric average characteristic path length. Accumulative seizure burden only affects L-FTE network. Better LFT performance and longer educational years seem to promote left fronto-temporal networks, and decreased the demand from RR intra-hemispheric connectivity in L-FTE. LFT scores in R-FTE are maintained by preserved RR intra-hemispheric networks. However, CFT scores and educational years seem to have no effect on the CFT network topology in both FTE., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A genetically encoded caffeine-operated synthetic module (COSMO) is introduced herein as a robust chemically induced dimerization (CID) system. COSMO enables chemogenetic manipulation of biological processes by caffeine and its metabolites, as well as caffeinated beverages, including coffee, tea, soda, and energy drinks. This CID tool, evolved from an anti-caffeine nanobody via cell-based high-throughput screening, permits caffeine-inducible gating of calcium channels, tumor killing via necroptosis, growth factors-independent activation of tyrosine receptor kinase signaling, and enhancement of nanobody-mediated antigen recognition for the severe acute respiratory distress coronavirus 2 (SARS-CoV-2) spike protein. Further rationalized engineering of COSMO leads to 34-217-fold enhancement in caffeine sensitivity (EC 50 = 16.9 nanomolar), which makes it among the most potent CID systems like the FK506 binding protein (FKBP)-FKBP rapamycin binding domain (FRB)-rapamycin complex. Furthermore, bivalent COSMO (biCOMSO) connected with a long linker favors intramolecular dimerization and acts as a versatile precision switch when inserted in host proteins to achieve tailored function. Given the modularity and high transferability of COMSO and biCOSMO, these chemical biology tools are anticipated to greatly accelerate the development of therapeutic cells and biologics that can be switched on and off by caffeinated beverages commonly consumed in the daily life., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by Wiley‐VCH GmbH.)

Objective: : The relationship of antipsychotics and the risk of refracture in treated patients is unclear. The aim of this study is to evaluate the association between prolonged antipsychotic and the incidences of bone fractures and refractures in schizophrenia., Methods: This is a retrospective nested case-control study using Taiwan National Health Insurance Research Database recorded from 2000 to 2005, with cases followed up to end of 2011. Total of 7,842 schizophrenic patients, 3,955 had developed bone fractures were compared with 3,887 control subjects matched in age, sex, and index date. Antipsychotic drug exposure was classified based on the drug type and medication duration. Conditional logistic regression analyses were performed. Odds ratio (OR) and confidence interval (CI) were calculated., Results: We found (after adjustments) higher risks of developing fractures under continued use of typical (OR = 1.70; 95% CI, 1.51-1.91) or atypical antipsychotics (OR = 1.43; 95% CI, 1.28-1.60) were found. Additionally, continued use typical (OR = 1.84; 95% CI, 1.35-2.50) or atypical antipsychotics (OR = 1.44; 95% CI, 1.06-1.95) was positively associated with refracture risks. Moreover, refractures were associated with continuous use of chlorpromazine (one typical antipsychotics, OR = 2.45; 95% CI, 1.14-5.25), and risperidone (OR = 1.48; 95% CI, 1.01-2.16) or zotepine (OR = 2.15; 95% CI, 1.06-4.36) (two atypical antipsychotics)., Conclusion: Higher risks of bone fracture and refracture were found in schizophrenia under prolonged medication with typical or atypical antipsychotics. We therefore recommend that clinicians should pay more attention on bone density monitoring for patients using long-term antipsychotics.

Withaferin A (WFA), a Withania somnifera -derived triterpenoid, is an anticancer natural product. The anticancer effect of nonionizing radiation such as ultraviolet-C (UVC) as well as the combined treatment of UVC and WFA is rarely investigated. Low dose UVC and/or WFA treatments (12 J/m 2 and/or 1 μM) were chosen to evaluate antioral cancer cell line effects by examining cytotoxicity, cell cycle disruption, apoptosis induction, and DNA damage. For two cancer cell lines (Ca9-22 and HSC-3), single treatment (UVC or WFA) showed about 80% viability, while a combined treatment of UVC/WFA showed about 40% viability. In contrast, there was noncytotoxicity to normal oral cell lines (HGF-1). Compared to single treatment and control, low dose UVC/WFA shows high inductions of apoptosis in terms of flow cytometric detections for subG1, annexin V, pancaspase changes as well as Western blotting for detecting cleaved poly (ADP-ribose) polymerase (c-PARP) and caspase 3 (c-Cas 3) and luciferase assay for detecting Cas 3/7 activity. Low dose UVC/WFA also showed high inductions of oxidative stress and DNA damage in terms of flow cytometric detections of reactive oxygen species (ROS), mitochondrial superoxide (MitoSOX) generation, and membrane potential (MitoMP) destruction, γH2AX and 8-oxo-2'deoxyguanosine (8-oxodG) types of DNA damages. For comparison, low dose UVC/WFA show rare inductions of annexin V, Cas 3/7 activity, ROS, MitoSOX, and MitoMP changes to normal oral HGF-1 cells. Therefore, low dose UVC/WFA provides a novel selectively killing mechanism to oral cancer cells, suggesting that WFA is a UVC sensitizer to inhibit the proliferation of oral cancer cells.

Molecular mechanisms that prompt or mitigate excessive alcohol consumption could be partly explained by metabolic shifts. This genome-wide association study aims to identify the susceptibility gene loci for excessive alcohol consumption by jointly measuring weekly alcohol consumption and γ-GT levels. We analysed the Taiwan Biobank data of 18,363 Taiwanese people, including 1945 with excessive alcohol use. We found that one or two copies of the G allele in rs671 (ALDH2) increased the risk of excessive alcohol consumption, while one or two copies of the C allele in rs3782886 (BRAP) reduced the risk of excessive alcohol consumption. To minimize the influence of extensive regional linkage disequilibrium, we used the ridge regression. The ridge coefficients of rs7398833, rs671 and rs3782886 were unchanged across different values of the shrinkage parameter. The three variants corresponded to posttranscriptional activity, including cut-like homeobox 2 (a protein coded by CUX2), Glu504Lys of acetaldehyde dehydrogenase 2 (a protein encoded by ALDH2) and Glu4Gly of BRCA1-associated protein (a protein encoded by BRAP). We found that Glu504Lys of ALDH2 and Glu4Gly of BRAP are involved in the negative regulation of excessive alcohol consumption. The mechanism underlying the γ-GT-catalytic metabolic reaction in excessive alcohol consumption is associated with ALDH2, BRAP and CUX2. Further study is needed to clarify the roles of ALDH2, BRAP and CUX2 in the liver-brain endocrine axis connecting metabolic shifts with excessive alcohol consumption.

Background: Chronic kidney disease (CKD), low serum albumin, and anemia are known risk factors for cognitive decline in older people. We investigated the association between kidney function and cognitive impairment severity in oldest-old people with a diagnosis of Alzheimer's disease (AD)., Methods: A cross-sectional study of patients aged 80 years and older was conducted at a veterans' home in Taiwan between 2012 and 2016. Their estimated glomerular filtration rate (eGFR) was determined using the Modification of Diet in Renal Diseases (MDRD) equation. Cognitive function was evaluated with the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR)., Results: A total of 84 patients (age mean ± SD, 86.6 ± 3.9 years) had MMSE scores of 10.1 ± 6.7, and CDR scores of 1.6 ± 0.7. The average eGFR was 61.7 ± 21.5 mL/min/1.73m 2 . The mean hemoglobin concentration was 12.7 ± 1.7 g/dl, and the mean albumin concentration was 4.5 ± 4.8 g/dl. Multivariate regression analyses showed that scores of CDR were significantly correlated with eGFR after adjustment for potential confounders. The scores of MMSE were significantly correlated with serum albumin and hemoglobin after adjustment for potential confounders., Conclusions: We found dementia severity was significantly associated with kidney function, serum albumin, and hemoglobin in the oldest-old with AD. We recommend that oldest-old people with a diagnosis of AD be evaluated to determine kidney function, as well as nutritional and hematological status. Further study is needed to establish whether prevention of CKD deterioration, and correction of malnutrition and anemia may help to slow cognitive decline in oldest-old people with dementia.

Background: Sleep is a key factor for health-related quality of life since sleep disturbances are a significant and common problem for patients with various human diseases such as psychiatric disorders. While single nucleotide polymorphisms (SNPs) in circadian clock genes have been indicated to be associated with sleep duration, most of the association studies have been investigated in populations with European ancestry. It is believed that no studies have been conducted to investigate a link between sleep duration and the circadian clock genes RORA and RORB, which play a key role, with NR1D1, in an additional feedback loop for the circadian rhythm machinery., Methods: In this study, we assessed the relationships between sleep duration and SNPs in the circadian clock genes NR1D1, RORA, and RORB in the Taiwan Biobank with a sample of 10,112 Taiwanese subjects., Results: From our data, we revealed a novel significant association in sleep duration with the rs75981965 SNP (P = 9.93 × 10 -5 ) in the RORA gene that has not been previously identified. The association of sleep duration with this SNP remained significant after performing Bonferroni correction. RORA is a potential candidate for sleep duration as RORA has been suggested to play a key role in the regulation of sleep disorders. Additionally, we pinpointed the effects of interactions between RORA rs75981965 and environmental factors such as tea consumption (P = 0.0015), coffee consumption (P = 0.0029), physical activity (P = 0.011), alcohol consumption (P = 0.0146), and smoking (P = 0.0223) in influencing sleep duration. We also found interactions between RORA and NR1D1 (P = 0.0023) as well as between RORA and RORB (P = 0.0061) in affecting sleep duration., Conclusions: Our results indicate that the circadian clock gene RORA may contribute to sleep duration independently as well as through gene-gene and gene-environment interactions in the Taiwanese population., (Copyright © 2020 Elsevier B.V. All rights reserved.)