Case report: Response to tepotinib in Chinese non-small cell lung cancer patients harboring METex14 skipping with varying features.

MET exon 14 (METex14) skipping is the most reported MET mutation in non-small cell lung cancer (NSCLC) and has been confirmed to respond to MET tyrosine kinase inhibitors (TKI) in clinical trials. While MET TKI tepotinib was recently approved for METex14 skipping NSCLC in China, real-world evidence is limited. We report our experience treating NSCLC patients referred from oncology sites across China with tepotinib in the Boao Lecheng Pilot Zone. Four patients have been prescribed the drug with a median age of 67 years (range, 61-71 years). One patient has concomitant BRAF V600E mutation, and another patient had savolitinib as first line of therapy but discontinued due to hepatotoxicity. Till the end of follow-up, four patients were all on tepotinib therapy, with a median duration of therapy of 19 months. One patient achieved partial response and three achieved stable disease. Three patients had peripheral edema, but all were mild. Our experience showed in real clinical setting, tepotinib had robust and durable clinical activity and a favorable toxicity profile in Chinese patients with METex14 skipping NSCLC. It is the first report on the effectiveness of tepotinib in a patient with both METex14 skipping and BRAF V600E mutations and successful MET inhibitor switch after MET inhibitor-induced liver injury.

The effect of miR-381 on proliferation and prognosis of breast cancer by altering CCNA2 expression.

BACKGROUND: MiR-381 can regulate the expression of cyclin A2 (CCNA2) to inhibit the proliferation and migration of bladder cancer cells, but whether miR-381 has the same function in breast cancer is not well know. METHODS: The over express or silence miR-381 expressing cell lines were constructed by lentivirus infection to reveal the biological functions of miR-381 in vitro. The expression of miR-381 and CCNA2 in 162 breast cancer patients were detected to further reveal their impact and predictive value on progression-free survival (PFS) and overall survival (OS). RESULTS: After transfection of MDA-MB-231 and MCF-7 cells with miR-381 mimics, the expression of miR-381 was effectively up-regulated and CCNA2 was effectively down-regulated, while the opposite results were observed in tumour cell which transfected with miR-381 inhibitors. After transfection of cell lines with miR-381 mimics, tumour cell activity was significantly reduced, while the opposite results were observed in tumour cell which transfected with miR-381 inhibitors. The area under curves (AUCs) of miRNA-381 and CCNA2 for predicting PFS and OS were 0.711, 0.695, 0.694 and 0.675 respectively. Cox regression analysis showed that miRNA-381 ≥ 1.65 2-ΔΔCt and CCNA ≥ 2.95 2-ΔΔCt were the influence factors of PFS and OS, the hazard ratio (HR) values were 0.553, 2.075, 0.462 and 2.089, respectively. CONCLUSION: miR-381 inhibitors breast cancer cells proliferation and migration by down-regulating the expression of CCNA2, both of them can predict the prognosis of breast cancer.

miR-381 can regulate the expression of cyclin A2 and inhibit the proliferation and migration of bladder cancer cells, but whether miR-381 has the same function in breast cancer is not well know. We analysed the levels of miR-381 and cyclin A2 in breast cancer patients and breast cancer cells to reveal the mechanism of miR-381 affecting the expression of cyclin A2. We found miRNA-381 affects the proliferation and migration of breast cancer cells by down-regulating the expression of cyclin A2. The expression of serum miR-381 and cyclin A2 have important values in predicting the prognosis of breast cancer. Our findings provide mechanistic insights into how miR-381 regulates the proliferation and migration of breast cancer, as well as a new target for clinical treatment. Future research may focus on how to improve patient prognosis by up-regulating expression of miR-381 and down-regulating the expression of cyclin A2.

Inverted U-shaped relationship between sleep duration and phenotypic age in US adults: a population-based study.

Sleep is a modifiable behavior that can be targeted in interventions aimed at promoting healthy aging. This study aims to (i) identify the sleep duration trend in US adults; (ii) investigate the relationship between sleep duration and phenotypic age; and (iii) explore the role of exercise in this relationship. Phenotypic age as a novel index was calculated according to biomarkers collected from US adults based on the National Health and Nutrition Examination Survey (NHANES). Sleep information was self-reported by participants and discerned through individual interviews. The principal analytical method employed was weighted multivariable linear regression modeling, which accommodated for the complex multi-stage sampling design. The potential non-linear relationship was explored using a restricted cubic spline (RCS) model. Furthermore, subgroup analyses evaluated the potential effects of sociodemographic and lifestyle factors on the primary study outcomes. A total of 13,569 participants were finally included in, thereby resulting in a weighted population of 78,880,615. An examination of the temporal trends in sleep duration revealed a declining proportion of individuals with insufficient and markedly deficient sleep time since the 2015-2016 cycle. Taken normal sleep group as a reference, participants with extreme short sleep [ß (95% CI) 0.582 (0.018, 1.146), p = 0.044] and long sleep [ß (95% CI) 0.694 (0.186, 1.203), p = 0.010] were both positively associated with phenotypic age using the fully adjusted model. According to the dose-response relationship between sleep duration and phenotypic age, long sleep duration can benefit from regular exercise activity, whereas short sleep duration with more exercise tended to have higher phenotypic age. There is an inverted U-shaped relationship between short and long sleep durations and phenotypic age. This study represents an important step forward in our understanding of the complex relationship between sleep and healthy aging. By shedding light on this topic and providing practical exercise recommendations for promoting healthy sleep habits, researchers can help individuals live longer, healthier, and more fulfilling lives.

Investigating the Effect of Different Types of Exercise on Upper Limb Functional Recovery in Patients with Right Hemisphere Damage Based on fNIRS.

To investigate the effects of functional occupational therapy (FOT) combined with different types of exercise on upper limb motor function recovery and brain function remodeling in patients with right hemisphere damage (RHD) by analyzing functional near-infrared spectroscopy (fNIRS). Patients (n = 32) with RHD at Beijing Bo'ai Hospital were recruited and randomly allocated to receive either FOT combined with passive motion (N=16) or FOT combined with assisted active movement (N=16). The passive motion group (FOT-PM) received functional occupational therapy for 20 min and passive exercise for 10 min in each session, while the assisted active movement group (FOT-AAM) received functional occupational therapy for 20 min and assisted active exercise for 10 min. Both groups received conventional drug therapy and other rehabilitation therapy. Treatment was performed once a day, 5 times a week for 4 weeks. The recovery of motor function and activities of daily living (ADL) was assessed using Fugl-Meyer Assessment upper extremity (FMA-UE) and modified Barthel index (MBI) before and after treatment, and brain activation of the bilateral motor area was analyzed with fNIRS. The findings suggested that FOT combined with AAM was more effective than FOT combined with PM in improving the motor function of RHD patients' upper limbs and fingers, improving their ability to perform activities of daily living, and facilitating brain function remodeling of the motor area.

miR-708-5p deficiency involves the degeneration of mandibular condylar chondrocytes via the TLR4/NF-κB pathway.

OBJECTIVE: Ageing and aberrant biomechanical stimulation are two major risk factors for osteoarthritis (OA). One of the main characteristics of aged cartilage is cellular senescence. One of the main characteristics of osteoarthritic joints is cartilage degeneration. The cells in the temporomandibular joint (TMJ) cartilage are zonally arranged. The deep zone cells are differentiated from the superficial zone cells (SZCs). The purpose of the present study was to investigate whether degenerative shear stress (SS) stimulates the senescence programme in TMJ SZCs, and to determine which miRNA is involved in this process. METHOD: SZCs were isolated from the TMJ condyles of 3-week-old rats and treated with continuous passaging or SS. RNA sequencing was conducted to identify miRNA(s) that overlap with those involved in the replication senescence process and the SS-induced degeneration programme. Unilateral anterior crossbite (UAC), which is TMJ-OA inducible, was applied to 2-month-old and 12-month-old mice for 3 weeks. The effect of TMJ local injection of agomiR-708-5p was evaluated histologically. RESULTS: Both replication and SS treatment induced SZC senescence. miR-708-5p was identified. Knocking down miR-708-5p in SS-treated SZCs led to more severe senescence by alleviating the inhibitory impact of miR-708-5p on the TLR4/NF-κB pathway. miR-708-5p expression in mouse TMJ cartilage decreased with age. UAC induced more severe osteoarthritic cartilage lesions in 12-month-old mice than in 2-month-old mice. Injection of agomiR-708-5p suppressed UAC-induced osteoarthritic cartilage lesions. CONCLUSIONS: Age-related miR-708-5p deficiency is involved in the mechanically stimulated OA process. Intra-articular administration of agomiR-708-5p is a promising new strategy for OA treatment.

Binary Logistic Regression Analysis on the Association of Occlusion with the Temporomandibular Joint Arthralgia in the Partial Denture Wearers-A Retrospective Study.

PURPOSE: To analyze the potential association between the occlusion features and the incidence of temporomandibular joint (TMJ) arthralgia in patients with partial dentures. MATERIALS AND METHODS: A total of 101 partial denture wearers were collected, 45 with unilateral TMJ arthralgia diagnosed according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD). Binary logistic regression analysis was adopted. The TMJ asymptomatic group (n = 45) was quantified as 0, while the TMJ arthralgia group (n = 56) was quantified as 1. In total, 13 occlusion variables were analyzed: gender, age, number of prosthetic teeth, number of dentition quadrants with a prosthetic tooth, anterior or posterior prosthesis location in maxillary or mandibular dentition, occluded prosthesis pair, anterior overjet, and overbite relation. Simple and multiple binary logistic models were adopted, accordingly, for the risk impact of them on TMJ arthralgia. RESULTS: Overbite (OR = 2.238) and maxillary anterior prosthesis (OR = 0.305) were entered into the simple binary logistic model; while overbite (OR = 2.774) plus maxillary anterior prosthesis (OR = 0.347), overbite (OR = 3.425) plus unilateral maxillary posterior prosthesis (OR = 4.672), and overbite (OR = 3.476) plus overjet (OR = 0.436) and mandibular anterior prosthesis (OR = 0.177) were entered into the multivariate logistic regression model (all, P < .05). CONCLUSIONS: Partial denture wearers with a deep overbite, especially those with a unilateral maxillary posterior prosthesis, had a higher prevalence of unilateral TMJ arthralgia.

An extra-erythrocyte role of haemoglobin body in chondrocyte hypoxia adaption.

Although haemoglobin is a known carrier of oxygen in erythrocytes that functions to transport oxygen over a long range, its physiological roles outside erythrocytes are largely elusive1,2. Here we found that chondrocytes produced massive amounts of haemoglobin to form eosin-positive bodies in their cytoplasm. The haemoglobin body (Hedy) is a membraneless condensate characterized by phase separation. Production of haemoglobin in chondrocytes is controlled by hypoxia and is dependent on KLF1 rather than the HIF1/2α pathway. Deletion of haemoglobin in chondrocytes leads to Hedy loss along with severe hypoxia, enhanced glycolysis and extensive cell death in the centre of cartilaginous tissue, which is attributed to the loss of the Hedy-controlled oxygen supply under hypoxic conditions. These results demonstrate an extra-erythrocyte role of haemoglobin in chondrocytes, and uncover a heretofore unrecognized mechanism in which chondrocytes survive a hypoxic environment through Hedy.

CaSR modulates proliferation of the superficial zone cells in temporomandibular joint cartilage via the PTHrP nuclear localization sequence.

The superficial zone cells in mandibular condylar cartilage are proliferative. The present purpose was to delineate the relation of calcium-sensing receptor (CaSR) and parathyroid hormone-related peptide nuclear localization sequence (PTHrP87-139 ), and their role in the proliferation behaviors of the superficial zone cells. A gain- and loss-of-function strategy were used in an in vitro fluid flow shear stress (FFSS) model and an in vivo bilateral elevation bite model which showed mandibular condylar cartilage thickening. CaSR and PTHrP87-139 were modulated through treating the isolated superficial zone cells with activator/SiRNA and via deleting CaSR or parathyroid hormone-related peptide (PTHrP) gene in mice with the promoter gene of proteoglycan 4 (Prg4-CreERT2 ) in the tamoxifen-inducible pattern with or without additional injection of Cinacalcet, the CaSR agonist, or PTHrP87-139 peptide. FFSS stimulated CaSR and PTHrP expression, and accelerated proliferation of the Prg4-expressing superficial zone cells, in which process CaSR acted as an up-streamer of PTHrP. Proteoglycan 4 specific knockout of CaSR or PTHrP reduced the cartilage thickness, suppressed the proliferation and early differentiation of the superficial zone cells, and inhibited cartilage thickening and matrix production promoted by bilateral elevation bite. Injections of CaSR agonist Cinacalcet could not improve the phenotype caused by PTHrP mutation. Injections of PTHrP87-139 peptide rescued the cartilage from knockout of CaSR gene. CaSR modulates proliferation of the superficial zone cells in mandibular condylar cartilage through activation of PTHrP nuclear localization sequence. Our data support the therapeutic target of CaSR in promoting PTHrP production in superficial zone cartilage.

Reconstructed magnetic resonance image-based effusion volume assessment for temporomandibular joint arthralgia.

BACKGROUND: Joint effusion is often noticed in magnetic resonance image (MRI) and its diagnostic value for arthralgia of the temporomandibular joint (TMJ) remains obscure. OBJECTIVE: To develop a method for quantitatively evaluating the joint effusion revealed in MRI and its diagnostic value for arthralgia of the TMJ. METHODS: Two-hundreds and twenty-eight TMJs, 101 with arthralgia (Group P) and 105 without (Group NP) from 103 patients, and 22 TMJs (Group CON) from 11 asymptomatic volunteers were examined by using MRI. The effusion volume was measured after constructing a three-dimensional structure of the joint effusion revealed in MRI by using the ITK-SNAP software. The diagnostic capabilities of the effusion volume on arthralgia were evaluated with receiver operating characteristic (ROC) curve analysis. RESULTS: Totally 146 joints showed MRI signs of joint effusion, including nine joints from Group CON. However, the medium volume was greater in Group P (66.65 mm3 ), but was much similar in Group CON (18.33 mm3 ) to Group NP (27.12 mm3 ). The effusion volume larger than 38.20 mm3 was validated to discriminate Group P from Group NP. The AUC value was 0.801 (95% CI 0.728 to 0.874), with a sensitivity of 75% and specificity of 78.9%. The median volume of the joint effusion was larger in those with than without bone marrow oedema, osteoarthritis, Type-III disc configurations, disc displacement and higher signal intensity of the retrodiscal tissue (all, p < .05). CONCLUSION: The present method for evaluate joint effusion volume well discriminated painful TMJs from non-pain ones.

Zonal interdependence in the temporomandibular joint cartilage.

The temporomandibular joint (TMJ) cartilage is biomechanical sensitive. Cells in TMJ cartilage are zonally arranged, earlier differentiated in the super zone and late differentiated in the deep zone. The purpose was to detect the zonal interdependence in TMJ cartilage under dental biomechanical stimulations. Here, we obtained the Sox9CreER ; Rosa26tdTomato and Col10CreER ; Rosa26tdTomato mice to label super zone Sox9-expressing (Sox9+ ) or deep zone Col10-expressing (Col10+ ) cells by tdTomato (TdT), and Sox9CreER ; Rosa26DTA and Col10CreER ; Rosa26DTA mice to ablate Sox9+ or Col10+ cells selectively. These mice were subjected to unilateral anterior crossbite (UAC) or bilateral anterior elevation (BAE) dental stimulation, which promoted terminal differentiation or proliferation of TMJ chondrocytes, respectively. In both UAC and BAE models, the Sox9-TdT+ cells performed as proliferation and mature differentiation, showing as expressing Ki67 and Col-X, respectively; while the Col10-TdT+ cells performed as terminal differentiation, showing as expressing osteocalcin (OCN). In both Sox9+ - and Col10+ -cells ablation groups, there were reductions in cell number, cartilage thickness and matrix amount, subchondral bone loss, and condylar deformation. The UAC-promoted terminal differentiation was enhanced, and the BAE-promoted cellular proliferation was ruined. Impressively, when Col10+ cells were ablated, the UAC-promoted DAP3 expression, an anoikis marker, was further increased, while the BAE-suppressed DAP3 expression was instead greatly increased. These findings demonstrated that the cartilage zones function interdependently. The super zone harbors the cells that undergo differentiation to deep zone cells, the deep zone contains load-bearing matrix which is structural essential for the cells located inside or superficial.

Uptight responses between clenching and forearm raising with factors of visual feedback and maintenance effort in healthy young women: An experimental study on factorial design.

BACKGROUND: To achieve different central preset force levels requires various fine-tuning efforts and may elicit different uptight responses. The mandibular lever system has a distinct regularity in the fine-tuning function of the upper limbs. The purpose of the present study was to detect whether the uptight responses elicited from motivating clenching differ from those induced by motivating forearm raising at different force levels. METHODS: Twenty-five healthy females were enrolled in this study. The target was low, medium, and maximum force levels with or without visual feedback and/or maintenance effort. Surface electromyographic (SEMG) activity was recorded from the bilateral anterior temporalis and masseter or left biceps brachii muscle (BicL), and the T-Scan III System synchronously recorded the sensitive force values. The uptight responses and task difficulties were recorded for occlusal and left forearm lifting tasks using a unique visual analogue scale. RESULTS: The highest uptight response value was achieved at a low clenching force level with visual feedback requiring no maintenance effort but at a maximum forearm-raising force level with visual feedback and maintenance effort. The SEMG activities of both jaw-closing muscles and BicL were associated with the central preset force level (P < 0.001). However, the maintenance effort only increased the jaw-closing muscles' SEMG activity at the maximal force level (P < 0.001). CONCLUSIONS: Clenching at the central preset lower force level with visual feedback is prone to elicit a higher degree of uptight response. The constant need for a low-intensity bite can have a negative effect on an individual's mood.

Design and dynamic analysis of jumping wheel-legged robot in complex terrain environment.

Wheel-legged robots have fast and stable motion characteristics on flat roads, but there are the problems of poor balance ability and low movement level in special terrains such as rough roads. In this paper, a new type of wheel-legged robot with parallel four-bar mechanism is proposed, and the linear quadratic regulator (LQR) controller and fuzzy proportion differentiation (PD) jumping controller are designed and developed to achieve stable motion so that the robot has the ability to jump over obstacles and adapt to rough terrain. The amount of energy released by the parallel four-bar linkage mechanism changes with the change of the link angle, and the height of the jump trajectory changes accordingly, which improves the robot's ability to overcome obstacles facing vertical obstacles. Simulations and real scene tests are performed in different terrain environments to verify obstacle crossing capabilities. The simulation results show that, in the pothole terrain, the maximum height error of the two hip joint motors is 2 mm for the obstacle surmounting method of the adaptive retractable wheel-legs; in the process of single leg obstacle surmounting, the maximum height error of the hip joint motors is only 6.6 mm. The comparison of simulation data and real scene experimental results shows that the robot has better robustness in moving under complex terrains.

Pralsetinib for the treatment of a RET-positive advanced non-small-cell lung cancer patient harboring both ANK-RET and CCDC6-RET fusions with coronary heart disease: a case report.

Background: Rearranged during transfection (RET) is one of the rare driver genes of non-small-cell lung cancer (NSCLC), having a gene fusion incidence of 1-2% in NSCLC. Before the emergence of specific RET inhibitors, multikinase inhibitors such as cabozantinib and vandetanib were tried for RET fusion-positive NSCLC, but their efficacies were poor, and the U.S. Food and Drug Administration did not approve the application of these drugs for such patients. In the phase I/II ARROW clinical trial, pralsetinib significantly improved the overall remission rate and disease progression-free survival (PFS) of RET fusion-positive NSCLC patients. In the clinic, it is necessary to conduct adequate molecular screening of patients to guide drug choices. With the wide application of second-generation sequencing technology in clinical practice, many RET fusion partners have been discovered. It is rare for one patient with two RET fusions. Case Description: This paper reports a rare case of RET dual fusion in an advanced NSCLC patient who had coronary heart disease. After the failure of first-line treatment with platinum-based chemotherapy and post-line treatment with small-molecule targeted therapy of anlotinib and alectinib, the application of pralsetinib (400 mg, qd) reduced the tumor volume by 79% and achieved partial remission (based on the evaluation criteria of the World Health Organization) or reduced tumor volume by 17% (based on the Response Evaluation Criteria in Solid Tumors). It had an overall manageable safety profile. Conclusions: This patient with two different RET fusions was sensitive to pralsetinib. Patients with well-controlled coronary heart disease and recurrent myocardial infarction might benefit from pralsetinib. The pathogenesis of RET-dual-fusion NSCLC and its clinical impact need to be further studied to provide a theoretical basis for personalized treatment.

Reconfigurable and Efficient Implementation of 16 Boolean Logics and Full-Adder Functions with Memristor Crossbar for Beyond von Neumann In-Memory Computing.

The rise of emerging technologies such as Big Data, the Internet of Things, and artificial intelligence, which requires efficient power schemes, is driving brainstorming in data computing and storage technologies. In this study, merely relying on the fundamental structure of two memristors and a resistor, arbitrary Boolean logic can be reconfigured and calculated in two steps, while no additional voltage sources are needed beyond "±VP " and 0, and all state reversals are based on memristor set switching. Utilizing the proposed logic scheme in an elegant form of unity structure and minimum cost, the implementation of a 1-bit adder is demonstrated economically, and a promising circuit scheme for the N-bit adder is exhibited. Some critical issues including the crosstalk problem, energy consumption, and peripheral circuits are further simulated and discussed. Compared with existing works on memristive logic, such methods support building a memristor-based digital in-memory calculation system with high functional reconfigurability, simple voltage sources, and low power and area consumption.

Activation of the VpdmVGLUT1-VPM pathway contributes to anxiety-like behaviors induced by malocclusion.

Occlusal disharmony has a negative impact on emotion. The mesencephalic trigeminal nucleus (Vme) neurons are the primary afferent nuclei that convey proprioceptive information from proprioceptors and low-threshold mechanoreceptors in the periodontal ligament and jaw muscles in the cranio-oro-facial regions. The dorsomedial part of the principal sensory trigeminal nucleus (Vpdm) and the ventral posteromedial nucleus (VPM) of thalamus have been proven to be crucial relay stations in ascending pathway of proprioception. The VPM sends numerous projections to primary somatosensory areas (SI), which modulate emotion processing. The present study aimed to demonstrate the ascending trigeminal-thalamic-cortex pathway which would mediate malocclusion-induced negative emotion. Unilateral anterior crossbite (UAC) model created by disturbing the dental occlusion was applied. Tract-tracing techniques were used to identify the existence of Vme-Vpdm-VPM pathway and Vpdm-VPM-SI pathway. Chemogenetic and optogenetic methods were taken to modulate the activation of VpdmVGLUT1 neurons and the Vpdm-VPM pathway. Morphological evidence indicated the involvement of the Vme-Vpdm-VPM pathway, Vpdm-VPM-SI pathway and VpdmVGLUT1-VPM pathway in orofacial proprioception in wild-type mice and vesicular glutamate transporter 1 (VGLUT1): tdTomato mice, respectively. Furthermore, chemogenetic inhibition of VpdmVGLUT1 neurons and the Vpdm-VPM pathway alleviated anxiety-like behaviors in a unilateral anterior crossbite (UAC) model, whereas chemogenetic activation induced anxiety-like behaviors in controls and did not aggravate these behaviors in UAC mice. Finally, optogenetic inhibition of the VpdmVGLUT1-VPM pathway in VGLUT1-IRES-Cre mice reversed UAC-induced anxiety comorbidity. In conclusion, these results suggest that the VpdmVGLUT1-VPM neural pathway participates in the modulation of malocclusion-induced anxiety comorbidity. These findings provide new insights into the links between occlusion and emotion and deepen our understanding of the impact of occlusal disharmony on brain dysfunction.

Long-term effect of bilateral anterior elevation of occlusion on the temporomandibular joints.

OBJECTIVE: Incisors tubed prosthesis with bilateral anterior elevation (BAE) relation had been reported to stimulate the proliferative response in the mandibular condylar cartilage of mice, thus the prosthetic occlusion elevation had been proposed to treat cartilage degeneration. Currently, we aimed to detect the long-term effect of BAE on temporomandibular joints (TMJs). MATERIALS AND METHODS: Twelve 6-week-old female mice were assigned to age-matched control and BAE groups (n = 6). Micro-CT images and the macro- and micro-morphology of the mandibular condyles were analyzed at 29 weeks. RESULTS: Compared with the age-matched controls, in BAE group, there were loss of subchondral cortical bone and heavy loss of the subchondral trabecular bone at the superior sites of the TMJ condyles, but hyperostosis at the inferior sites as revealed by micro-CT images and histological slices. In BAE group, cartilage thickness and matrix area were increased with upregulated expression of type II, type X collagen, and Ki67, but the expression of cleaved caspase-3 was downregulated (all, p < 0.05). CONCLUSION: In addition to cartilage thickening, long-term BAE induces loss of the subchondral cortical bone and heavy loss of the underneath subchondral trabecular bone, but hyperostosis further underneath. Using BAE as a treatment remains double-edged.

Elder Mice Exhibit More Severe Degeneration and Milder Regeneration in Temporomandibular Joints Subjected to Bilateral Anterior Crossbite.

Temporomandibular joints (TMJs) have a biomechanical relationship with dental occlusion. Aberrant occlusion initiates degenerative remodeling responses in TMJ condyles. Aging is a promoting factor of osteoarthritis (OA) development. The aim of this study was to assess the effect of aging on degenerative remodeling in TMJ condyles in response to occlusal biomechanical stimulation caused by the installation of aberrant prostheses and observe rehabilitation after their removal. The experiments involved 84 female C57BL/6J mice (42 at 6 weeks old and 42 at 28 weeks old). A bilateral anterior crossbite (BAC) model was developed, and the TMJs were sampled at 3, 7, and 11 weeks. BAC was removed at 7 weeks in a subset of mice, which accepted BAC treatment at 6 week of age, and maintained for another 4 weeks after BAC removal. TMJ changes were assessed with micro-CT, histomorphology, immunohistochemistry (IHC), and immunofluorescence staining assays. The results showed that BAC induced typical OA-like TMJ lesions that were more severe in the elder groups as evaluated by the acellular zones, clustered chondrocytes, fissures between cartilage and subchondral bone, reductions in matrix amount and the cartilage thickness as revealed by histomorphological measurements, and subchondral bone loss as detected on micro-CT images. IHC indicated significant increases in cleaved caspase-3-expressing cells and decreases in ki67-positive cells in the BAC groups. There were obvious age-dependent changes in the numbers of superficial zone cells and CD90-expressing cells. Supportively, cleaved caspase-3-expressing cells obviously increased, while ki67-expressing cells significantly decreased with aging. In the elder BAC groups, the superficial zone cells such as CD90-expressing cells were greatly reduced. At 11 weeks, the superficial zone cells were almost non-existent, and there were clear serrated injuries on the cartilage surface. BAC removal attenuated the degenerative changes in the condylar cartilage and subchondral bone. Notably, the rescue effect was more pronounced in the younger animals. Our findings demonstrate the impacts of aging on both TMJ degenerative changes in response to BAC and regenerative changes following BAC removal. The reduced number of chondro-progenitor cells in aged TMJ cartilage provides an explanation for this age-related decline in TMJ rehabilitative behaviors.

Determination of the complete mitochondrial genome of Lardoglyphus konoi (Acari: Astigmata).

The mitochondrial genome of Lardoglyphus konoi was 14,269 bp long and consisted of 37 genes including 22 transfer RNAs, 13 protein-coding genes and 2 ribosomal RNA genes. All the 13 protein-coding genes had complete start/stop codons. Most inferred tRNAs were extremely truncated and the T- or D-arm was missing. The position of two rRNAs and the largest non-coding region were separated by tRNAs. The Bayesian phylogenetic tree indicated that L. konoi was closely related to Carpoglyphus lactis.

Development of a biomechanical model for dynamic occlusal stress analysis.

The use of traditional finite element method (FEM) in occlusal stress analysis is limited due to the complexity of musculature simulation. The present purpose was to develop a displacement boundary condition (DBC)-FEM, which evaded the muscle factor, to predict the dynamic occlusal stress. The geometry of the DBC-FEM was developed based on the scanned plastic casts obtained from a volunteer. The electrognathographic and video recorded jaw positional messages were adopted to analyze the dynamic occlusal stress. The volunteer exhibited asymmetrical lateral movements, so that the occlusal stress was further analyzed by using the parameters obtained from the right-side eccentric movement, which was 6.9 mm long, in the stress task of the left-side eccentric movement, which was 4.1 mm long. Further, virtual occlusion modification was performed by using the carving tool software aiming to improve the occlusal morphology at the loading sites. T-Scan Occlusal System was used as a control of the in vivo detection for the location and strength of the occlusal contacts. Data obtained from the calculation using the present developed DBC-FEM indicated that the stress distribution on the dental surface changed dynamically with the occlusal contacts. Consistent with the T-Scan recordings, the right-side molars always showed contacts and higher levels of stress. Replacing the left-side eccentric movement trace by the right-side one enhanced the simulated stress on the right-side molars while modification of the right-side molars reduced the simulated stress. The present DBC-FEM offers a creative approach for pragmatic occlusion stress prediction.

HMGB2 promotes chondrocyte proliferation under negative pressure through the phosphorylation of AKT.

Cells in articular cartilage are zonal arranged. Cells in superficial zone cartilage are generally small and proliferative. Appropriate negative pressure stimulation is beneficial to cell survival and tissue repair. Whether negative pressure has promotive impact on the proliferation activity of the superficial zone chondrocytes is of interest. In this study, we isolated superficial chondrocytes from the mandibular condylar cartilage of rats. After negative pressure treatment, the cells were collected for RNA-sequencing, quantitative real-time PCR and western blotting assays, aiming to detect the proliferative responses of chondrocytes to negative pressure and explore the potential molecular mechanisms. Data from RNA-sequencing analysis indicated that the superficial chondrocytes responded to the 4 h -10 kPa treatment by a significant increase in proliferation. In addition, the expression of high-mobility group box 2 (HMGB2) and the phosphorylation of AKT were obviously promoted. Knockdown of HMGB2 decreased AKT phosphorylation and diminished the negative pressure-induced proliferation of chondrocytes, as shown by decreased expression of Ki67 and cyclin-dependent kinase 6 (CDK6). In contrast, overexpression of HMGB2 enhanced AKT phosphorylation and further promoted proliferative activity. Moreover, LY294002, an AKT inhibitor, suppressed the proliferative activity of chondrocytes under negative pressure, while SC79, an activator of AKT phosphorylation, enhanced the proliferation of chondrocytes. Our data demonstrated that HMGB2 exhibits a promotion impact on chondrocyte proliferation under negative pressure via the phosphorylation of AKT. These results provide a new perspective for superficial zone chondrocytes proliferation under negative pressure, which should be benefit for cartilage regeneration.