Mitochondrial dysfunction has emerged as a critical factor in the etiology of various neurodevelopmental disorders, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and Rett syndrome. Alt...Mitochondrial dysfunction has emerged as a critical factor in the etiology of various neurodevelopmental disorders, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and Rett syndrome. Although these conditions differ in clinical presentation, they share fundamental pathological features that may stem from abnormal mitochondrial dynamics and impaired autophagic clearance, which contribute to redox imbalance and oxidative stress in neurons. This review aimed to elucidate the relationship between mitochondrial dynamics dysfunction and neurodevelopmental disorders. Mitochondria are highly dynamic organelles that undergo continuous fusion and fission to meet the substantial energy demands of neural cells. Dysregulation of these processes, as observed in certain neurodevelopmental disorders, causes accumulation of damaged mitochondria, exacerbating oxidative damage and impairing neuronal function. The phosphatase and tensin homolog-induced putative kinase 1/E3 ubiquitin-protein ligase pathway is crucial for mitophagy, the process of selectively removing malfunctioning mitochondria. Mutations in genes encoding mitochondrial fusion proteins have been identified in autism spectrum disorders, linking disruptions in the fusion-fission equilibrium to neurodevelopmental impairments. Additionally, animal models of Rett syndrome have shown pronounced defects in mitophagy, reinforcing the notion that mitochondrial quality control is indispensable for neuronal health. Clinical studies have highlighted the importance of mitochondrial disturbances in neurodevelopmental disorders. In autism spectrum disorders, elevated oxidative stress markers and mitochondrial DNA deletions indicate compromised mitochondrial function. Attention-deficit/hyperactivity disorder has also been associated with cognitive deficits linked to mitochondrial dysfunction and oxidative stress. Moreover, induced pluripotent stem cell models derived from patients with Rett syndrome have shown impaired mitochondrial dynamics and heightened vulnerability to oxidative injury, suggesting the role of defective mitochondrial homeostasis in these disorders. From a translational standpoint, multiple therapeutic approaches targeting mitochondrial pathways show promise. Interventions aimed at preserving normal fusion-fission cycles or enhancing mitophagy can reduce oxidative damage by limiting the accumulation of defective mitochondria. Pharmacological modulation of mitochondrial permeability and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, an essential regulator of mitochondrial biogenesis, may also ameliorate cellular energy deficits. Identifying early biomarkers of mitochondrial impairment is crucial for precision medicine, since it can help clinicians tailor interventions to individual patient profiles and improve prognoses. Furthermore, integrating mitochondria-focused strategies with established therapies, such as antioxidants or behavioral interventions, may enhance treatment efficacy and yield better clinical outcomes. Leveraging these pathways could open avenues for regenerative strategies, given the influence of mitochondria on neuronal repair and plasticity. In conclusion, this review indicates mitochondrial homeostasis as a unifying therapeutic axis within neurodevelopmental pathophysiology. Disruptions in mitochondrial dynamics and autophagic clearance converge on oxidative stress, and researchers should prioritize validating these interventions in clinical settings to advance precision medicine and enhance outcomes for individuals affected by neurodevelopmental disorders.展开更多
In extreme heat transfer environments, functionally graded materials(FGMs)have aroused great concern due to the excellent thermal shock resistance. With the development of micro-scale devices, the size-dependent effec...In extreme heat transfer environments, functionally graded materials(FGMs)have aroused great concern due to the excellent thermal shock resistance. With the development of micro-scale devices, the size-dependent effect has become an important issue. However, the classical continuum mechanical model fails on the micro-scale due to the influence of the size-dependent effect. Meanwhile, for thermoelastic behaviors limited to small-scale problems, Fourier's heat conduction law cannot explain the thermal wave effect. In order to capture the size-dependent effect and the thermal wave effect, the nonlocal generalized thermoelastic theory for the formulation of an FGM microbeam is adopted in the present work. For numerical validation, the transient responses for a simply supported FGM microbeam heated by the ramp-type heating are considered.The governing equations are formulated and solved by employing the Laplace transform techniques. In the numerical results, the effects of the ramp-heating time parameter, the nonlocal parameter, and the power-law index on the considered physical quantities are presented and discussed in detail.展开更多
Classical thermo-viscoelastic models may be challenged to predict the precise thermo-mechanical behavior of viscoelastic materials without considering the memorydependent effect.Meanwhile,with the miniaturization of d...Classical thermo-viscoelastic models may be challenged to predict the precise thermo-mechanical behavior of viscoelastic materials without considering the memorydependent effect.Meanwhile,with the miniaturization of devices,the size-dependent effect on elastic deformation is becoming more and more important.To capture the memory-dependent effect and the size-dependent effect,the present study aims at developing a modified fractional-order thermo-viscoelastic coupling model at the microscale to account for two fundamentally distinct fractional-order models which govern the memory-dependent features of thermal conduction and stress-strain relation,respectively.Then,the modified theory is used to study the dynamic response of a polymer micro-rod heated by a moving heat source.The governing equations are obtained and solved by the Laplace transform method.In calculation,the effects of the fractional-order parameter,the fractional-order strain parameter,the mechanical relaxation parameter,and the nonlocal parameter on the variations of the considered variables are analyzed and discussed in detail.展开更多
Base editors of the Cas9 system have been widely used for precise nucleotide substitution in crops. In this study, Cas12a was applied to construct plant cytosine base editors(CBEs). The main elements of Cas12aCBEs wer...Base editors of the Cas9 system have been widely used for precise nucleotide substitution in crops. In this study, Cas12a was applied to construct plant cytosine base editors(CBEs). The main elements of Cas12aCBEs were engineered and their efficiency was evaluated in stably transformed rice cells. An optimized ttCas12a-hyA3Bctd editor, consisting of a LbCas12a variant carrying catalytic inactive D832A and temperature-tolerance D156R double mutations, a truncated human APOBEC3B deaminase, a human RAD51 single-stranded DNA-binding domain, and double copies of UGI, outperformed other Cas12aCBEs in base editing efficiency. In T0transgenic rice plants, ttCas12a-hyA3Bctd edited an average of42.01% and a maximum of 68.75% of lines at six genomic targets. A-to-G conversions were generated in rice by an adenine base editor with a similar architecture to the optimized CBE. Our results provide preliminary evidence for the feasibility of robust and efficient plant Cas12a base editing systems, which could be useful for precise crop breeding.展开更多
文摘Mitochondrial dysfunction has emerged as a critical factor in the etiology of various neurodevelopmental disorders, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and Rett syndrome. Although these conditions differ in clinical presentation, they share fundamental pathological features that may stem from abnormal mitochondrial dynamics and impaired autophagic clearance, which contribute to redox imbalance and oxidative stress in neurons. This review aimed to elucidate the relationship between mitochondrial dynamics dysfunction and neurodevelopmental disorders. Mitochondria are highly dynamic organelles that undergo continuous fusion and fission to meet the substantial energy demands of neural cells. Dysregulation of these processes, as observed in certain neurodevelopmental disorders, causes accumulation of damaged mitochondria, exacerbating oxidative damage and impairing neuronal function. The phosphatase and tensin homolog-induced putative kinase 1/E3 ubiquitin-protein ligase pathway is crucial for mitophagy, the process of selectively removing malfunctioning mitochondria. Mutations in genes encoding mitochondrial fusion proteins have been identified in autism spectrum disorders, linking disruptions in the fusion-fission equilibrium to neurodevelopmental impairments. Additionally, animal models of Rett syndrome have shown pronounced defects in mitophagy, reinforcing the notion that mitochondrial quality control is indispensable for neuronal health. Clinical studies have highlighted the importance of mitochondrial disturbances in neurodevelopmental disorders. In autism spectrum disorders, elevated oxidative stress markers and mitochondrial DNA deletions indicate compromised mitochondrial function. Attention-deficit/hyperactivity disorder has also been associated with cognitive deficits linked to mitochondrial dysfunction and oxidative stress. Moreover, induced pluripotent stem cell models derived from patients with Rett syndrome have shown impaired mitochondrial dynamics and heightened vulnerability to oxidative injury, suggesting the role of defective mitochondrial homeostasis in these disorders. From a translational standpoint, multiple therapeutic approaches targeting mitochondrial pathways show promise. Interventions aimed at preserving normal fusion-fission cycles or enhancing mitophagy can reduce oxidative damage by limiting the accumulation of defective mitochondria. Pharmacological modulation of mitochondrial permeability and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, an essential regulator of mitochondrial biogenesis, may also ameliorate cellular energy deficits. Identifying early biomarkers of mitochondrial impairment is crucial for precision medicine, since it can help clinicians tailor interventions to individual patient profiles and improve prognoses. Furthermore, integrating mitochondria-focused strategies with established therapies, such as antioxidants or behavioral interventions, may enhance treatment efficacy and yield better clinical outcomes. Leveraging these pathways could open avenues for regenerative strategies, given the influence of mitochondria on neuronal repair and plasticity. In conclusion, this review indicates mitochondrial homeostasis as a unifying therapeutic axis within neurodevelopmental pathophysiology. Disruptions in mitochondrial dynamics and autophagic clearance converge on oxidative stress, and researchers should prioritize validating these interventions in clinical settings to advance precision medicine and enhance outcomes for individuals affected by neurodevelopmental disorders.
基金Project supported by the National Natural Science Foundation of China (Nos. 11972176 and12062011)the Incubation Programme of Excellent Doctoral Dissertation-Lanzhou University of Technology。
文摘In extreme heat transfer environments, functionally graded materials(FGMs)have aroused great concern due to the excellent thermal shock resistance. With the development of micro-scale devices, the size-dependent effect has become an important issue. However, the classical continuum mechanical model fails on the micro-scale due to the influence of the size-dependent effect. Meanwhile, for thermoelastic behaviors limited to small-scale problems, Fourier's heat conduction law cannot explain the thermal wave effect. In order to capture the size-dependent effect and the thermal wave effect, the nonlocal generalized thermoelastic theory for the formulation of an FGM microbeam is adopted in the present work. For numerical validation, the transient responses for a simply supported FGM microbeam heated by the ramp-type heating are considered.The governing equations are formulated and solved by employing the Laplace transform techniques. In the numerical results, the effects of the ramp-heating time parameter, the nonlocal parameter, and the power-law index on the considered physical quantities are presented and discussed in detail.
基金Project supported by the National Natural Science Foundation of China(Nos.11972176 and12062011)。
文摘Classical thermo-viscoelastic models may be challenged to predict the precise thermo-mechanical behavior of viscoelastic materials without considering the memorydependent effect.Meanwhile,with the miniaturization of devices,the size-dependent effect on elastic deformation is becoming more and more important.To capture the memory-dependent effect and the size-dependent effect,the present study aims at developing a modified fractional-order thermo-viscoelastic coupling model at the microscale to account for two fundamentally distinct fractional-order models which govern the memory-dependent features of thermal conduction and stress-strain relation,respectively.Then,the modified theory is used to study the dynamic response of a polymer micro-rod heated by a moving heat source.The governing equations are obtained and solved by the Laplace transform method.In calculation,the effects of the fractional-order parameter,the fractional-order strain parameter,the mechanical relaxation parameter,and the nonlocal parameter on the variations of the considered variables are analyzed and discussed in detail.
基金funded by the National Natural Science Foundation of China (U19A2022 and 32000284)the Natural Science Foundation of Anhui Province (2208085Y11, 2108085Y07,2008085QC101, and 2008085MC71)+2 种基金the University Synergy Innovation Program of Anhui Province (GXXT-2021-056)Open Research Fund Program of Anhui Province Key Laboratory of Rice Genetics and Breeding (SDKF-2021-01 and SDKF-2022-04)Natural Science Research Project for Anhui Universities(KJ2021A0196)。
文摘Base editors of the Cas9 system have been widely used for precise nucleotide substitution in crops. In this study, Cas12a was applied to construct plant cytosine base editors(CBEs). The main elements of Cas12aCBEs were engineered and their efficiency was evaluated in stably transformed rice cells. An optimized ttCas12a-hyA3Bctd editor, consisting of a LbCas12a variant carrying catalytic inactive D832A and temperature-tolerance D156R double mutations, a truncated human APOBEC3B deaminase, a human RAD51 single-stranded DNA-binding domain, and double copies of UGI, outperformed other Cas12aCBEs in base editing efficiency. In T0transgenic rice plants, ttCas12a-hyA3Bctd edited an average of42.01% and a maximum of 68.75% of lines at six genomic targets. A-to-G conversions were generated in rice by an adenine base editor with a similar architecture to the optimized CBE. Our results provide preliminary evidence for the feasibility of robust and efficient plant Cas12a base editing systems, which could be useful for precise crop breeding.
