Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease.

The SLC25A26 gene encodes a mitochondrial inner membrane carrier that transports S-adenosylmethionine (SAM) into the mitochondrial matrix in exchange for S-adenosylhomocysteine (SAH). SAM is the predominant methyl-group donor for most cellular methylation processes, of which SAH is produced as a by-product. Pathogenic, biallelic SLC25A26 variants are a recognized cause of mitochondrial disease in children, with a severe neonatal onset caused by decreased SAM transport activity. Here, we describe two, unrelated adult cases, one of whom presented with recurrent episodes of severe abdominal pain and metabolic decompensation with lactic acidosis. Both patients had exercise intolerance and mitochondrial myopathy associated with biallelic variants in SLC25A26, which led to marked respiratory chain deficiencies and mitochondrial histopathological abnormalities in skeletal muscle that are comparable to those previously described in early-onset cases. We demonstrate using both mouse and fruit fly models that impairment of SAH, rather than SAM, transport across the mitochondrial membrane is likely the cause of this milder, late-onset phenotype. Our findings associate a novel pathomechanism with a known disease-causing protein and highlight the quests of precision medicine in optimizing diagnosis, therapeutic intervention and prognosis.

Mitochondrial OXPHOS Biogenesis: Co-Regulation of Protein Synthesis, Import, and Assembly Pathways.

The assembly of mitochondrial oxidative phosphorylation (OXPHOS) complexes is an intricate process, which-given their dual-genetic control-requires tight co-regulation of two evolutionarily distinct gene expression machineries. Moreover, fine-tuning protein synthesis to the nascent assembly of OXPHOS complexes requires regulatory mechanisms such as translational plasticity and translational activators that can coordinate mitochondrial translation with the import of nuclear-encoded mitochondrial proteins. The intricacy of OXPHOS complex biogenesis is further evidenced by the requirement of many tightly orchestrated steps and ancillary factors. Early-stage ancillary chaperones have essential roles in coordinating OXPHOS assembly, whilst late-stage assembly factors-also known as the LYRM (leucine-tyrosine-arginine motif) proteins-together with the mitochondrial acyl carrier protein (ACP)-regulate the incorporation and activation of late-incorporating OXPHOS subunits and/or co-factors. In this review, we describe recent discoveries providing insights into the mechanisms required for optimal OXPHOS biogenesis, including the coordination of mitochondrial gene expression with the availability of nuclear-encoded factors entering via mitochondrial protein import systems.

[Effect of kinetin on immunity and splenic lymphocyte proliferation in vitro in D-galactose-induced aging rats].

The purpose of this paper is to study the effect of kinetin (Kn) on immunity and splenic lymphocyte proliferation in vitro of aging rats induced by D-galactose (D-gal). Fifty SD rats were randomly divided into five groups: control group, aging model group, Kn low dose group, Kn middle dose group and Kn high dose group. The aging model group was proposed by napes subcutaneous injection of D-gal (125 mg/kg) for 45 d, and anti-aging groups were intragastrically administered with 5, 10, 20 mg/kg of Kn respectively from day 11. IgG, IgA, IgM contents of serum, the apoptosis percentage, stimulation index (SI) and proliferation index (PI) of splenic lymphocyte in vitro were evaluated. The results showed that the apoptosis percentage of splenic lymphocyte in aging model rats was higher, the serum IgG, IgA and IgM contents, SI and PI were lower than control group. Kn significantly decreased the apoptosis percentage of splenic lymphocyte, while increased the serum IgG, IgA and IgM contents, SI and PI in aging model group. These results suggest that Kn could inhibit the apoptosis, while promote the proliferation of splenic lymphocyte, and then effectively enhance the immune power of the aging rats and slow down the aging process.

Multiple Lung Cavity Lesions, Thoracic Wall Abscess and Vertebral Destruction Caused by Streptococcus constellatus Infection: A Case Report.

Disseminated infection caused by Streptococcus constellatus was seldom occurred. We reported a case of Streptococcus constellatus infection, presenting as multiple pulmonary cavities, thoracic wall abscess and vertebral destruction. The 37-year-old male had recurrent fever, chest wall swelling and pain, and lower limb numbness, he had weak physical condition and previously suffered from poorly controlled diabetes and severe periodontal disease for 3 years. Definite diagnosis of Streptococcus constellatus infection was made by metagenomic next­generation sequencing (mNGS) in abscess drainage fluid. Systemic antibiotics and thoracic wall drainage were given, and the pulmonary cavity and the thoracic intermuscular abscess were significantly decreased. Few to no study reported the disseminated infection (pulmonary cavities, thoracic wall abscess and vertebral destruction) caused by Streptococcus constellatus. This case report highlighted the importance of mNGS for accurate diagnosis, as well as the timely drainage and antibiotics for effective treatment of Streptococcus constellatus infection.

A Comparison of the Performances of Artificial Intelligence System and Radiologists in the Ultrasound Diagnosis of Thyroid Nodules.

AIMS: The purpose of this paper is to prospectively evaluate the performance of an artificial intelligence (AI) system in diagnosing thyroid nodules and to assess its potential value in comparison with the performance of radiologists with different levels of experience, as well as the factors affecting its diagnostic accuracy. BACKGROUND: In recent years, medical imaging diagnosis using AI has become a popular topic in clinical application research. OBJECTIVE: This study aimed to evaluate the performance of an AI system in diagnosing thyroid nodules and compare it with the performance levels of different radiologists. METHODS: This study involved 426 patients screened for thyroid nodules at the First Affiliated Hospital of Guangzhou Medical University between July 2017 and March 2019. All of the nodules were evaluated by radiologists with various levels of experience and an AI system. The diagnostic performances of two junior and two senior radiologists, an AI system, and an AI-assisted junior radiologist were compared, as were their diagnostic results with respect to nodules of different sizes. RESULTS: The senior radiologists, the AI system, and the AI-assisted junior radiologist performed better than the junior radiologist (p < 0.05). The area under the curves of the AI system and the AI-assisted junior radiologist were similar to the curve of the senior radiologists (p > 0.05). The diagnostic results concerning the two nodule sizes showed that the diagnostic error rates of the AI system, junior radiologists, and senior radiologists for nodules with a maximum diameter of ≤1 cm (Dmax ≤ 1 cm) were higher than those for nodules with a maximum diameter of 1 cm (Dmax > 1 cm) (23.4% vs. 12.1%, p = 0.002; 26.6% vs. 7.3%, p < 0.001; and 38.3% vs. 14.6%, p < 0.001). CONCLUSION: The AI system is a decision-making tool that could potentially improve the diagnostic efficiency of junior radiologists. Micronodules with Dmax ≤ 1cm were significantly correlated with diagnostic accuracy; accordingly, more micronodules of this size, in particular, should be added to the AI system as training samples. Other: The system could be a potential decision-making tool for effectively improving the diagnostic efficiency of junior radiologists in the community.

Interrogating Mitochondrial Biology and Disease Using CRISPR/Cas9 Gene Editing.

Mitochondrial disease originates from genetic changes that impact human bodily functions by disrupting the mitochondrial oxidative phosphorylation system. MitoCarta is a curated and published inventory that sheds light on the mitochondrial proteome, but the function of some mitochondrially-localised proteins remains poorly characterised. Consequently, various gene editing systems have been employed to uncover the involvement of these proteins in mitochondrial biology and disease. CRISPR/Cas9 is an efficient, versatile, and highly accurate genome editing tool that was first introduced over a decade ago and has since become an indispensable tool for targeted genetic manipulation in biological research. The broad spectrum of CRISPR/Cas9 applications serves as an attractive and tractable system to study genes and pathways that are essential for the regulation and maintenance of mitochondrial health. It has opened possibilities of generating reliable cell and animal models of human disease, and with further exploitation of the technology, large-scale genomic screenings have uncovered a wealth of fundamental mechanistic insights. In this review, we describe the applications of CRISPR/Cas9 system as a genome editing tool to uncover new insights into pathomechanisms of mitochondrial diseases and/or biological processes involved in mitochondrial function.