The Essential Role of m6A mRNA Methylation and m6A Reader Protein YTHDF1 in Maintaining Cell-Type Specific Functions in the Basal Ganglia

The N6-methyladenosine (m6A) methylation, identified in the 1970s, has become increasingly understood with the development of recent high-throughput sequencing techniques. The discovery of its distinct distribution and associated effectors has enabled many functional studies on this reversible modification. m6A methylation plays an essential role in the post-transcriptional regulation of mRNA, dynamically influencing mRNA metabolism and various cellular functions.In neurons, precise control of protein synthesis is crucial during the activity-dependent transportation of mRNAs. Thus, post-transcriptional regulation offers a potentially ideal mechanism to dynamically drive local translation in neurons, allowing synaptic plasticity regulation and dendritic remodeling. m6A level dramatically increases by adulthood, suggesting its unique role in the adult brain, which is a topic just beginning to be systematically studied. For my thesis, I take advantage of the fact that there are only two prominent neuronal cell types throughout the striatum: the dopamine (DA) D1 and D2 receptor-expressing medium spiny projection neurons (SPNs). Moreover, D1 and D2 SPNs have well-documented opposing functions in motor control, simplifying the molecular studies and allowing comparison of behavioral phenotypes. In the first part of my thesis, by using transgenic mouse models with selective deletion of Mettl14 in D1 and D2 SPNs, I found that Mettl14 deficiency blunted responses to environmental challenges at cellular and behavioral levels in the adult brain. One of m6A modification’s downstream reader proteins, YTHDF1, has been shown to promote protein synthesis in neurons and regulate synaptic plasticity and learning. However, it is unclear if YTHDF1 is the primary downstream mediator of m6A function in the brain. In the second part, I found that Ythdf1 deletion in D1 and D2 SPNs resembled the behavioral impairments caused by Mettl14 deletion in a cell type-specific manner, suggesting YTHDF1 as the primary mediator of the functional consequences of m6A modification in the striatum. Moreover, striatal neurons from Ythdf1 constitutive knockout mice were incapable of adapting to environmental challenges. DA affects striatal neuronal activity and regulates corticostriatal plasticity. In the third part, I examined the role of m6A mRNA methylation in dopaminergic neurons. I found that in all three cell types: D1-SPNs, D2-SPNs, and dopaminergic neurons, Ythdf1 deletion resembled the behavioral impairments caused by Mettl14 deletion. Down-regulation of m6A is found to induce cell apoptosis in the dopaminergic cells in vitro. However, I found no significant difference in tyrosine hydroxylase (TH)-positive cell number in the midbrain of Mettl14 conditional knockout mice. This suggests that m6A depletion did not cause dopaminergic neuron degeneration in any age group. The fourth part is our ongoing experiments to examine the role of m6A modification in maintaining cell identity and normal functions in the adult brain. I found that Mettl14 deletion in D1-SPNs caused behavioral impairments in an age-dependent manner, suggesting the significance of m6A increases as the mice age. In the future, we plan to explore the expression profile of the transcription factors (TFs) and track the temporal features of m6A distribution on these genes in D1 and D2 SPNs

Advances in biomimetic mineralization of tooth enamel based on cell-free strategies

Tooth enamel is a highly-mineralized hard tissue covering the outermost layer of the dental crown, and amelogenesis is inseparable from the participation of necessary components such as ameloblasts, organic matrix proteins, and mineral ions, such as Ca2+ and PO43-. However, mature enamel is an acellular tissue and it is difficult to self-repair once damaged. The current treatment methods for enamel damage are filling or repairing with alloys, ceramics, or composite resins. However, the mechanical properties of these materials are quite different from the natural enamel and they can’t ensure a completely closed interface with the remaining enamel surface, which usually causes a series of post-repair problems. At present, the biomimetic mineralization of tooth enamel is a research hotspot in the field of prosthodontics, and has great clinical application needs and prospects, especially the researches on cell-free strategies have made significant accomplishment. Here, based on the cell-free strategies, we review the recent knowledge from ex situ and in situ two dimensions in the remineralization of tooth ename

Trajectory planning for autonomous intersection management of connected vehicles

International audienceThis paper proposes a cooperative scheduling mechanism for autonomous vehicles passing through an intersection, called TP-AIM. The main objective of this research is to ensure safe driving while minimizing delay in an intersection without traffic lights. Firstly, an intersection management system, used as an info-collecting-organizing center, assigns reasonable priorities for all present vehicles and hence plans their trajectories. Secondly, a window searching algorithm is performed to find an entering window, which can produce a collision-free trajectory with minimal delay, besides backup windows. Finally, vehicles can arrange their trajectory individually, by applying dynamic programming to compute velocity profile, in order to pass through intersection. MATLAB/Simulink and SUMO based simulations are established among three types of traffic mechanisms with different traffic flows. The results show that the proposed TP-AIM mechanism significantly reduces the average evacuation time and increases throughput by over 20%. Moreover, the paper investigates intersection delay, which can be reduced to less than 10% compared to classical light management systems. Both safety and efficiency can be guaranteed in our proposed mechanism

Efficacy of a modified twin block appliance compared with the traditional twin block appliance in children with hyperdivergent mandibular retrognathia: protocol for a single-centre, single-blind, randomised controlled trial

Introduction Compensatory mouth breathing, caused by nasopharyngeal obstructive diseases, is the main cause of hyperdivergent mandibular retrognathia in children. Such deformities require effective growth guidance before pubertal growth peaks. The traditional mandibular advancement device, twin block (TB), can guide the forward development of the mandible. However, the side effect of increasing the vertical dimension of the lower facial third, worsens the facial profile of children with divergent growth trends. To solve this problem, a modified TB (LLTB) appliance was designed to control the vertical dimension by intruding incisors and inhibiting the elongation of posterior teeth during the advancement of the mandible, which could avoid the side effects of traditional appliances and effectively guide the growth of the mandible in a normal direction.Methods and analysis The study was designed as a single-centre, single-blind, randomised, parallel controlled trial. We aim to enrol 60 children aged 9–14 years with hyperdivergent skeletal class II malocclusion, using a 1:1 allocation ratio. The participants were will be randomly assigned to receive either the TB or LLTB treatment. The primary outcome will be a change in the angle of the mandibular plane relative to the anterior cranial base. The secondary outcomes will include changes in the sagittal maxillomandibular relation, occlusal plane, facial height, morphology of the mandible and upper airway width. Safety endpoints will also be evaluated.Ethics and dissemination Ethical approval was obtained from the ethics committee of Shanghai Stomatological Hospital. Both participants and their guardians will be fully informed of the study and sign an informed consent form before participating in the trial. The results will be publicly available in peer-reviewed scientific journals.Trial registration number ChiCTR2000035882

Melatonin Prevents NaAsO₂-Induced Developmental Cardiotoxicity in Zebrafish through Regulating Oxidative Stress and Apoptosis

Melatonin is an indoleamine hormone secreted by the pineal gland. It has antioxidation and anti-apoptosis effects and a clear protective effect against cardiovascular diseases. Our previous studies demonstrated that embryonic exposure to sodium arsenite (NaAsO2) can lead to an abnormal cardiac development. The aim of this study was to determine whether melatonin could protect against NaAsO2-induced generation of reactive oxygen species (ROS), oxidative stress, apoptosis, and abnormal cardiac development in a zebrafish (Danio rerio) model. We found that melatonin decreased NaAsO2-induced zebrafish embryonic heart malformations and abnormal heart rates at a melatonin concentration as low as 10−9 mol/L. The NaAsO2-induced oxidative stress was counteracted by melatonin supplementation. Melatonin blunted the NaAsO2-induced overproduction of ROS, the upregulation of oxidative stress-related genes (sod2, cat, gpx, nrf2, ho-1), and the production of antioxidant enzymes (Total SOD, SOD1, SOD2, CAT). Melatonin attenuated the NaAsO2-induced oxidative damage, DNA damage, and apoptosis, based on malonaldehyde and 8-OHdG levels and apoptosis-related gene expression (caspase-3, bax, bcl-2), respectively. Melatonin also maintained the control levels of heart development-related genes (nkx2.5, sox9b) affected by NaAsO2. In conclusion, melatonin protected against NaAsO2-induced heart malformations by inhibiting the oxidative stress and apoptosis in zebrafish