Sleep–wake regulation is controlled by circadian and homeostatic processes, with adenosine acting as a key molecular mediator of homeostatic sleep pressure. Extracellular adenosine accumulates during wakefulness as a result of neuronal energy metabolism, particularly in the basal forebrain, and declines during recovery sleep, thereby reflecting the physiological need for sleep.The sleep-promoting effects of adenosine are mediated primarily by two G protein–coupled receptor subtypes, the adenosine A1 receptor and the adenosine A2A receptor. The adenosine A1 receptor, coupled to inhibitory Gi/o proteins and widely expressed in the cortex, hippocampus, thalamus, and basal forebrain, suppresses wake-promoting neuronal activity and facilitates slow-wave activity during non-rapid eye movement sleep. In contrast, the adenosine A2A receptor, coupled to stimulatory Golf proteins and enriched in the striatum and nucleus accumbens, promotes sleep by activating neurons in the preoptic hypothalamus and engaging the indirect basal ganglia pathway. Despite these well-established roles, the contributions of dysregulation of the adenosine A1 receptor and the adenosine A2A receptor to specific sleep disorders remain incompletely understood. This review examines how signaling of the adenosine A1 receptor and the adenosine A2A receptor is altered in insomnia, obstructive sleep apnea, narcolepsy, and restless legs syndrome, and evaluates the therapeutic potential of receptor-selective strategies for adenosine receptor–targeted treatment.

Objective: To propose the utilization of virtual tooth models (VTMs) created by combining tooth root data from cone-beam computed tomography (CBCT) and crown data gathered through intraoral scanning to assess inter-root distance and angulation during orthodontic treatment when repeated radiographic monitoring becomes necessary. Methods: Patients with planned dental implant placement in edentulous areas during or after orthodontic treatment and who underwent intraoral and CBCT scans at the pretreatment and posttreatment stages were selected. Tooth models were fabricated by merging intraorally scanned crowns with the corresponding CBCT-scanned roots from the pretreatment. Tooth positions posttreatment was estimated by integrating models into posttreatment intraoral scans. Moreover, the actual positions were obtained from posttreatment CBCTs. Discrepancies in the estimated and actual tooth positions, including interradicular distances and inter-root angulations, were compared. Results: The minimum inter-radicular distance between two adjacent teeth demonstrated no significant difference between the estimated and actual tooth positions. The difference in inter-root angulation was not statistically significant. Most interradicular distances measured at each landmark revealed no significant differences between the estimated and actual tooth positions, except at the buccolingual midpoint of the cemento-enamel junction, where a slight discrepancy was observed. Conclusions The tooth position of VTMs demonstrated clinically acceptable accuracy compared to CBCT scans. Additionally, VTMs can benefit both clinicians and patients by enabling accurate assessment of the inter-radicular space for dental implant placement without repeated CBCT scans.

Objective: To evaluate the effectiveness of a squatting posture grading system established to screen for limited ankle dorsiflexion. Methods: The squat posture grading system categorizes subjects’ squat posture into three grades. Grade 1 is defined as being able to maintain a squatting posture with heels on the ground in full ankle dorsiflexion without effort. Grade 2 is defined as being able to perform the same position, but unable to maintain the position for more than 5 seconds or requiring trunk and leg muscle efforts to maintain the position. Grade 3 is defined as being unable to maintain the same position and falling backwards immediately if attempted to touch the ground with heels. Next, subjects’ ankle dorsiflexion angles were directly measured in knee flexed and extended position by goniometer. Results: Out of the 92 total subjects, 35 were in grade 1, 18 were in grade 2, and 39 were in grade 3. The average ankle dorsiflexion angle with knee flexed position were 23.13° for grade 1, 16.03° for grade 2, and 9.31° for grade 3. The average ankle dorsiflexion angle with knee extended position were 15.16° for grade 1, 7.92° for grade 2, and 3.40° for grade 3. Ankle dorsiflexion angles showed a significant decrease from grade 1 to 3 (p<0.05). Conclusion The squatting posture grading system defined in this study effectively graded the subjects based on the difference in their average ankle dorsiflexion angle. This system could be used as a quick screening method for limited ankle dorsiflexion.

We identified drugs or mechanisms targeting ABCB1 (or P-glycoprotein; P-gp)-overexpressing drug-resistant cancer populations, given that these cells play a key role in tumor recurrence. Specifically, we searched for Akt inhibitors that could increase cytotoxicity in P-gp-overexpressing drug-resistant cancer cells. We performed cytotoxicity assays using five cell lines: 1. MCF-7/ADR, 2. KBV20C cancer cells (P-gp overexpression, vincristine [VIC] resistance, and GSK690693-resistance), 3. MCF-7, 4. normal HaCaT cells (non-P-gp-overexpressing, VIC-sensitive, and GSK690693-sensitive), and 5. MDA-MB-231 cancer cells (non-Pgp overexpression, relatively VIC-resistance, and GSK690693-sensitive). Herein, we found that low-dose perifosine markedly and selectively sensitizes both MCF-7/ADR and KBV20C drug-resistant cancer cells exhibiting P-gp overexpression. Compared with other Akt inhibitors (AZD5363, BKM120, and GSK690693), low-dose perifosine specifically sensitized P-gp-overexpressing resistant MCF-7/ADR cancer cells. Conversely, Akt inhibitors (other than perifosine) could enhance sensitization effects in drugsensitive MCF-7 and HaCaT cells. Considering that perifosine has both an alkyl-phospholipid structure and is an allosteric inhibitor for membrane-localizing Akt-targeting, we examined structurally and functionally similar Akt inhibitors (miltefosine and MK-2206).However, we found that these inhibitors were non-specific, suggesting that the specificity of perifosine in P-gp-overexpressing resistant cancer cells is unrelated to phospholipid localizing membranes or allosteric inhibition. Furthermore, we examined the molecular mechanism of low-dose perifosine in drug-resistant MCF-7/ADR cancer cells. MCF-7/ADR cells exhibited increased apoptosis via G2 arrest and autophagy induction. However, no increase in P-gp-inhibitory activity was observed in drug-resistant MCF-7/ADR cancer cells. Single low-dose perifosine treatment exerted a sensitization effect similar to co-treatment with VIC in P-gp-overexpressing drug-resistant MCF-7/ADR cancer cells, suggesting that single treatment with low-dose perifosine is a more powerful tool against P-gp-overexpressing drug-resistant cancer cells. These findings could contribute to its clinical use as a first-line treatment, explicitly targeting P-gp-overexpressing resistant cancer populations in heterogeneous tumor populations.Therefore, perifosine may be valuable in delaying or reducing cancer recurrence by targeting P-gp-overexpressing drug-resistant cancer cells.

Objective: To propose the utilization of virtual tooth models (VTMs) created by combining tooth root data from cone-beam computed tomography (CBCT) and crown data gathered through intraoral scanning to assess inter-root distance and angulation during orthodontic treatment when repeated radiographic monitoring becomes necessary. Methods: Patients with planned dental implant placement in edentulous areas during or after orthodontic treatment and who underwent intraoral and CBCT scans at the pretreatment and posttreatment stages were selected. Tooth models were fabricated by merging intraorally scanned crowns with the corresponding CBCT-scanned roots from the pretreatment. Tooth positions posttreatment was estimated by integrating models into posttreatment intraoral scans. Moreover, the actual positions were obtained from posttreatment CBCTs. Discrepancies in the estimated and actual tooth positions, including interradicular distances and inter-root angulations, were compared. Results: The minimum inter-radicular distance between two adjacent teeth demonstrated no significant difference between the estimated and actual tooth positions. The difference in inter-root angulation was not statistically significant. Most interradicular distances measured at each landmark revealed no significant differences between the estimated and actual tooth positions, except at the buccolingual midpoint of the cemento-enamel junction, where a slight discrepancy was observed. Conclusions The tooth position of VTMs demonstrated clinically acceptable accuracy compared to CBCT scans. Additionally, VTMs can benefit both clinicians and patients by enabling accurate assessment of the inter-radicular space for dental implant placement without repeated CBCT scans.

We identified drugs or mechanisms targeting ABCB1 (or P-glycoprotein; P-gp)-overexpressing drug-resistant cancer populations, given that these cells play a key role in tumor recurrence. Specifically, we searched for Akt inhibitors that could increase cytotoxicity in P-gp-overexpressing drug-resistant cancer cells. We performed cytotoxicity assays using five cell lines: 1. MCF-7/ADR, 2. KBV20C cancer cells (P-gp overexpression, vincristine [VIC] resistance, and GSK690693-resistance), 3. MCF-7, 4. normal HaCaT cells (non-P-gp-overexpressing, VIC-sensitive, and GSK690693-sensitive), and 5. MDA-MB-231 cancer cells (non-Pgp overexpression, relatively VIC-resistance, and GSK690693-sensitive). Herein, we found that low-dose perifosine markedly and selectively sensitizes both MCF-7/ADR and KBV20C drug-resistant cancer cells exhibiting P-gp overexpression. Compared with other Akt inhibitors (AZD5363, BKM120, and GSK690693), low-dose perifosine specifically sensitized P-gp-overexpressing resistant MCF-7/ADR cancer cells. Conversely, Akt inhibitors (other than perifosine) could enhance sensitization effects in drugsensitive MCF-7 and HaCaT cells. Considering that perifosine has both an alkyl-phospholipid structure and is an allosteric inhibitor for membrane-localizing Akt-targeting, we examined structurally and functionally similar Akt inhibitors (miltefosine and MK-2206).However, we found that these inhibitors were non-specific, suggesting that the specificity of perifosine in P-gp-overexpressing resistant cancer cells is unrelated to phospholipid localizing membranes or allosteric inhibition. Furthermore, we examined the molecular mechanism of low-dose perifosine in drug-resistant MCF-7/ADR cancer cells. MCF-7/ADR cells exhibited increased apoptosis via G2 arrest and autophagy induction. However, no increase in P-gp-inhibitory activity was observed in drug-resistant MCF-7/ADR cancer cells. Single low-dose perifosine treatment exerted a sensitization effect similar to co-treatment with VIC in P-gp-overexpressing drug-resistant MCF-7/ADR cancer cells, suggesting that single treatment with low-dose perifosine is a more powerful tool against P-gp-overexpressing drug-resistant cancer cells. These findings could contribute to its clinical use as a first-line treatment, explicitly targeting P-gp-overexpressing resistant cancer populations in heterogeneous tumor populations.Therefore, perifosine may be valuable in delaying or reducing cancer recurrence by targeting P-gp-overexpressing drug-resistant cancer cells.

Objective: To evaluate the effectiveness of a squatting posture grading system established to screen for limited ankle dorsiflexion. Methods: The squat posture grading system categorizes subjects’ squat posture into three grades. Grade 1 is defined as being able to maintain a squatting posture with heels on the ground in full ankle dorsiflexion without effort. Grade 2 is defined as being able to perform the same position, but unable to maintain the position for more than 5 seconds or requiring trunk and leg muscle efforts to maintain the position. Grade 3 is defined as being unable to maintain the same position and falling backwards immediately if attempted to touch the ground with heels. Next, subjects’ ankle dorsiflexion angles were directly measured in knee flexed and extended position by goniometer. Results: Out of the 92 total subjects, 35 were in grade 1, 18 were in grade 2, and 39 were in grade 3. The average ankle dorsiflexion angle with knee flexed position were 23.13° for grade 1, 16.03° for grade 2, and 9.31° for grade 3. The average ankle dorsiflexion angle with knee extended position were 15.16° for grade 1, 7.92° for grade 2, and 3.40° for grade 3. Ankle dorsiflexion angles showed a significant decrease from grade 1 to 3 (p<0.05). Conclusion The squatting posture grading system defined in this study effectively graded the subjects based on the difference in their average ankle dorsiflexion angle. This system could be used as a quick screening method for limited ankle dorsiflexion.

We identified drugs or mechanisms targeting ABCB1 (or P-glycoprotein; P-gp)-overexpressing drug-resistant cancer populations, given that these cells play a key role in tumor recurrence. Specifically, we searched for Akt inhibitors that could increase cytotoxicity in P-gp-overexpressing drug-resistant cancer cells. We performed cytotoxicity assays using five cell lines: 1. MCF-7/ADR, 2. KBV20C cancer cells (P-gp overexpression, vincristine [VIC] resistance, and GSK690693-resistance), 3. MCF-7, 4. normal HaCaT cells (non-P-gp-overexpressing, VIC-sensitive, and GSK690693-sensitive), and 5. MDA-MB-231 cancer cells (non-Pgp overexpression, relatively VIC-resistance, and GSK690693-sensitive). Herein, we found that low-dose perifosine markedly and selectively sensitizes both MCF-7/ADR and KBV20C drug-resistant cancer cells exhibiting P-gp overexpression. Compared with other Akt inhibitors (AZD5363, BKM120, and GSK690693), low-dose perifosine specifically sensitized P-gp-overexpressing resistant MCF-7/ADR cancer cells. Conversely, Akt inhibitors (other than perifosine) could enhance sensitization effects in drugsensitive MCF-7 and HaCaT cells. Considering that perifosine has both an alkyl-phospholipid structure and is an allosteric inhibitor for membrane-localizing Akt-targeting, we examined structurally and functionally similar Akt inhibitors (miltefosine and MK-2206).However, we found that these inhibitors were non-specific, suggesting that the specificity of perifosine in P-gp-overexpressing resistant cancer cells is unrelated to phospholipid localizing membranes or allosteric inhibition. Furthermore, we examined the molecular mechanism of low-dose perifosine in drug-resistant MCF-7/ADR cancer cells. MCF-7/ADR cells exhibited increased apoptosis via G2 arrest and autophagy induction. However, no increase in P-gp-inhibitory activity was observed in drug-resistant MCF-7/ADR cancer cells. Single low-dose perifosine treatment exerted a sensitization effect similar to co-treatment with VIC in P-gp-overexpressing drug-resistant MCF-7/ADR cancer cells, suggesting that single treatment with low-dose perifosine is a more powerful tool against P-gp-overexpressing drug-resistant cancer cells. These findings could contribute to its clinical use as a first-line treatment, explicitly targeting P-gp-overexpressing resistant cancer populations in heterogeneous tumor populations.Therefore, perifosine may be valuable in delaying or reducing cancer recurrence by targeting P-gp-overexpressing drug-resistant cancer cells.

Objective: To propose the utilization of virtual tooth models (VTMs) created by combining tooth root data from cone-beam computed tomography (CBCT) and crown data gathered through intraoral scanning to assess inter-root distance and angulation during orthodontic treatment when repeated radiographic monitoring becomes necessary. Methods: Patients with planned dental implant placement in edentulous areas during or after orthodontic treatment and who underwent intraoral and CBCT scans at the pretreatment and posttreatment stages were selected. Tooth models were fabricated by merging intraorally scanned crowns with the corresponding CBCT-scanned roots from the pretreatment. Tooth positions posttreatment was estimated by integrating models into posttreatment intraoral scans. Moreover, the actual positions were obtained from posttreatment CBCTs. Discrepancies in the estimated and actual tooth positions, including interradicular distances and inter-root angulations, were compared. Results: The minimum inter-radicular distance between two adjacent teeth demonstrated no significant difference between the estimated and actual tooth positions. The difference in inter-root angulation was not statistically significant. Most interradicular distances measured at each landmark revealed no significant differences between the estimated and actual tooth positions, except at the buccolingual midpoint of the cemento-enamel junction, where a slight discrepancy was observed. Conclusions The tooth position of VTMs demonstrated clinically acceptable accuracy compared to CBCT scans. Additionally, VTMs can benefit both clinicians and patients by enabling accurate assessment of the inter-radicular space for dental implant placement without repeated CBCT scans.

Objective: To propose the utilization of virtual tooth models (VTMs) created by combining tooth root data from cone-beam computed tomography (CBCT) and crown data gathered through intraoral scanning to assess inter-root distance and angulation during orthodontic treatment when repeated radiographic monitoring becomes necessary. Methods: Patients with planned dental implant placement in edentulous areas during or after orthodontic treatment and who underwent intraoral and CBCT scans at the pretreatment and posttreatment stages were selected. Tooth models were fabricated by merging intraorally scanned crowns with the corresponding CBCT-scanned roots from the pretreatment. Tooth positions posttreatment was estimated by integrating models into posttreatment intraoral scans. Moreover, the actual positions were obtained from posttreatment CBCTs. Discrepancies in the estimated and actual tooth positions, including interradicular distances and inter-root angulations, were compared. Results: The minimum inter-radicular distance between two adjacent teeth demonstrated no significant difference between the estimated and actual tooth positions. The difference in inter-root angulation was not statistically significant. Most interradicular distances measured at each landmark revealed no significant differences between the estimated and actual tooth positions, except at the buccolingual midpoint of the cemento-enamel junction, where a slight discrepancy was observed. Conclusions The tooth position of VTMs demonstrated clinically acceptable accuracy compared to CBCT scans. Additionally, VTMs can benefit both clinicians and patients by enabling accurate assessment of the inter-radicular space for dental implant placement without repeated CBCT scans.