Mitochondria are vital subcellular organelles that generate most cellular chemical energy, regulate cell metabolism and maintain cell function. Mitochondrial dysfunction is directly linked to ...numerous diseases including neurodegenerative disorders, diabetes, thyroid squamous disease, cancer and septicemia. Thus, the design of specific mitochondria-targeting molecules and the realization of real-time acquisition of mitochondrial activity are powerful tools in the study and treatment of mitochondria dysfunction in related diseases. Recent advances in mitochondria-targeting agents have led to several important mitochondria chemical probes that offer the opportunity for selective targeting molecules, novel biological applications and therapeutic strategies. This review details the structural and physiological functional characteristics of mitochondria, and comprehensively summarizes and classifies mitochondria-targeting agents. In addition, their pros and cons and their related chemical biological applications are discussed. Finally, the potential biomedical applications of these agents are briefly prospected.
Oncolytic viruses have the capacity to selectively kill infected tumor cells and trigger protective immunity. As such, oncolytic virotherapy has become a promising immunotherapy strategy against ...cancer. A variety of viruses from different families have been proven to have oncolytic potential. Senecavirus A (SVA) was the first picornavirus to be tested in humans for its oncolytic potential and was shown to penetrate solid tumors through the vascular system. SVA displays several properties that make it a suitable model, such as its inability to integrate into human genome DNA and the absence of any viral-encoded oncogenes. In addition, genetic engineering of SVA based on the manipulation of infectious clones facilitates the development of recombinant viruses with improved therapeutic indexes to satisfy the criteria of safety and efficacy regulations. This review summarizes the current knowledge and strategies of genetic engineering for SVA, and addresses the current challenges and future directions of SVA as an oncolytic agent.
Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an infrequent autosomal dominant genetic disorder caused by haploinsufficiency of the GATA binding protein 3 (
GATA3
) gene. In ...this report, we present a case study of a 6-year-old female patient manifesting seizures, tetany, hypoparathyroidism, and sensorineural hearing loss. A heterozygous variant, c.1050 + 2T>C, in the
GATA3
gene was discovered by genetic testing. Moreover, a minigene splicing experiment revealed that the aforementioned variation causes incorrect splicing and premature cessation of protein synthesis. The clinical profile of the patient closely resembles the well-known phenomenology of HDR syndrome, supporting the association between the condition and the
GATA3
variant. The challenges in early diagnosis highlight the importance of employing next-generation sequencing for timely detection of rare diseases. Additionally, this research contributes to a deeper understanding of the genotype-phenotype correlations in HDR syndrome, underscoring the critical need for improved diagnostic and therapeutic strategies.
As a precision transmission mechanism, the trochoidal roller pinion rack has been paid more and more attention in recent years, but its meshing characteristics have not been deeply explored. In order ...to investigate the meshing characteristics of the trochoidal roller pinion rack transmission, it is particularly important to research its line of action and meshing stiffness. The equation of the line of action of the trochoidal roller pinion rack is deduced by using its tooth profile formation principle. The motion simulation of the trochoidal roller pinion rack transmission is carried out to verify the correctness of the theoretical derivation of the equation of the line of action, and the influence of the basic parameters on the line of action is summarized. The meshing stiffness of the trochoidal roller pinion rack is calculated based on the energy method used for gear meshing stiffness, and the meshing stiffness is defined considering the time-varying characteristics of its pressure angle, and the influence of each basic parameter on the meshing stiffness is studied. The results shows that the meshing stiffness increases first and then decreases in the double tooth meshing area, while the meshing stiffness gradually decreases in the single tooth meshing area. The basic parameters including number of roller pins, the module, the rack tooth profile offset coefficient, the diameter coefficient of roller pin, and the addendum coefficient of rack have different effects on the line of action and meshing stiffness. The research conclusion can provide reference for the parameter design of the trochoidal roller pinion rack, and provide the meshing stiffness calculation method for the dynamic analysis of the transmission.
Previous studies have shown that the FMDV Asia1/YS/CHA/05 high-fidelity mutagen-resistant variants are attenuated (Zeng et al., 2014). Here, we introduced the same single or multiple-amino-acid ...substitutions responsible for increased 3Dpol fidelity of type Asia1 FMDV into the type O FMDV O/YS/CHA/05 infectious clone. The rescued viruses O-DA and O-DAMM are lower replication fidelity mutants and showed an attenuated phenotype. These results demonstrated that the same amino acid substitution of 3Dpol in different serotypes of FMDV strains had different effects on viral fidelity. In addition, nucleoside analogues were used to select high-fidelity mutagen-resistant type O FMDV variants. The rescued mutagen-resistant type O FMDV high-fidelity variants exhibited significantly attenuated fitness and a reduced virulence phenotype. These results have important implications for understanding the molecular mechanism of FMDV evolution and pathogenicity, especially in developing a safer modified live-attenuated vaccine against FMDV.
•The same amino acid substitution of 3Dpol in different serotypes of FMDV strains had different effects on viral fidelity.•Nucleoside analogues were used to select a panel of high-fidelity mutagen resistant type O FMDV variants.•The type O FMDV polymerase mutants with multiple amino acid substitutions significantly reduced virulence.
Senecavirus A (SVA) is an important emerging swine pathogen that causes vesicular lesions in swine and acute death in newborn piglets. VP2 plays a significant role in the production of antibodies, ...which can be used in development of diagnostic tools and vaccines. Herein, the aim of the current study was to identify B-cell epitopes (BCEs) of SVA for generation of epitope-based SVA marker vaccine. Three monoclonal antibodies (mAbs), named 2E4, 1B8, and 2C7, against the SVA VP2 protein were obtained, and two novel linear BCEs,
SLGTYYR
and
SPYFNGL
, were identified by peptide scanning. The epitope
SLGTYYR
was recognized by the mAb 1B8 and was fully exposed on the VP2 surface, and alanine scanning analysis revealed that it contained a high continuity of key amino acids. Importantly, we confirmed that
SLGTYYR
locates on "the puff" region within the VP2 EF loop, and contains three key amino acid residues involved in receptor binding. Moreover, a single mutation, Y182A, blocked the interaction of the mutant virus with the mAb 1B8, indicating that this mutation is the pivotal point for antibody recognition. In summary, the BCEs that identified in this study could be used to develop diagnostic tools and an epitope-based SVA marker vaccine.
Wear is an inevitable phenomenon in gear systems and has a great impact on performance and longevity. In view of the fact that the actual variation of meshing stiffness in the double teeth contact ...region and the nonlinear relationship between meshing stiffness and force are ignored in previous wear prediction studies, a new method with loss-of-lubrication is proposed in this study. A translational-torsional dynamic model is developed for the coupling effect between wear and dynamic characteristics of external spur gears. To obtain more precise dynamic responses, the meshing stiffness and force are coupled with tooth wear, taking into account the structural coupling effect and nonlinear contact. The tooth surface is then discretized, and a wear model is developed based on Archard wear equation, in which the average pressure is used for the engaging point. Experiments and numerical simulations are carried out to analyze the wear pattern and the interaction between wear and dynamic responses. The results show that the progressive wear process is self-adaptive. Meanwhile, the area with the largest wear depth moves slightly from the dedendum and addendum to the pitch line as the wear cycle increases. When the wear depth is at the level of the tooth profile deviation, the influence of wear on meshing stiffness is very small within the single tooth contact region. However, there is a significant decrease in the stiffness of the double teeth contact, and this decrease is related to the wear cycle and torque. At the initial wear phase, as the load increases, the fluctuation of the wear depth within the engaging-in region intensifies and the overall wear depth increases. With the increment of rotate speed, the engaging-in impact makes the fluctuant area of wear depth become larger.
Postmenopausal women are more prone to develop muscle weakness, which is strongly associated with impairment of mitochondrial function in skeletal muscle. This study aimed to examine the impact of a ...passive exercise modality, whole-body vibration training (WBVT), on muscle mitochondrial function in ovariectomized (OVX) mice, in comparison with 17β-estradiol (E
) replacement.
Female C57BL/6J mice were assigned to four groups: sham operation control group (Sham), ovariectomized group (OVX), OVX with E
supplement group (OVX+E), and OVX with WBVT group (OVX+W). The estrous cycle, body weight, body composition, and muscle strength of the mice were monitored after the operation. Serum E
level was assessed by enzyme-linked immunosorbent assay (ELISA). The ATP levels were determined using a luciferase-catalyzed bioluminescence assay. The activity of mitochondrial respiration chain complexes was evaluated using high-resolution respirometry (O2K). Expression levels of oxidative phosphorylation (OXPHOS), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and mitochondrial transcription factor A (TFAM) were detected using western blotting.
We observed decreased muscle strength and impaired mitochondrial function in the skeletal muscle of OVX mice. The vibration training alleviated these impairments as much as the E
supplement. In addition, the vibration training was superior to the ovariectomy and the estradiol replacement regarding the protein expression of PGC-1α and TFAM.
WBVT improves the OVX-induced decline in muscle strength and impairment of mitochondrial function in the skeletal muscle. This passive exercise strategy may be useful as an alternative to E
replacement for preventing menopausal muscular weakness. Further studies are needed to understand the effects of WBVT on various physiological systems, and precautions should be taken when implementing it in patient treatment.
Focusing on safety, comfort and with an overall aim of the comprehensive improvement of a vision-based intelligent vehicle, a novel Advanced Emergency Braking System (AEBS) is proposed based on ...Nonlinear Model Predictive Algorithm. Considering the nonlinearities of vehicle dynamics, a vision-based longitudinal vehicle dynamics model is established. On account of the nonlinear coupling characteristics of the driver, surroundings, and vehicle itself, a hierarchical control structure is proposed to decouple and coordinate the system. To avoid or reduce the collision risk between the intelligent vehicle and collision objects, a coordinated cost function of tracking safety, comfort, and fuel economy is formulated. Based on the terminal constraints of stable tracking, a multi-objective optimization controller is proposed using the theory of non-linear model predictive control. To quickly and precisely track control target in a finite time, an electronic brake controller for AEBS is designed based on the Nonsingular Fast Terminal Sliding Mode (NFTSM) control theory. To validate the performance and advantages of the proposed algorithm, simulations are implemented. According to the simulation results, the proposed algorithm has better integrated performance in reducing the collision risk and improving the driving comfort and fuel economy of the smart car compared with the existing single AEBS.
PDF
