Electroregulation of graphene-nanofluid interactions to coenhance water permeation and ion rejection in vertical graphene membranes.

Graphene oxide (GO) membranes with nanoconfined interlayer channels theoretically enable anomalous nanofluid transport for ultrahigh filtration performance. However, it is still a significant challenge for current GO laminar membranes to achieve ultrafast water permeation and high ion rejection simultaneously, because of the contradictory effect that exists between the water-membrane hydrogen-bond interaction and the ion-membrane electrostatic interaction. Here, we report a vertically aligned reduced GO (VARGO) membrane and propose an electropolarization strategy for regulating the interfacial hydrogen-bond and electrostatic interactions to concurrently enhance water permeation and ion rejection. The membrane with an electro-assistance of 2.5 V exhibited an ultrahigh water permeance of 684.9 L m-2 h-1 bar-1, which is 1-2 orders of magnitude higher than those of reported GO-based laminar membranes. Meanwhile, the rejection rate of the membrane for NaCl was as high as 88.7%, outperforming most reported graphene-based membranes (typically 10 to 50%). Molecular dynamics simulations and density-function theory calculations revealed that the electropolarized VARGO nanochannels induced the well-ordered arrangement of nanoconfined water molecules, increasing the water transport efficiency, and thereby resulting in improved water permeation. Moreover, the electropolarization effect enhanced the surface electron density of the VARGO nanochannels and reinforced the interfacial attractive interactions between the cations in water and the oxygen groups and π-electrons on the VARGO surface, strengthening the ion-partitioning and Donnan effect for the electrostatic exclusion of ions. This finding offers an electroregulation strategy for membranes to achieve both high water permeability and high ion rejection performance.

SIRT5 Regulates Ferroptosis through the Nrf2/HO-1 Signaling Axis to Participate in Ischemia-Reperfusion Injury in Ischemic Stroke.

This work aimed to study the role and mechanism of SIRT5 regulation of ferroptosis in cerebral ischemia-reperfusion (I/R) injury. A model of middle cerebral artery occlusion in rats was prepared using the method of thread occlusion. The ferroptosis inhibitor was injected intraperitoneally while the SIRT5 interfering lentivirus were injected into the brain, and neurological disorders were scored in the rats. TTC staining was used to detect infarct volume, and immunohistochemistry was used to detect the expression of SIRT5 in tissues. Rat hippocampal neuronal cells H19-7 were transduced with SIRT5 interfering lentivirus and ferroptosis was induced using erastin. The CCK8 detection kit was used to detect cell viability. Commercial kits were used to detect levels of iron ions, ROS, MDA, SOD, and inflammatory factor (TNF-α and IL-6) in brain tissue or cell supernatant. Western blot was used to detect the expression changes of ferroptosis related proteins GPX4, Nrf2, and HO-1 in tissues or cells. Compared with the sham group, the MCAO model group showed higher levels of neurological impairment score, increased cerebral infarction volume, iron ions, inflammatory factors, and oxidative stress levels in rats. Compared with the MCAO group, the MCAO + fer-1 group exhibited lower levels of neurological impairment scores, cerebral infarction volume, decreased iron ions, inflammatory factors, and oxidative stress levels in rats. Meanwhile, compared with the MCAO + DMSO/LV-shRNA group, the MCAO + fer-1/LV-shSIRT5 group showed a significant decrease in neurological impairment scores, cerebral infarction volume, iron ions, inflammatory factors, and oxidative stress levels in rats. In vitro experiments have found that LV-shSIRT5 can prevent erastin-induced cell ferroptosis. In summary, SIRT5 regulates ferroptosis through the Nrf2/HO-1 signaling axis to participate in ischemia-reperfusion injury in ischemic stroke.

Interoceptive awareness mediated the effects of a 15-minute diaphragmatic breathing on empathy for pain: A randomized controlled trial.

Although empathy for pain plays an important role in positive interpersonal relationships and encourages engagement in prosocial behavior, it remains largely unknown whether empathy for pain could be effectively altered by psychophysiological techniques. This study aimed to investigate the impact of a single session of diaphragmatic breathing practice on empathy for pain and examine the potential mechanism involving interoceptive awareness. A total of 66 healthy participants were randomly assigned to the intervention group or the control group. The intervention group received a 15-minute diaphragmatic breathing (DB) practice with real-time biofeedback, while the control group was to gaze at a black screen at rest and not engaged in any other activities. Before and after the invention, all participants were instructed to evaluate the intensity and unpleasantness of empathy for pain while watching different pictures with pain or non-pain conditions. The Multidimensional Assessment of Interoceptive Awareness (MAIA) was then administered to measure interoceptive awareness. The results indicated a significant interaction between group and time with regard to empathy for pain and MAIA. The DB group showed a statistically significant decrease in both pain intensity and unpleasantness during the pain picture condition, as well as a noteworthy increase in MAIA scores. The control group did not demonstrate any substantial changes. More importantly, the regulation of attention, a dimension of MAIA, had a significant mediating effect on the impact of diaphragmatic breathing on reported unpleasantness. Diaphragmatic breathing could serve as a simple, convenient, and practical strategy to optimize human empathy for pain that warrants further investigation, which has important implications not only for individuals with impaired empathy for pain but also for the improvement of interoceptive awareness.

Metagenomic Next-Generation Sequencing as an Effective Diagnostic Tool for Talaromycosis in HIV-Negative Patients.

The diagnosis of Talaromyces marneffei infection in HIV-negative patients remains challenging. There is an urgent need for rapid and convenient methods to diagnose this complicated disease. The aim of this study was to evaluate the diagnostic efficiency of metagenomic next-generation sequencing (mNGS) for talaromycosis in non-HIV-infected patients by comparing mNGS with traditional microbial culture. In total, 66 samples from 57 patients were analyzed via both mNGS and microbial culture. The ROC curve showed a sensitivity for mNGS of 97.22%, which was greater than that of microbial culture (61.11%). Samples from the respiratory tract, infectious skin lesions, and lymph nodes are recommended as routine samples for talaromycosis detection via mNGS. Furthermore, mNGS significantly reduced the diagnostic time compared to microbial culture. Overall, our study demonstrated that mNGS is a promising tool for rapid and accurate pathogenic detection in HIV-negative patients with talaromycosis.

Optimising breathlessness triggered services for older people with advanced diseases: a multicentre economic study (OPTBreathe).

BACKGROUND: In advanced disease, breathlessness becomes severe, increasing health services use. Breathlessness triggered services demonstrate effectiveness in trials and meta-analyses but lack health economic assessment. METHODS: Our economic study included a discrete choice experiment (DCE), followed by a cost-effectiveness analysis modelling. The DCE comprised face-to-face interviews with older patients with chronic breathlessness and their carers across nine UK centres. Conditional logistic regression analysis of DCE data determined the preferences (or not, indicated by negative ß coefficients) for service attributes. Economic modelling estimated the costs and quality-adjusted life years (QALYs) over 5 years. FINDINGS: The DCE recruited 190 patients and 68 carers. Offering breathlessness services in person from general practitioner (GP) surgeries was not preferred (ß=-0.30, 95% CI -0.40 to -0.21); hospital outpatient clinics (0.16, 0.06 to 0.25) or via home visits (0.15, 0.06 to 0.24) were preferred. Inperson services with comprehensive treatment review (0.15, 0.07 to 0.21) and holistic support (0.19, 0.07 to 0.31) were preferred to those without. Cost-effectiveness analysis found the most and the least preferred models of breathlessness services were cost-effective compared with usual care. The most preferred service had £5719 lower costs (95% CI -6043 to 5395), with 0.004 (95% CI -0.003 to 0.011) QALY benefits per patient. Uptake was higher when attributes were tailored to individual preferences (86% vs 40%). CONCLUSION: Breathlessness services are cost-effective compared with usual care for health and social care, giving cost savings and better quality of life. Uptake of breathlessness services is higher when service attributes are individually tailored.

Metasurface absorber with ultra-thin thickness designed for a terahertz focal plane array detector.

Terahertz (THz) refers to electromagnetic waves with frequency from 0.1 to 10 THz, which lies between millimeter waves and infrared light. This paper proposes an ultra-thin metasurface absorber which is perfectly suited to be the signal coupling part of terahertz focal plane array (FPA) detector. The absorptance of the proposed metasurface is higher than 80% from 4.46 to 5.76 THz (25.4%) while the thickness is merely 1.12 µm (0.018 λ). Since the metasurface absorber will be applied to terahertz FPA detector which requires planar array formation, it is divided into meta-atoms. Each meta-atom consists of the same unit cell layout, and air gaps are introduced between adjacent meta-atoms to enhance the thermal isolation, which is crucial for FPA detector to obtain desired imaging results. Due to the symmetrical layout of meta-atoms, absorptance keeps stable for different polarized waves, moreover, good absorptance could also be achieved for incidence angles range of ± 30 °. Spectral measurements show good agreement with the simulation. As a result, features of ultra-thin thickness, polarization insensitivity, and high absorptance make the proposed metasurface absorber well suited to highly efficient coupling of terahertz signals in FPA detector.

Rh(III)-Catalyzed Dual C-H Functionalization and C-O/C-N Annulations of Monoamide Fumarates.

Pyrano[4,3-c]pyridine-diones, which are the key skeleton of bioactive compounds and functional materials, are usually prepared via a multistep synthesis using expensive substrates. This work demonstrates that Rh(III)-catalyzed dual C(sp2)-H functionalization and C-O/C-N annulation of monoamide fumarates can produce pyrano[4,3-c]pyridine-1,5(6H)-diones in high yield (up to 82%) in a single step. The substrates of monoamide fumarates and acetylenes are structurally simple, readily available, and inexpensive. The additive AgSbF6 effectively raised the yields. On account of easier dehydrogenation of OH in the COOH group than NH in the amide group in the reaction, the process first undergoes C-O annulation and then is succeeded by C-N annulation.

Effects of Tai Chi or Conventional Exercise on Central Obesity in Middle-Aged and Older Adults : A Three-Group Randomized Controlled Trial.

BACKGROUND: Central obesity is a major manifestation of metabolic syndrome, which is a common health problem in middle-aged and older adults. OBJECTIVE: To examine the therapeutic efficacy of tai chi for management of central obesity. DESIGN: Randomized, controlled, assessor-blinded trial. (ClinicalTrials.gov: NCT03107741). SETTING: A single research site in Hong Kong between 27 February 2016 and 28 February 2019. PARTICIPANTS: Adults aged 50 years or older with central obesity. INTERVENTION: 543 participants were randomly assigned in a 1:1:1 ratio to a control group with no exercise intervention (n = 181), conventional exercise consisting of aerobic exercise and strength training (EX group) (n = 181), and a tai chi group (TC group) (n = 181). Interventions lasted 12 weeks. MEASUREMENTS: Outcomes were assessed at baseline, week 12, and week 38. The primary outcome was waist circumference (WC). Secondary outcomes were body weight; body mass index; high-density lipoprotein cholesterol (HDL-C), triglyceride, and fasting plasma glucose levels; blood pressure; and incidence of remission of central obesity. RESULTS: The adjusted mean difference in WC from baseline to week 12 in the control group was 0.8 cm (95% CI, -4.1 to 5.7 cm). Both intervention groups showed reductions in WC relative to control (adjusted mean differences: TC group vs. control, -1.8 cm [CI, -2.3 to -1.4 cm]; P < 0.001; EX group vs. control: -1.3 cm [CI, -1.8 to -0.9 cm]; P < 0.001); both intervention groups also showed reductions in body weight (P < 0.05) and attenuation of the decrease in HDL-C level relative to the control group. The favorable changes in WC and body weight were maintained in both the TC and EX groups, whereas the beneficial effect on HDL-C was only maintained in the TC group at week 38. LIMITATIONS: High attrition and no dietary intervention. CONCLUSION: Tai chi is an effective approach to reduce WC in adults with central obesity aged 50 years or older. PRIMARY FUNDING SOURCE: Health and Medical Research Fund.

Suppressing Non-Radiative Relaxation through Single-Atom Metal Modification for Enhanced Fluorescence Efficiency in Molybdenum Disulfide Quantum Dots.

To enhance the fluorescence efficiency of semiconductor nanocrystal quantum dots (QDs), strategies via enhancing photo-absorption and eliminating non-radiative relaxation have been proposed. In this study, we demonstrate that fluorescence efficiency of molybdenum disulfide quantum dots (MoS2 QDs) can be enhanced by single-atom metal (Au, Ag, Pt, Cu) modification. Four-fold enhancement of the fluorescence emission of MoS2 QDs is observed with single-atom Au modification. The underlying mechanism is ascribed to the passivation of non-radiative surface states owing to the new defect energy level of Au in the forbidden band that can trap excess electrons in n-type MoS2 , increasing the recombination probability of conduction band electrons with valence band holes of MoS2 . Our results open an avenue for enhancing the fluorescence efficiency of QDs via the modification of atomically dispersed metals, and extend their scopes and potentials in a fundamental way for economic efficiency and stability of single-atom metals.

Structural abnormalities of cingulate cortex in patients with first-episode drug-naïve schizophrenia comorbid with depressive symptoms.

Depressive symptoms are common in patients with first-episode psychosis. However, the neural mechanisms underlying the comorbid depression in schizophrenia are still unknown. The main purpose of this study was to characterize the structural abnormalities of first-episodes drug-naïve (FEDN) schizophrenia comorbid with depression by utilizing both volume-based and surface-based morphometric measurements. Forty-two patients with FEDN schizophrenia and 29 healthy controls were recruited. The 24-item Hamilton Depression Rating Scale (HAMD-24) was administrated to divide all patients into depressive patients (DP) and non-depressive patients (NDP). Compared with NDP, DP had a significantly larger volume and surface area in the left isthmus cingulate cortex and also had a greater volume in the left posterior cingulate cortex. Correlation analysis showed that HAMD total score was positively correlated with the surface area of the left isthmus cingulate and gray matter volume of the left isthmus cingulate cortex. In addition, gray matter volume of the left isthmus cingulate was also correlated with the PANSS general psychopathology or total score. The findings suggest that prominent structural abnormalities of gray matter are mainly concentrated on the cingulate cortex in FEDN schizophrenia patients comorbid with depression, which may contribute to depressive symptoms and psychopathological symptoms.

Solvothermal Synthesis of Novel Magnetic Nickel Based Iron Oxide Nanocomposites for Selective Capture of Global- and Mono-Phosphopeptides.

A facile solvothermal method was developed for synthesis of magnetic nickel-based iron oxide nanocomposites (MNFOs) with different ratios of Ni2+ to Fe3+ for different reaction time. Two factors including dosage of Ni source and length of reaction were investigated for influence on the morphology and composition of MNFOs, as well as their distinct selectivity for different phosphopeptides. After thorough characterization, the possible formation mechanism of MNFOs was proposed. Very interestingly, MNFOs with Ni2+/Fe3+ ratios of 4:5 prepared for 8 h (MNFO-S) and for 24 h (MNFO-L) can selectively capture global- and monophosphopeptides at the fmol level with excellent enrichment performance. These two affinity probes have been exploited to isolate and enrich the phosphopeptides from human normal hepatic cells HL 7702 after exposure to atmospheric fine particulates (PM2.1), which revealed that the protein phosphorylation level was increased significantly in cells after stimulation by fine particulate matters. The findings could provide a new insight for the nickel-based affinity protocol to analyze the mutation of phosphopeptides during cellular signaling pathways in response to exogenous environment stimulation. Consequently, this present work proposed a promising strategy to isolate monophosphopeptides from global phosphopeptides for phosphoproteome research.

Brain Functional Specialization Is Enhanced Among Tai Chi Chuan Practitioners.

OBJECTIVE: To investigate the effect of long-term Tai Chi Chuan (TCC) practice on practitioners' brain functional specialization compare with the TCC novices. DESIGN: A cross-sectional study. SETTING: A psychology Institute. PARTICIPANTS: TCC practitioners (N=22) (52.4±6.8y; 7 men; educated years: 12.18±3.03y) and 18 healthy adults (54.8±6.8y; 8 men; education years: 11.78±2.90y) matched by age, sex, and education were enrolled. MAIN OUTCOME MEASURES: Participants underwent functional magnetic resonance imaging scanning and cognitive test to measure the differences in functional specialization and cognitive function. Functional specialization was evaluated by voxel-mirrored homotopic connectivity (VMHC) method. RESULTS: Lower middle frontal gyrus VMHC in TCC practitioners compared to controls. For TCC practitioners, the longer they practice, the lower their VMHC in precentral and precuneus. TCC practitioners showed better cognition performance. CONCLUSIONS: Changed VMHC indicated that TCC practice could enhance functional specialization in the middle frontal cortex of practitioners, which may be associated with higher-order cognitive ability.

Hypothesized Mechanisms Through Which Exercise May Attenuate Memory Interference.

In this paper we introduce a mechanistic model through which exercise may enhance episodic memory, specifically via attenuating proactive and retroactive memory interference. We discuss the various types of memory, different stages of memory function, review the mechanisms behind forgetting, and the mechanistic role of exercise in facilitating pattern separation (to attenuate memory interference).

[Regulation mechanism of plant hormones on secondary metabolites].

Plant hormones participate in the regulation of plant growth, and have significant physiological activities. Secondary metabolites are important raw materials of pharmaceutical and chemical industry, which have attracted extensive attention due to their economic and medicinal value. With the development of biotechnology, plant hormones have played an important role in regulating the synthesis of secondary metabolites. This paper mainly introduces the synthesis pathway, signal transduction mechanism and regulation of secondary metabolites of auxin, cytokinin, gibberellin, abscisic acid, ethylene, brassinosteroids and methyl jasmonate in plants. Researching the accumulation of secondary metabolites from a micro aspect is helpful to better understand the formation of plant hormones and their development in the process of secondary metabolism. In additionally, it provides a reference for the rational utilization of plant hormones and the scientific and efficient improvement of the production of secondary metabolites in plants.

[Quality-based soil fertility quality assessment of American ginseng main production areas in Shandong province].

The soil fertility quality is one of the most critical indicators of soil productivity. It directly affects the yield, quality and agricultural efficiency of Chinese medicinal materials. In order to establish the American ginseng planting soil fertility quality evaluation method based on the effective components of American ginseng, Wendeng district, Weihai city, Shandong province, the main producing area of American ginseng, was cited as a case for the study. Twenty-two 4-years American ginseng sampling sites are located at 7 towns. The samples of soil and plant root were collected in the autumn of 2017-2019. The saponin contents of American ginseng and 11 soil chemical properties were measured. The minimum data set(MDS) for assessment of the quality of soil fertility quality was established by correlation analysis and principal component analysis. The evaluation indexes were normalized by membership function. Soil quality index(SQI) that indicates soil comprehensive fertility quality level was calculated according to the critical value of membership function and weight value of each soil index in MDS. The results showed that the total saponin(Rg_1+Re+Rb_1) content of American ginseng in samples ranged from 1.76% to 7.94%. The yield of 8 plots in 2019 ranged from 3 818.7 kg·hm~(-2) to 8 996.4 kg·hm~(-2). MDS includes organic matter, alkaline nitrogen, exchangeable calcium, exchangeable magnesium, effective iron, effective copper, and effective zinc. Based on the mean of 4.825% of total saponin, threshold value of SQI for the region was determined to be 0.15, and 86.36% of soil samples in the county were above the threshold value. The methods and parameters are applicable to selection of high quality American ginseng planting sites and guiding rational fertilization. It also provides a reference for the evaluation of soil fertility quality of other medicinal plants.

Tumor suppressor KIF1Bß regulates mitochondrial apoptosis in collaboration with YME1L1.

KIF1Bß, a member of the kinesin superfamily of motor proteins, is a haploinsufficient tumor suppressor mapped to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors, including neuroblastoma and pheochromocytoma. While KIF1Bß acts downstream of the nerve growth factor (NGF) pathway to induce apoptosis, further molecular functions of this gene product have largely been unexplored. In this study, we report that KIF1Bß destabilizes the morphological structure of mitochondria, which is critical for cell survival and apoptosis. We identified YME1L1, a mitochondrial metalloprotease responsible for the cleavage of the mitochondrial GTPase OPA1, as a physical interacting partner of KIF1Bß. KIF1Bß interacted with YME1L1 through its death-inducing region, as initiated the protease activity of YME1L1 to cleave the long forms of OPA1, resulting in mitochondrial fragmentation. Overexpression of YME1L1 promoted apoptosis, while knockdown of YME1L1 promoted cell growth. High YME1L1 expression was significantly associated with a better prognosis in neuroblastoma. Furthermore, in NGF-deprived PC12 cells, KIF1Bß and YME1L1 were upregulated, accompanied by mitochondrial fragmentation and apoptotic cell death. Small interfering RNA-mediated knockdown of either protein alone, however, remarkably inhibited the NGF depletion-induced apoptosis. Our findings indicate that tumor suppressor KIF1Bß plays an important role in intrinsic mitochondria-mediated apoptosis through the regulation of structural and functional dynamics of mitochondria in collaboration with YME1L1. Dysfunction of the KIF1Bß/YME1L1/OPA1 mechanism may be involved in malignant biological features of neural crest-derived tumors as well as the initiation and progression of neurodegenerative diseases.

Improving psychological outcomes for orphans living with HIV in Tanzania through a novel intervention to improve resilience: findings from a pilot RCT.

Parental death and HIV are associated with poor mental health for orphans in sub-Saharan Africa. This study aimed to evaluate a theory-based intervention for orphaned children on treatment in Tanzania, in terms of feasibility, acceptability and preliminary outcomes. A pilot RCT with nested focus group (FGD) allocated 48 children to usual care or residential "Memory Work Therapy". Children completed outcome measures at T0 (baseline), T1 (2 weeks following intervention) and T2 (9 weeks from T0). Forty percent of eligible children assented. T1 intervention effects were found on all total measures: Brief Symptom Inventory d = 0.99, p < .001; Rosenberg Self Esteem Scale d = 0.65, p = .001; Strengths and Difficulties Questionnaire d = 0.64, p = .002; Self-efficacy questionnaire for children both "social" and "emotional" subscales, d = 0.54, p = .008 and d = 0.63, p = .002, respectively. At T2, significant effects remained for all measures and SES effect increased from medium to large (T1 = 0.65, T2 = 1.33). FGD data found children valued a calm environment that met their basic needs, enabling them to reflect, highlight support resources, and strengthen ability to recognize personal skills. The intervention has strong feasibility and acceptability, with no attrition or missing data. Memory Work Therapy has high potential effect size and should be tested in a fully powered trial. Clinical trials.gov NCT02180750.

Topological Characterization of Carbon Graphite and Crystal Cubic Carbon Structures.

Graph theory is used for modeling, designing, analysis and understanding chemical structures or chemical networks and their properties. The molecular graph is a graph consisting of atoms called vertices and the chemical bond between atoms called edges. In this article, we study the chemical graphs of carbon graphite and crystal structure of cubic carbon. Moreover, we compute and give closed formulas of degree based additive topological indices, namely hyper-Zagreb index, first multiple and second multiple Zagreb indices, and first and second Zagreb polynomials.

Effects of dietary addition of heat-killed Mycobacterium phlei on growth performance, immune status and anti-oxidative capacity in early weaned piglets.

The contradiction between high susceptibility of early weaned piglets to enteric pathogens and rigid restriction of antibiotic use in the diet is still prominent in the livestock production industry. To address this issue, the study was designed to replace dietary antibiotics partly or completely by an immunostimulant, namely heat-killed Mycobacterium phlei (M. phlei). Piglets (n = 192) were randomly assigned to one of the four groups: (1) basal diet (Group A), (2) basal diet + a mixture of antibiotics (80 mg/kg diet, Group B), (3) basal diet + a mixture of antibiotics (same as in Group B, but 40 mg/kg diet) + heat-killed M. phlei (1.5 g/kg diet) (Group C) and (4) basal diet + heat-killed M. phlei (3 g/kg diet) (Group D). All piglets received the respective diets from days 21 to 51 of age and were weaned at the age of 28 d. Compared with the Control (Group A), in all other groups the average daily gain, average daily feed intake, small intestinal villus height:crypt depth ratio and protein levels of occludin and ZO-1 in the jejunal mucosa were increased. A decreased incidence of diarrhoea in conjunction with an increased sIgA concentration in the intestinal mucosa and serum IL-12 and IFN-γ concentrations was found in groups supplemented with heat-killed M. phlei (Groups C and D), but not in Group B. Groups C and D also showed decreased IL-2 concentrations in the intestinal mucosa with lower TLR4 and phosphor-IκB protein levels. The antioxidant capacity was reinforced in Groups C and D, as evidenced by the reduction in malondialdehyde and enhanced activities of antioxidant enzymes in serum. These data indicate that heat-killed M. phlei is a promising alternative to antibiotic use for early weaned piglets via induction of protective immune responses.

Designer aminoglycosides that selectively inhibit cytoplasmic rather than mitochondrial ribosomes show decreased ototoxicity: a strategy for the treatment of genetic diseases.

There is compelling evidence that aminoglycoside (AG) antibiotics can induce the mammalian ribosome to suppress disease-causing nonsense mutations and partially restore the expression of functional proteins. However, prolonged AG treatment can cause detrimental side effects in patients, including most prominently, ototoxicity. Recent mechanistic discussions have considered the relative contributions of mitochondrial and cytoplasmic protein synthesis inhibition to AG-induced ototoxicity. We show that AGs inhibit mitochondrial protein synthesis in mammalian cells and perturb cell respiration, leading to a time- and dose-dependent increase in superoxide overproduction and accumulation of free ferrous iron in mitochondria caused by oxidative damage of mitochondrial aconitase, ultimately leading to cell apoptosis via the Fenton reaction. These deleterious effects increase with the increased potency of AG to inhibit the mitochondrial rather than cytoplasmic protein synthesis, which in turn correlates with their ototoxic potential in both murine cochlear explants and the guinea pig in vivo. The deleterious effects of AGs were alleviated in synthetic derivatives specially designed for the treatment of genetic diseases caused by nonsense mutations and possessing low affinity toward mitochondrial ribosomes. This work highlights the benefit of a mechanism-based drug redesign strategy that can maximize the translational value of "readthrough therapy" while mitigating drug-induced side effects. This approach holds promise for patients suffering from genetic diseases caused by nonsense mutations.