GTPBP8 plays a role in mitoribosome formation in human mitochondria.

Mitochondrial gene expression relies on mitoribosomes to translate mitochondrial mRNAs. The biogenesis of mitoribosomes is an intricate process involving multiple assembly factors. Among these factors, GTP-binding proteins (GTPBPs) play important roles. In bacterial systems, numerous GTPBPs are required for ribosome subunit maturation, with EngB being a GTPBP involved in the ribosomal large subunit assembly. In this study, we focus on exploring the function of GTPBP8, the human homolog of EngB. We find that ablation of GTPBP8 leads to the inhibition of mitochondrial translation, resulting in significant impairment of oxidative phosphorylation. Structural analysis of mitoribosomes from GTPBP8 knock-out cells shows the accumulation of mitoribosomal large subunit assembly intermediates that are incapable of forming functional monosomes. Furthermore, fPAR-CLIP analysis reveals that GTPBP8 is an RNA-binding protein that interacts specifically with the mitochondrial ribosome large subunit 16 S rRNA. Our study highlights the role of GTPBP8 as a component of the mitochondrial gene expression machinery involved in mitochondrial large subunit maturation.

Deep eutectic solvent pretreatment of cellulose and development of hydrophobic foaming material.

This work aims to investigate the effects of deep eutectic solvents (DES) on the chemical and physical structure of cellulose. Choline chloride-oxalic acid and choline chloride-oxalic acid-glycerol were selected as solvents and cotton fibers was sued as raw materials to explore the difference between cotton fibers treated separately with two different DES. According to yield analysis, ternary solvents alleviated the degradation of cellulose when comparing to binary solvents, resulting in over 90 % of cellulose being obtained. Particularly, there is an esterification reaction of cellulose during treatment with the DES system, which also affects the performance of the subsequent products. Through the simple use of mechanical foaming with polyvinyl alcohol and the palm wax impregnation process, foams with a water contact angle greater than 140° and excellent mechanical properties can be obtained. The resultant foam material has 5 % linear elastic area, and prominent compressive strength providing potential use in the packaging industry in the replacement of plastic.

Characterization of a Salmonella enterica serovar Typhimurium lineage with rough colony morphology and multidrug resistance.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a major cause of salmonellosis, and the emergence of multidrug-resistant pathovariants has become a growing concern. Here, we investigate a distinct rough colony variant exhibiting a strong biofilm-forming ability isolated in China. Whole-genome sequencing on 2,212 Chinese isolates and 1,739 publicly available genomes reveals the population structure and evolutionary history of the rough colony variants. Characterized by macro, red, dry, and rough (mrdar) colonies, these variants demonstrate enhanced biofilm formation at 28 °C and 37 °C compared to typical rdar colonies. The mrdar variants exhibit extensive multidrug resistance, with significantly higher resistance to at least five classes of antimicrobial agents compared to non-mrdar variants. This resistance is primarily conferred by an IncHI2 plasmid harboring 19 antimicrobial resistance genes. Phylogenomic analysis divides the global collections into six lineages. The majority of mrdar variants belong to sublineage L6.5, which originated from Chinese smooth colony strains and possibly emerged circa 1977. Among the mrdar variants, upregulation of the csgDEFG operons is observed, probably due to a distinct point mutation (-44G > T) in the csgD gene promoter. Pangenome and genome-wide association analyses identify 87 specific accessory genes and 72 distinct single nucleotide polymorphisms associated with the mrdar morphotype.

Alpha-ketoglutarate ameliorates age-related and surgery induced temporomandibular joint osteoarthritis via regulating IKK/NF-κB signaling.

Recent studies have shed light on the important role of aging in the pathogenesis of joint degenerative diseases and the anti-aging effect of alpha-ketoglutarate (αKG). However, whether αKG has any effect on temporomandibular joint osteoarthritis (TMJOA) is unknown. Here, we demonstrate that αKG administration improves condylar cartilage health of middle-aged/aged mice, and ameliorates pathological changes in a rat model of partial discectomy (PDE) induced TMJOA. In vitro, αKG reverses IL-1ß-induced/H2O2-induced decrease of chondrogenic markers (Col2, Acan and Sox9), and inhibited IL-1ß-induced/ H2O2-induced elevation of cartilage catabolic markers (ADAMTS5 and MMP13) in condylar chondrocytes. In addition, αKG downregulates senescence-associated (SA) hallmarks of aged chondrocytes, including the mRNA/protein level of SA genes (p16 and p53), markers of nuclear disorders (Lamin A/C) and SA-ß-gal activities. Mechanically, αKG decreases the expressions of p-IKK and p-NF-κB, protecting TMJ from inflammation and senescence-related damage by regulating the NF-κB signaling. Collectively, our findings illuminate that αKG can ameliorate age-related TMJOA and PDE-induced TMJOA, maintain the homeostasis of cartilage matrix, and exert anti-aging effects in chondrocytes, with a promising therapeutic potential in TMJOA, especially age-related TMJOA.

Nanolignin-containing cellulose nanofibrils (LCNF)-enabled multifunctional ratiometric fluorescent bio-nanocomposite films for food freshness monitoring.

Herein, the nanolignin-containing cellulose nanofibrils (LCNF)-enabled ratiometric fluorescent bio-nanocomposite film is developed. Interestingly, the inclusion of LCNF in the cellulose-based film enhances the detecting performance of food freshness, such as high sensitivity to biogenic amines (BAs) (limit of detection (LOD) of up to 1.83 ppm) and ultrahigh discernible fluorescence color difference (ΔE = 113.11). The underlying mechanisms are the fluorescence resonance energy transfer (FRET), π - π interaction, and cation - π interaction between LCNF and fluorescein isothiocyanate (FITC), as well as the increased hydrophobicity due to lignin, which increases the interactions of amines with FITC. Its color stability (up to 28 days) and mechanical property (49.4 Mpa) are simultaneously improved. Furthermore, a smartphone based detecting platform is developed to achieve access to food safety. This work presents a novel technology, which can have a great potential in the field of food packaging and safety.

Applying ICF Framework to Explore the Factors That Influence Quality of Life in Patients After Lung Surgery.

OBJECTIVE: To explore the relationship between pulmonary function, physical activity, and health-related quality of life (QoL) in resected lung cancer patients based on the International Classification of Functioning, Disability, and Health (ICF) framework developed by the World Health Organization to describe health and health-related states. METHODS: A quantitative study was designed with postoperative lung cancer survivors to assess personal characteristics. We also assessed functional impairment related to the lung using forced vital capacity (FVC) and forced expiratory volume at 1 second (FEV1), activity limitations using maximal oxygen consumption (VO2max), anaerobic threshold (AT) and 6-minute walking distance (6MWD), and participation restriction using the 36-item Short Form Health Survey V1 (SF-36). Data analyses were conducted using the multivariate method and Smart- PLS to examine path coefficient among the measures. RESULTS: Forty-one patients were enrolled in this study. FVC and FEV1 were poorly correlated with QoL, and 6MWD, AT, or VO2max were positively associated with QoL. AT or VO2max showed a significant (p<0.01) direct path with SF-36 in the ICF model. Although age and body mass index were not strongly correlated with QoL, these personal factors had a medium to large effect on perceived QoL. CONCLUSION: Disability is a complex in patients with lung resection, and physical activity plays an important role in enabling participation. Improving VO2max and AT is needed to improve the QoL of resected lung cancer patients. We should also pay more attention to contextual factors that have a significant impact on social participation.

Factors Influencing Plasma Concentrations of Valproic Acid in Pediatric Patients With Epilepsy and the Clinical Significance of CYP2C9 Genotypes in Personalized Valproic Acid Therapy.

BACKGROUND: The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing. METHODS: The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR. RESULTS: The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes ( P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV. CONCLUSIONS: Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy.

Super flexible, self-healing, and self-adhesive double network hydrogel reinforced by okara cellulose nanofibrils.

Inspired by the mussel, tannic acid (TA) was modified onto the surface of self-made cellulose nanofibrils (CNFs) to prepare TA@CNFs, which was introduced into borax crosslinked polyvinyl alcohol (PVA) to prepare PTC double-network hydrogel with self-healing properties. Through the comparative observation of TEM images and infrared spectra before and after tannic acid modification, the formation of TA@CNFs was proved. The introduction of TA@CNFs greatly increases the fracture stress of PTC hydrogel, which is more than 10 times higher than that of PVA hydrogel without TA@CNFs, and has high fracture strain (1723 %). Moreover, PTC hydrogel has the ability of rapid self-healing, which can heal to the original form within two minutes. In addition, the temperature response ability of PTC hydrogel makes it capable of reshaping. The self-adhesion ability of PTC hydrogel enables it to adhere to the human epidermis to detect motion signals, as sensitive and as stable as a flexible sensor.

Research on the anti-aging efficacy of fermented lysate VHProbi® MixA as the functional skincare ingredient.

AIMS: This study aimed to investigate the efficacy of a cream containing VHProbi® MixA for improving skin aging. METHODS AND RESULTS: In vitro studies demonstrated that the lysate produced from Lacticaseibacillus paracasei E12 (E12) exhibited immunoregulatory effects in a 3D skin model, with significant reductions in levels of interleukin (IL)-1α, IL-1ß, and IL-8 (P < 0.05) compared with the control group. In addition, the lysate of E12 mitigated the hydrogen peroxide-induced mortality of 3D skin cells and enhanced the transepithelial electrical resistance to show significant differences in comparison with control (P < 0.05), suggesting favorable antioxidant effects. The antioxidant capacity of the lysate of E12 was also confirmed using the Caenorhabditis elegans N2 model. C. elegans N2 fed the E12 strain showed a significantly higher % survival than those fed Escherichia coli OP50 (P < 0.05). Subsequently, VHProbi® MixA was formulated using the fermented lysates of E12, Lactiplantibacillus plantarum E15, and Limosilactobacillus reuteri E18. In a clinical study to ascertain if a cream containing VHProbi® MixA could improve the skin aging trends, participants were asked to use the investigational products for 60 days, and six indicators, transepidermal water loss (TEWL), hydration, elasticity, wrinkles, skin texture (roughness), and pores were measured at baseline and the endpoint of the study. A self-evaluation questionnaire analysis was also provided. TEWL, wrinkles, skin texture, and thickness of pores decreased significantly after treatment with the cream for 60 days (P < 0.01), whereas hydration and elasticity increased significantly (P < 0.01), in comparison to the baseline measurements. CONCLUSIONS: We hypothesize that the use of the cream containing VHProbi® MixA could be favorable for skin anti-aging management.

Current surgical status of hip fracture among elderly in China.

OBJECTIVE: Hip fracture patients are recommended to undergo surgery within 24-36 h. The present study aimed to analyze the current status of hip fracture surgery among the elderly in China. METHODS: The baseline information, such as the patient's age, gender, place of residence, place of treatment, fracture type, admission, and operation time, of hip fracture patients >65-years-old were retrieved from the hospital quality monitoring system (HQMS) database from 2013 to 2017 and analyzed. RESULTS: A total of 304,279 patients >65-years-old with hip fractures were included in this study. The average length of hospital stay was 15 days, and the average waiting time for surgery after admission was 96 h. The average surgery rate of elderly hip fractures in China was 59.6 %, of which the lowest was recorded in the Northwest China (46.4 %). CONCLUSIONS: The major issues in diagnosing and treating elderly patients with hip fractures in China are the long waiting time for surgery and the low surgery rate.

The value of elastography strain rate ratio in benign and malignant BI-RADS-US 3-4 breast masses.

In the realm of breast diagnostics, Breast Imaging Reporting and Data System (BI-RADS) serves as a systematic framework, guiding a methodical exploration into the nuanced narratives of masses. The current study aims to investigate the value of strain rate ratio (SR) of elastography for benign and malignant breast masses categorized by BI-RADS for Ultrasonography (BI-RADS-US) category 3-4. Ultrasonographic data of 1099 breast masses that underwent both elastography and pathological examination were retrospectively analyzed by non-parametric test, consistency analysis and receiver operating characteristic (ROC) curve sequentially. ROC curve was used to evaluate the diagnostic effect of SR method in different BI-RADS categories of breast lesions. The maximum Youden index obtained from the ROC curve was 0.845. At a cut-off value of 3.57, the SR values' diagnostic sensitivity, specificity, accuracy, positive predictive value and negative predictive value for distinguishing benign and malignant breast lesions were 85.7 %, 98.8 %, 93.6 %, 97.9 % and 91.45 %, respectively. Consistency analysis showed that the consistency between SR value and pathological diagnosis was 93.6 % (κ = 0.864). In addition, the SR values between benign and malignant lesions of BI-RADS 3 and 4 were statistically different (P < 0.001). ROC analysis indicated that the diagnostic area under curve (AUC) for SR value in BI-RADS 3, 4a, 4b and 4c lesions were 0.985, 0.866, 0.793 and 0.916, respectively. In addition, the study observed 58 cases of missed diagnosis and 20 cases of misdiagnosis in evaluating benign and malignant breast lesions. The elastic SR ratio method has a good diagnostic value for the evaluation of breast masses, particularly for lesions with a score of 3-4. The elastic SR ratio method is instrumental in enhancing the accuracy of diagnosis.

Association of gut microbiome and oral cavity cancer: A two sample mendelian randomization and case-control study.

INTRODUCTION: Considering the interconnectedness of the oral cavity and gut tract and the presence of abundant natural microbiota in both. We utilized Mendelian Randomization (MR) in a two-sample study to unveil the genetic causal impact of gut microbiota on the development of oral cavity cancer. MATERIALS & METHODS: The instrumental variables employed in this study consisted of single nucleotide polymorphisms (SNPs) that demonstrated a robust association with 211 distinct gut microbiota taxa, encompassing a sample size of 18,340 individuals. Our investigation sought to explore the potential causal relationship between these genetic variants and the incidence of oral cavity cancer. To accomplish this, we adopted a random effect inverse variance-weighted approach to analyze the causal effect. Additionally, sensitivity analyses were performed utilizing Cochran's Q tests, funnel plots, leave-one-out analyses, and MR-Egger intercept tests, to assess the robustness and validity of our findings. RESULTS: Five gut microbiota taxa (the family Prevotellaceae, the genus Alloprevotella, the genus Erysipelatoclostridium, the genus Parabacteroides, the genus Ruminococcus gauvreauii group) are predicted to play a causal role in promoting the initiation of the risk of oral cavity cancer. While the genus Christensenellaceae R 7 group, the genus Intestinimonas, the genus Ruminococcaceae, and the order Bacillales causally reduce the risk of oral cavity cancer. Furthermore, no significant evidence suggesting heterogeneity or pleiotropy was observed. DISCUSSION: The novel genetic causal effects of 211 gut microbiota taxa on oral cavity cancer are elucidated in this investigation, thus offering valuable insights for clinical interventions targeting oral cavity cancer.

Dynamic mechanical properties of different types of rocks under impact loading.

To study the mechanical properties of different types of rocks under impact loading, static mechanical parameter tests and split-Hopkinson pressure bar (SHPB) dynamic impact experiments were conducted on five typical rock specimens. The mechanical properties and failure modes of different rock specimens under the same static and dynamic loading were investigated. The differences between numerical simulation results and laboratory test results under different constitutive models in LS-DYNA were also compared and analyzed. The results show that with the increase of SHPB impact pressure (0.5-0.8 MPa), the stress peak values of granite, marble, and limestone also increase, while gypsum and reef limestone follow no particular trend. At the same time, both HJC and RHT constitutive models can simulate the laboratory impact test results of granite, marble, and limestone, however, the gypsum and reef limestone are not modelled by the HJC constitutive model, while the RHT constitutive model can describe the deformation-damage-failure process of rock specimens with different strengths. Therefore, the RHT model can better reflect the real deformation and failure of rocks.

The alleviating effect of Scutellaria amoena extract on the regulation of gut microbiota and its metabolites in NASH rats by inhibiting the NLRP3/ASC/caspase-1 axis.

Background: Scutellaria amoena (SA) is the root of S. amoena C.H. Wright of Labiatae, also known as Scutellaria southwestern. This is mainly distributed in Sichuan, Yunnan, and Guizhou in China. In southwest China, SA is used as an alternative method to genuine medicine for the treatment of allergy, diarrhea, inflammation, hepatitis, and bronchitis. Thus far, studies on the effects of SA on non-alcoholic steatohepatitis (NASH) are lacking. This paper investigated the effect of SA on the regulation of gut microbiota and its metabolites in NASH rats by inhibiting the NOD-like receptor 3 (NLRP3)/apoptosis-associated speck-like protein (ASC)/caspase-1 axis. Methods: A NASH rat model was induced by a high-fat diet (HFD) for 12 weeks, and rats were orally given different doses of SA extracts (150 and 300 mg/kg/d) for 6 weeks. Changes in histological parameters, body weight, organ indexes, cytokines, and biochemical parameters related to NLRP3 in NASH rats were checked. 16S rRNA gene sequencing and UPLC-MS/MS technology were used to analyze the changes in the gut microbiota composition and its metabolites in NASH rats. Results: SA significantly inhibited the HFD-induced increase in body weight, lipid levels, and inflammatory infiltration. SA notably inhibited the HFD-induced increase in the upper and lower factors of NLRP3, such as transforming growth factor (TGF)-ß, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-18, pro-IL-18, IL-1ß, pro-IL-1ß, NLRP3, ASC, and caspase-1. Additionally, mRNA expressions of caspase-1, NLRP3, and ASC were significantly downregulated after SA treatment. The results of the intestinal flora showed that SA could increase the diversity of flora and change its structure and composition in NASH rats by reducing Firmicutes/Bacteroidetes (F/B) ratio, Blautia (genus), Lachospiraceae (family), and Christensenellaceae R-7 group (genus), and increasing Muribaculaceae (family) and Bacteroides (genus). The metabolomics revealed that 24 metabolites were possibly the key metabolites for SA to regulate the metabolic balance of NASH rats, including chenodeoxycholic acid, xanthine, and 9-OxoODE. Nine metabolic pathways were identified, including primary bile acid biosynthesis, bile secretion, purine metabolism, and secondary bile acid biosynthesis. Conclusion: SA can regulate the intestinal microbial balance and metabolic disorder by inhibiting the NLRP3/ASC/caspase-1 axis to relieve NASH.

Oat milk analogue versus traditional milk: Comprehensive evaluation of scientific evidence for processing techniques and health effects.

Milk, enriched with high-quality protein, is a healthy and nutritious food that meets people's needs. However, consumers are turning their attention to plant-based milk due to several concerns, such as lactose intolerance, allergies and some diseases caused by milk; carbon emission from cattle farming; economical aspects; and low access to vitamins and minerals. Oat milk, which is produced from whole grain oats, is lactose free and rich in a variety of nutrients and phytochemicals. With the significant development of food processing methods and advancement in milk simulation products, the production of plant-based milk, such as cereal milk, has greatly progressed. This review described some features of oat milk analogue versus traditional milk and compared the properties, processing technologies, health effects, environmental friendliness, and consumer acceptance of these products. It is expected to provide a reference for evaluating development trends and helping consumers choose between oat milk and traditional milk.

Flexible circuit mechanisms for context-dependent song sequencing.

Sequenced behaviours, including locomotion, reaching and vocalization, are patterned differently in different contexts, enabling animals to adjust to their environments. How contextual information shapes neural activity to flexibly alter the patterning of actions is not fully understood. Previous work has indicated that this could be achieved via parallel motor circuits, with differing sensitivities to context1,2. Here we demonstrate that a single pathway operates in two regimes dependent on recent sensory history. We leverage the Drosophila song production system3 to investigate the role of several neuron types4-7 in song patterning near versus far from the female fly. Male flies sing 'simple' trains of only one mode far from the female fly but complex song sequences comprising alternations between modes when near her. We find that ventral nerve cord (VNC) circuits are shaped by mutual inhibition and rebound excitability8 between nodes driving the two song modes. Brief sensory input to a direct brain-to-VNC excitatory pathway drives simple song far from the female, whereas prolonged input enables complex song production via simultaneous recruitment of functional disinhibition of VNC circuitry. Thus, female proximity unlocks motor circuit dynamics in the correct context. We construct a compact circuit model to demonstrate that the identified mechanisms suffice to replicate natural song dynamics. These results highlight how canonical circuit motifs8,9 can be combined to enable circuit flexibility required for dynamic communication.

Graft onto approaches for nanocellulose-based advanced functional materials.

The resurgence of cellulose as nano-dimensional 'nanocellulose' has unlocked a sustainable bioeconomy for the development of advanced functional biomaterials. Bestowed with multifunctional attributes, such as renewability and abundance of its source, biodegradability, biocompatibility, superior mechanical, optical, and rheological properties, tunable self-assembly and surface chemistry, nanocellulose presents exclusive opportunities for a wide range of novel applications. However, to alleviate its intrinsic hydrophilicity-related constraints surface functionalization is inevitably needed to foster various targeted applications. The abundant surface hydroxyl groups on nanocellulose offer opportunities for grafting small molecules or macromolecular entities using either a 'graft onto' or 'graft from' approach, resulting in materials with distinctive functionalities. Most of the reviews published to date extensively discussed 'graft from' modification approaches, however 'graft onto' approaches are not well discussed. Hence, this review aims to provide a comprehensive summary of 'graft onto' approaches. Furthermore, insight into some of the recently emerging applications of this grafted nanocellulose including advanced nanocomposite formulation, stimuli-responsive materials, bioimaging, sensing, biomedicine, packaging, and wastewater treatment has also been reviewed.

Shaping characteristics of excavation contours in sequential controlled fracture blasting of rock-anchored beams in Shuangjiangkou underground powerhouse.

Influences of high in-situ stress generally need to be considered when excavating deep underground caverns. The dynamic fracture behaviors of rocks under blast loads were investigated by using the rock-anchored beam excavation in underground powerhouses of Shuangjiangkou Hydropower Station in Sichuan Province, China as the engineering background. To solve the problems of the poor blasting breakage effect of rocks and the difficulty in protecting surrounding rocks during excavation, mechanical properties of granite under static and dynamic loads were investigated and the sequential controlled fracture blasting (SCFB) method was adopted during in-situ tests. Based on the Riedel-Hiermaier-Thoma constitutive model and the strength criterion, software LS-DYNA was employed to simulate the dynamic propagation of blasting-induced cracks. The contour shaping effect obtained via numerical simulation is generally consistent with the test results. The results show that SCFB can to some extent control the direction of crack initiation and rock fracture behavior of the blasthole wall cracks and the spacing of successive bursting holes is about 10 times the diameter of the blastholes when the cracks between the blastholes are shaped the best effect. Moreover, the magnitude and direction of principal in-situ stress can both affect the propagation path and length of blasting-induced cracks. The results of the research on the excavation and construction of deeply buried underground caverns have a certain reference value.

Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.

The mammalian respiratory chain complexes I, III2, and IV (CI, CIII2, and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI-CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and the regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knockin mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in mice but raise questions about their alternate functions, such as those relating to the regulation of protein stability and prevention of age-associated protein aggregation.

Discovery of two ent-atisane diterpenoid lactones with AChE inhibitory activity from the roots of Euphorbia fischeriana.

Euphorlactone A (1), a rare rearranged ent-atisane norditerpenoid with an undescribed 3-nor-2,4-olide-ent-atisane scaffold, and euphorlactone B (2), a new ent-atisane diterpenoid with an unprecedented seven-membered lactone ring C, were isolated from the roots of Euphorbia fischeriana. Their planar structures with absolute configurations were extensively elucidated by analysis of 1D and 2D NMR data, electronic circular dichroism (ECD) calculations, Rh2(OCOCF3)4-induced ECD curves, and single-crystal X-ray diffraction. Euphorlactone A (ELA) showed a remarkable AChE (acetylcholinesterase) inhibitory activity (IC50 = 2.13 ± 0.06 µM and Ki = 0.058 µM), which was five times stronger than that of the positive control (rivastigmine, IC50 = 12.46 ± 0.82 µM), and further in vitro enzyme inhibition kinetic analysis and molecular docking studies were performed to investigate the AChE inhibitory mechanism.