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Although the pathogenesis and mechanism of congenital skeletal dysplasia are better understood, progress in drug development and intervention research remains limited. Here we report that melatonin treatment elicits a mitigating effect on skeletal abnormalities caused by SLC26A2 deficiency. In addition to our previous finding of endoplasmic reticulum stress upon SLC26A2 deficiency, we found calcium (Ca2+) overload jointly contributed to SLC26A2-associated chondrodysplasias. Continuous endoplasmic reticulum stress and cytosolic Ca2+ overload in turn triggered apoptosis of growth plate chondrocytes. Melatonin, known for its anti-oxidant and anti-inflammatory properties, emerged as a promising therapeutic approach in our study, which enhanced survival, proliferation, and maturation of chondrocytes by attenuating endoplasmic reticulum stress and Ca2+ overload. Our findings not only demonstrated the efficacy of melatonin in ameliorating abnormal function and cell fate of SLC26A2-deficient chondrocytes in vitro but also underscored its role in partially alleviating the skeletal dysplasia seen in Col2a1-CreERT2; Slc26a2fl/fl mice. As revealed by histology and micro-CT analyses, melatonin significantly improved retarded cartilage growth, defective trabecular bone formation, and tibial genu varum in vivo. Collectively, these data shed translational insights for drug development and support melatonin as a potential treatment for SLC26A2-related chondrodysplasias.

Abstract Defined traffic laws must be respected by all vehicles when driving on the road, including self-driving vehicles without human drivers. Nevertheless, the ambiguity of human-oriented traffic laws, particularly compliance thresholds, poses a significant challenge to the implementation of regulations on self-driving vehicles, especially in detecting illegal driving behaviors. To address these challenges, here we present a trigger-based hierarchical online monitor for self-assessment of driving behavior, which aims to improve the rationality and real-time performance of the monitoring results. Furthermore, the general principle to determine the ambiguous compliance threshold based on real driving behaviors is proposed, and the specific outcomes and sensitivity of the compliance threshold selection are analyzed. In this work, the effectiveness and real-time capability of the online monitor were verified using both Chinese human driving behavior datasets and real vehicle field tests, indicating the potential for implementing regulations in self-driving vehicles for online monitoring.

Background: Mutations in Slc26a2 cause a spectrum of autosomal-recessive chondrodysplasia with a significant and negligible influence on the quality of life. It has been reported that Slc26a2 deficiency triggers the ATF6 branch of the UPR, which may, in turn, activate the negative regulator of the FGFR3 signaling pathway. However, the correlation between the deletion of Slc26a2 and the augmentation of downstream phosphorylation of FGFR3 has not been investigated in vivo. Methods: First, we constructed Slc26a2 and Fgfr3 double knockout mouse lines and observed gross views of the born mice and histological staining of the tibial growth plates. The second approach was to construct tamoxifen-inducible Cre-ERT2 mouse models to replicate SLC26A2-related non-lethal dysplastic conditions. Pharmacological intervention was performed by administering the FGFR3 inhibitor NVP-BGJ398. The effect of NVP-BGJ398 on chondrocytes was assessed by Alcian blue staining, proliferation, apoptosis, and chondrocyte-specific markers and then verified by western blotting for variations in the downstream markers of FGFR3. The growth process was detected using X-rays, micro-CT examination, histomorphometry staining of growth plates, and immunofluorescence. Results: Genetic ablation of Fgfr3 in embryonic Slc26a2-deficient chondrocytes slightly attenuated chondrodysplasia. Subsequently, in the constructed mild dysplasia model, we found that postnatal intervention with Fgfr3 gene in Slc26a2-deficient chondrocytes partially alleviated chondrodysplasia. In chondrocyte assays, NVP-BGJ398 suppressed the defective phenotype of Slc26a2-deficient chondrocytes and restored the phosphorylation downstream of FGFR3 in a concentration-dependent manner. In addition, in vivo experiments showed significant alleviation of impaired chondrocyte differentiation, and micro-CT analysis showed a clear improvement in trabecular bone microarchitectural parameters. Conclusion: Our results suggested that inhibition of FGFR3 signaling pathway overactivation and NVP-BGJ398 has promising therapeutic implications for the development of SLC26A2-related skeletal diseases in humans. The translational potential of this article: Our data provide genetic and pharmacological evidence that targeting FGFR3 signaling via NVP-BGJ398 could be a route for the treatment of SLC26A2-associated skeletal disorders, which promisingly advances translational applications and therapeutic development.

Introduction: Developmental engineering based on endochondral ossification has been proposed as a potential strategy for repairing of critical bone defects. Bone development is driven by growth plate-mediated endochondral ossification. Under physiological conditions, growth plate chondrocytes undergo compressive forces characterized by micro-mechanics, but the regulatory effect of micro-mechanical loading on endochondral bone formation has not been investigated.Methods: In this study, a periodic static compression (PSC) model characterized by micro-strain (with 0.5% strain) was designed to clarify the effects of biochemical/mechanical cues on endochondral bone formation. Hydrogel scaffolds loaded with bone marrow mesenchymal stem cells (BMSCs) were incubated in proliferation medium or chondrogenic medium, and PSC was performed continuously for 14 or 28 days. Subsequently, the scaffold pretreated for 28 days was implanted into rat femoral muscle pouches and femoral condylar defect sites. The chondrogenesis and bone defect repair were evaluated 4 or 10 weeks post-operation.Results: The results showed that PSC stimulation for 14 days significantly increased the number of COL II positive cells in proliferation medium. However, the chondrogenic efficiency of BMSCs was significantly improved in chondrogenic medium, with or without PSC application. The induced chondrocytes (ichondrocytes) spontaneously underwent hypertrophy and maturation, but long-term mechanical stimulation (loading for 28 days) significantly inhibited hypertrophy and mineralization in ichondrocytes. In the heterotopic ossification model, no chondrocytes were found and no significant difference in terms of mineral deposition in each group; However, 4 weeks after implantation into the femoral defect site, all scaffolds that were subjected to biochemical/mechanical cues, either solely or synergistically, showed typical chondrocytes and endochondral bone formation. In addition, simultaneous biochemical induction/mechanical loading significantly accelerated the bone regeneration.Discussion: Our findings suggest that microstrain mechanics, biochemical cues, and in vivo microenvironment synergistically regulate the differentiation fate of BMSCs. Meanwhile, this study shows the potential of micro-strain mechanics in the treatment of critical bone defects.

Flexsplines in harmonic gear reducers are usually characterized by a large number of teeth, small modulus, and poor stiffness, which makes them difficult to measure using conventional gear measuring centers. In order to efficiently evaluate the quality of flexsplines in harmonic gear reducers, a rapid measurement method for flexspline pitch using offset point laser sensors (PLS) is proposed. This paper investigates the principle of measuring the tooth flank of the flexspline under the offset of the PLS, establishes a model for collecting and analyzing gear surface data, builds an experimental system, calibrates the six pose parameters of the sensor using the geometric features of the flexspline’s outer circular surface, and completes the reconstruction of the left and right gear surfaces of the flexspline based on the measured data. In the experiment, the gear surface obtained by the proposed method is largely consistent with that measured by the video imaging method, and the repeatability of both single pitch deviation and cumulative pitch deviation is within ±3 µm.

This article proposes a new self-calibration method for circular encoders based on inertia and a single read-head. The velocity curves of the circular encoder are fitted with polynomials and, based on the principle of circle closure and the periodicity of the distribution for angle intervals, the proportionality between the theoretical value and the actual value of each angle interval is obtained. In the experimental system constructed, the feasibility of the proposed method was verified through self-calibration experiments, repeatability experiments, and comparative experiments with the time-measurement dynamic reversal (TDR) method. In addition, this article also proposes an iterative method to improve the self-calibration accuracy. Experimental verification was carried out, and the results show that the new method can effectively compensate for the error of angle measurement in the circular encoder. The peak-to-peak value of the error of angle measurement was reduced from 239.343” to 11.867”, and the repeatability of the calibration results of the new method was less than 2.77”.

To improve the measuring accuracy of circular encoders in special applications, self-calibration of the circular encoder is necessary. The commonly used self-calibration method, namely the Equal Division Average (EDA) method, requires a large number of reading heads and cannot be used when the structural space is limited. In this paper, a self-calibration method for a circular encoder based on two reading heads with adjustable positions (TRAP) is proposed. This TRAP method uses two reading heads to simulate multiple reading heads, which can be used to achieve self-calibration of circular encoders in limited space. This paper investigates the principle of simulating multiple reading heads with two reading heads, designs and builds an experimental system, and obtains and analyzes experimental data. The experimental results show that the peak-valley value of the angle measurement error is reduced from 252.41″ to 18.82″ after self-calibration with the TRAP method, and the repeatability of multiple self-calibration experimental results is less than 0.75″. The TRAP method breaks through the limitation of the number of reading heads that can be installed during the self-calibration of the circular encoder and can effectively suppress the angle measurement error of the circular encoder.

Double-flank measurement is the most commonly used method for full inspection of mass-produced gears and has high measurement efficiency, but it cannot obtain the analytical parameters and is not helpful enough to evaluate the NVH performance of the gears. Based on the double-flank rolling tester with a new principle, a simulation method for double-flank measurement and a solving method for analytical parameters are proposed. Using the simulation method, the double-flank measurements without random error can be obtained through the collision detection algorithm. The solving method uses the iteration to obtain the minimum rolling length of each position of the tooth surface, then obtains the analytical parameters of the gear. In the experiments, the difference between the profile deviations obtained by the solving method and superimposed in the simulation method is less than 0.03 μm. The experiment results have verified the correctness of the simulation method and the solving method. These methods can greatly improve the value of double-flank measurement.

Double-flank measurement is the most commonly used full inspection method on the shop floor. However, the double-flank measurement method cannot measure analytical parameters such as pitch deviations and profile deviations, and this limitation is a pain point in the field of gear measurement. This paper studies the measurability of the analytical parameters of gears based on the results of double-flank measurement, proposes the definition of measurable area, and gives the relationship between the size of the measurable area and the number of teeth and the pressure angle and the gear error. Digital simulation methods were used to conduct measurement experiments on gear analytical parameters. In the experiments, the measurability of the analytical parameters of gears with various typical profile deviations in the double-flank measurement process was verified and analyzed. The test results show that not all profile deviations are unmeasurable in the process of double-flank measurement, but there exists a profile region in which the analytical parameters of the gear can be measured accurately. The size of the measurable area of the profile is mainly determined by the number of teeth and pressure angle of the gear, while the pitch deviations are always measurable under normal conditions.

The clarity evaluation function plays a vital role in the autofocus technique. The accuracy and efficiency of the image clarity evaluation function directly affects the accuracy of autofocus and the speed of focusing. However, classical clarity function values are sensitive to changes in background brightness and changes in object contour length. This paper proposes a normalized absolute values adaptive (NAVA) evaluation function of image clarity. It can eliminate the influence of changes in background brightness and the length of the measured object contour on the image clarity function value. To verify the effectiveness of the NAVA function, several experiments were conducted under conditions of virtual master gear images and actual captured images. For actual captured images, the variation of the evaluation results of the NAVA function is far less than the corresponding variation of the classic clarity function. Compared with classical clarity evaluation functions, the NAVA function can provide normalized absolute clarity values. The correlations between the NAVA function results of image clarity and both the contour length and background brightness of the tested object are weak. The use of the NAVA function in automatic and manual focusing systems can further improve focusing efficiency.

We present a detailed theoretical study on terahertz (THz) cavity plasmon polariton in graphene embedded in a Fabry-Pérot cavity under optical modulation. Based on classical electromagnetic theory, we obtain analytically the dispersion equation for cavity plasmon polariton (CPP) modes. The obtained results show the existence of two types of CPP modes in THz range. One can be referred as Fabry-Pérot-like modes and another as surface-plasmon-like modes (SPLMs). Interestingly, the SPLMs can realize notable enhancement of wave localization in comparison with usual graphene plasmons. Moreover, a scheme to modulate the THz CPP modes via visible light irradiation is proposed and examined. We find that the optical pumping can affect rather efficiently the CPP modes via excitation of photon induced carriers. These important theoretical findings indicate that the CPP can be applied in all-optical tunable plasmonic devices in THz bandwidth. This paper is relevant to the application of graphene as advanced optical and plasmonic devices.