Temporally Decoupled Ammonia Splitting by a Zn-NH3 Battery with an Ammonia Oxidation/Hydrogen Evolution Bifunctional Electrocatalyst as a Cathode.

Ammonia splitting to hydrogen is a decisive route for hydrogen economy but is seriously limited by the complex device and low efficiency. Here, we design and propose a new rechargeable Zn-NH3 battery based on temporally decoupled ammonia splitting to achieve efficient NH3-to-H2 conversion. In this system, ammonia is oxidized into nitrogen during cathodic charging (2NH3 + 6OH- → N2 + 6H2O + 6e-) with external electrical energy conversion and storage, while during cathodic discharging, water is reduced to hydrogen (2H2O + 2e- → H2 + 2OH-) with electrical energy generation. In this loop, continuous and efficient H2 production without separation and purification is achieved. With the help of the ammonia oxidation reaction (AOR) and hydrogen evolution reaction (HER) bifunctional catalyst of Mo2C/NiCu@C, a rechargeable Zn-NH3 battery is realized that exhibits a high NH3-to-H2 FE of 91.6% with outstanding durability for 900 cycles (300 h) at 20 mA/cm2, enabling efficient and continuous NH3-to-H2 conversion.

Differences in acoustic parameters of hammering sounds between successful and unsuccessful initial cementless cup press-fit fixation in total hip arthroplasty.

Aims: It is important to analyze objectively the hammering sound in cup press-fit technique in total hip arthroplasty (THA) in order to better understand the change of the sound during impaction. We hypothesized that a specific characteristic would present in a hammering sound with successful fixation. We designed the study to quantitatively investigate the acoustic characteristics during cementless cup impaction in THA. Methods: In 52 THAs performed between November 2018 and April 2022, the acoustic parameters of the hammering sound of 224 impacts of successful press-fit fixation, and 55 impacts of unsuccessful press-fit fixation, were analyzed. The successful fixation was defined if the following two criteria were met: 1) intraoperatively, the stability of the cup was retained after manual application of the torque test; and 2) at one month postoperatively, the cup showed no translation on radiograph. Each hammering sound was converted to sound pressures in 24 frequency bands by fast Fourier transform analysis. Basic patient characteristics were assessed as potential contributors to the hammering sound. Results: The median sound pressure (SP) of successful fixation at 0.5 to 1.0 kHz was higher than that of unsuccessful fixation (0.0694 (interquartile range (IQR) 0.04721 to 0.09576) vs 0.05425 (IQR 0.03047 to 0.06803), p < 0.001). The median SP of successful fixation at 3.5 to 4.0 kHz and 4.0 to 4.5 kHz was lower than that of unsuccessful fixation (0.0812 (IQR 0.05631 to 0.01161) vs 0.1233 (IQR 0.0730 to 0.1449), p < 0.001; and 0.0891 (IQR 0.0526 to 0.0891) vs 0.0885 (IQR 0.0716 to 0.1048); p < 0.001, respectively). There was a statistically significant positive relationship between body weight and SP at 0.5 to 1.0 kHz (p < 0.001). Multivariate analyses indicated that the SP at 0.5 to 1.0 kHz and 3.5 to 4.0 kHz was independently associated with the successful fixation. Conclusion: The frequency bands of 0.5 to 1.0 and 3.5 to 4.0 kHz were the key to distinguish the sound characteristics between successful and unsuccessful press-fit cup fixation.

Effects of water fluoridation on early embryonic development of zebrafish.

Fluoride has strong electronegativity and exposes diversely in nature. Water fluoridation is the most pervasive form of occurrence, representing a significant threat to human health. In this study, we investigate the morphometric and physiological alterations triggered by fluoride stimulation during the embryogenesis of zebrafish and reveal its putative effects of stage- and/or dose-dependent. Fluoride exhibits potent biological activity and can be extensively absorbed by the yolk sac, exerting significant effects on the development of multiple organs. This is primarily manifested as restricted nutrient utilization and elevated levels of lipid peroxidation, further leading to the accumulation of superoxide in the yolk sac, liver, and intestines. Moreover, pericardial edema exerts pressure on the brain and eye development, resulting in spinal curvature and reduced body length. Besides, acute fluoride exposure with varying concentrations has led to diverse teratogenic outcomes. A low dose of water fluoridation tends to induce abnormal development of the embryonic yolk sac, while vascular malformation is widely observed in all fluoride-treated groups. The effect of fluoride exposure on blood circulation is universally present, even in zebrafish larvae that do not exhibit obvious deformities. Their swimming behavior is also affected by water fluoridation, resulting in reduced activity and delayed reactions. In conclusion, this study provides valuable insights into the monitoring of environmental quality related to water fluoridation and disease prevention.

Recent advances in the direct anterior approach to total hip arthroplasty: a surgeon's perspective.

INTRODUCTION: The direct anterior approach (DAA) has its origins in the first and oldest approach for hip replacement in the literature, but at the same time it would not be fanciful to suggest its increasing popularity as the latest approach for hip replacement procedures, especially among younger surgeons. However, in a geographical context, the DAA is not considered the major approach in most countries. Moreover, the term DAA encompasses numerous variations in terms of technique. AREAS COVERED: In this narrative review, we describe our recent experience of advances in the DAA in terms of improved techniques and devices, along with some of its disadvantages. Also, we express our perspective on its future application. EXPERT OPINIONS: The DAA is established as one of exemplary approaches to THA. The use of fluoroscopy, the traction table, and appropriate soft tissue management has become essential in the DAA for a safe and trouble-free procedure with adequate patient comfort. With the combination of recent technologies such as robotics, three-dimensional preoperative planning, and artificial intelligence (AI)-based surgeon assist systems, we can look forward to the DAA being performed more efficiently in the future.

Lipid accumulation product is a better predictor of metabolic syndrome in Chinese adolescents: a cross-sectional study.

Aim: Confirm and compare the degree of associations of non-traditional lipid profiles and metabolic syndrome (MetS) in Chinese adolescents, determine the lipid parameter with better predictive potential, and investigate their discriminatory power on MetS. Methods: Medical measurements, including anthropometric measurements and biochemical blood tests, were undergone among a total sample of 1112 adolescents (564 boys and 548 girls) aged from 13 to 18 years. Univariate and multivariate logistic regression analyses were applied for assessing the relationships between the levels of traditional/non-traditional lipid profiles and MetS. We performed Receiver Operating Characteristic (ROC) analyses to mensurate the effectiveness of lipid accumulation product (LAP) on the diagnosis of MetS. Meanwhile, areas under the ROC curve and the cut-off values were calculated for MetS and its components. Results: Univariate analysis showed that all our lipid profiles were closely associated with MetS (P< 0.05). LAP index showed the closest association with MetS than the other lipid profiles. Additionally, ROC analyses indicated that the LAP index showed sufficient capabilities to identify adolescents with MetS and its components. Conclusion: The LAP index is a simple and efficient tool to identify individuals with MetS in Chinese adolescents.

Chemical mitophagy modulators: Drug development strategies and novel regulatory mechanisms.

Maintaining mitochondrial homeostasis is a potential therapeutic strategy for various diseases, including neurodegenerative diseases, cardiovascular diseases, metabolic disorders, and cancer. Selective degradation of mitochondria by autophagy (mitophagy) is a fundamental mitochondrial quality control mechanism conserved from yeast to humans. Indeed, small-molecule modulators of mitophagy are valuable pharmaceutical tools that can be used to dissect complex biological processes and turn them into potential drugs. In the past few years, pharmacological regulation of mitophagy has shown promising therapeutic efficacy in various disease models. However, with the increasing number of chemical mitophagy modulator studies, frequent methodological flaws can be observed, leading some studies to draw unreliable or misleading conclusions. This review attempts (a) to summarize the molecular mechanisms of mitophagy; (b) to propose a Mitophagy Modulator Characterization System (MMCS); (c) to perform a comprehensive analysis of methods used to characterize mitophagy modulators, covering publications over the past 20 years; (d) to provide novel targets for pharmacological intervention of mitophagy. We believe this review will provide a panorama of current research on chemical mitophagy modulators and promote the development of safe and robust mitophagy modulators with therapeutic potential by introducing high methodological standards.

Nono deficiency impedes the proliferation and adhesion of H9c2 cardiomyocytes through Pi3k/Akt signaling pathway.

Congenital heart disease (CHD) is the most common type of birth defect and the main noninfectious cause of death during the neonatal stage. The non-POU domain containing, octamer-binding gene, NONO, performs a variety of roles involved in DNA repair, RNA synthesis, transcriptional and post-transcriptional regulation. Currently, hemizygous loss-of-function mutation of NONO have been described as the genetic origin of CHD. However, essential effects of NONO during cardiac development have not been fully elucidated. In this study, we aim to understand role of Nono in cardiomyocytes during development by utilizing the CRISPR/Cas9 gene editing system to deplete Nono in the rat cardiomyocytes H9c2. Functional comparison of H9c2 control and knockout cells showed that Nono deficiency suppressed cell proliferation and adhesion. Furthermore, Nono depletion significantly affected the mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis, resulting in H9c2 overall metabolic deficits. Mechanistically we demonstrated that the Nono knockout impeded the cardiomyocyte function by attenuating phosphatidyl inositol 3 kinase-serine/threonine kinase (Pi3k/Akt) signaling via the assay for transposase-accessible chromatin using sequencing in combination with RNA sequencing. From these results we propose a novel molecular mechanism of Nono to influence cardiomyocytes differentiation and proliferation during the development of embryonic heart. We conclude that NONO may represent an emerging possible biomarkers and targets for the diagnosis and treatment of human cardiac development defects.

Patients With Shorter Stature Exhibit Minimal Hammering Sound Changes During Cementless Stem Insertion in Total Hip Arthroplasty.

Background: Listening to the change in the hammering sound is 1 of the elements used to assess the cementless stem stability. This study aimed to quantitatively investigate the change in the acoustic characteristics between the early and late phases of cementless stem insertion in total hip arthroplasty and to identify which patient characteristics contribute to the change in the hammering sound. Methods: The acoustic parameters of the hammering sounds in the early and late phases of cementless taper-wedged stem insertion for 51 hips in 45 patients who underwent total hip arthroplasty (mean age = 68 years, height = 1.56 m, weight = 55.0 kg) were analyzed. Parameters including patient's basic characteristics, radiographical femoral morphology, and canal fill ratio were assessed as potential contributors to the change in the hammering sound. Results: The low-frequency bands (0.5-1.0 kHz and 1.0-1.5 kHz) showed the largest changes during stem insertion and were therefore considered key bands for the analysis of sound alterations. Multivariate linear regression analysis showed that height (ß = 8.312, P = .013) and proximal canal fill ratio (ß = -3.8568, P = .038) were independently associated with the sound alterations. The decision tree analysis identified height (≥1.66 m or <1.66 m) as the best single discriminator for the sound alteration. Conclusions: Patients with smaller stature showed the least change in the hammering sound during stem insertion. Understanding the acoustic characteristics of hammering sound alteration during cementless stem insertion may aid in the achievement of optimal stem insertion.

[QMEC-based Analysis of the Soil Microbial Functional Potentials across Different Tibetan Plateau Glacier Forelands].

Soil microorganisms dominate the biogeochemical cycles of elements in glacier forelands, which continue to expand due to the climate warming. We analyzed the soil microbial functional characteristics among three types of glacier forelands on the Tibetan Plateau: Yulong Glacier (Y), a temperate glacier; Tianshan Urumqi Glacier No.1 (T), a sub-continental glacier; and Laohugou Glacier No.12 (L), a continental glacier. Here, soil microbial functional genes were quantified using quantitative microbial element cycling technology (QMEC). We found that, in the three glacier forelands, the abundances of soil microbial functional genes related to hemicellulose degradation and reductive acetyl-CoA pathway were highest compared with other carbon-related functional genes. The main nitrogen cycling genes were involved in ammonification. The functional genes of the phosphorus cycle and sulfur cycle were related to organic phosphate mineralization and sulfur oxidation. Furthermore, the soils of the temperate glacier foreland with better hydrothermal conditions had the most complex microbial functional gene structure and the highest functional potentials, followed by those of the soils of continental glacier foreland with the driest environment. These significant differences in soil microbial functional genes among the three types of glacier forelands verified the impacts of geographic difference on microbial functional characteristics, as well as providing a basis for the study of soil microbial functions and biogeochemical cycles in glacier forelands.

Highly accurate acoustical prediction using support vector machine algorithm for post-operative subsidence after cementless total hip arthroplasty.

PURPOSE: Acoustic analysis has recently been applied to cementless total hip arthroplasty (THA). The aim of this study was to develop a machine learning algorithm to predict post-operative subsidence with high accuracy. METHODS: The acoustic parameters of the hammering sounds during a broaching procedure for 62 hips in 55 patients who underwent THAs with cementless taper-wedged stem were analysed. The patient's basic background such as age, sex, height, weight and body mass index, the femoral morphological parameters and the hammering sound characteristics of 24 features of normalised sound pressure (nSP) in 24 frequency ranges were applied to binary classification using a support vector machine using the following models with different features: model A, nSP only; model B, nSP + patients' basic background features; model C, nSP + patients' basic background features + femoral morphological parameters. RESULTS: In 62 hips with 310 hammering sounds, 12 hips (19.4%) showed ≥ 3 mm of post-operative subsidence; hence, 60 hammering sounds were set as positive examples and 250 hammering sounds were set as negative examples. The AUC was very high in all models. The accuracy (AUC/sensitivity/specificity/positive predictive value/negative predictive value/accuracy rate) of each model was as follows: model A, 0.963/0.656/0.996/0.980/0.925/0.934; model B, 0.9866/0.675/1.000/1.000/0.928/0.937 and model C, 0.998/0.750/1.000/1.000/0.950/0.957. CONCLUSION: In this study, we developed a high-accuracy machine learning algorithm for post-operative subsidence using acoustic parameters and additional pre-operative features. Our results represent a step toward the realisation of acoustic monitoring to avoid the complication in cementless THA.

Effects of bepridil on early cardiac development of zebrafish.

Bepridil is a commonly used medication for arrhythmia and heart failure. It primarily exerts hemodynamic effects by inhibiting Na+/K+ movement and regulating the Na+/Ca2+ exchange. In comparison to other Ca2+ inhibitors, bepridil has a long half-life and a complex pharmacology. Additionally, it is widely used in antiviral research and the treatment of various diseases. However, the toxicity of this compound and its other possible effects on embryonic development are unknown. In this study, we investigated the toxicity of bepridil on rat myocardial H9c2 cells. After treatment with bepridil, the cells became overloaded with Ca2+ and entered a state of cytoplasmic vacuolization and nuclear abnormality. Bepridil treatment resulted in several morphological abnormalities in zebrafish embryo models, including pericardium enlargement, yolk sac swelling, and growth stunting. The hemodynamic effects on fetal development resulted in abnormal cardiovascular circulation and myocardial weakness. After inhibiting the Ca2+ transmembrane, the liver of zebrafish larvae also displayed an ectopic and deficient spatial location. Additionally, the results of the RNA-seq analysis revealed the detailed gene expression profiles and metabolic responses to bepridil treatment in zebrafish embryonic development. Taken together, our study provides an important evaluation of antiarrhythmic agents for clinical use in prenatal heart patients.

The machine learning model based on trajectory analysis of ribonucleic acid test results predicts the necessity of quarantine in recurrently positive patients with SARS-CoV-2 infection.

Background: SARS-CoV-2 patients re-experiencing positive nucleic acid test results after recovery is a concerning phenomenon. Current pandemic prevention strategy demands the quarantine of all recurrently positive patients. This study provided evidence on whether quarantine is required in those patients, and predictive algorithms to detect subjects with infectious possibility. Methods: This observational study recruited recurrently positive patients who were admitted to our shelter hospital between May 12 and June 10, 2022. The demographic and epidemiologic data was collected, and nucleic acid tests were performed daily. virus isolation was done in randomly selected cases. The group-based trajectory model was developed based on the cycle threshold (Ct) value variations. Machine learning models were validated for prediction accuracy. Results: Among the 494 subjects, 72.04% were asymptomatic, and 23.08% had a Ct value under 30 at recurrence. Two trajectories were identified with either rapid (92.24%) or delayed (7.76%) recovery of Ct values. The latter had significantly higher incidence of comorbidities; lower Ct value at recurrence; more persistent cough; and more frequently reported close contacts infection compared with those recovered rapidly. However, negative virus isolation was reported in all selected samples. Our predictive model can efficiently discriminate those with delayed Ct value recovery and infectious potentials. Conclusion: Quarantine seems to be unnecessary for the majority of re-positive patients who may have low transmission risks. Our predictive algorithm can screen out the suspiciously infectious individuals for quarantine. These findings may assist the enaction of SARS-CoV-2 pandemic prevention strategies regarding recurrently positive patients in the future.

A retrospective study of Pupingqinghua prescription versus Lianhuaqingwen in Chinese participants infected with SARS-CoV-2 Omicron variants.

Background: Coronavirus disease (COVID-19) seriously endangers global public health. Pupingqinghua prescription (PPQH) is an herbal formula from traditional Chinese medicine used for treatment of SARS-CoV-2 infection. This study aims to evaluate the clinical efficacy and safety of PPQH in Chinese participants infected with the SARS-CoV-2 Omicron variant. Methods: A total of 873 SARS-CoV-2 (Omicron)-infected patients were included. Among them, the patients were divided into the PPQH group (653 cases) and LHQW group (220 cases) according to different medications. The effectiveness indicators (hematological indicators, Ct values of novel Coronavirus nucleic acid tests, and viral load-shedding time) and safety indicators (liver and kidney function and adverse events) were analyzed. Results: There was no significant difference in baseline characteristics between the PPQH group and the LHQW group, except the gender; After the treatment, the levels of IL-5, IL-6, IL-10, NK cells, and INF-α of the patients in the PPQH group showed a downward trend (p < 0.05); The viral load shedding time was 5.0 (5.0, 7.0) in the PPQH group and 5.0 (4.0, 7.0) in the LHQW group; both PPQH and LHQW can shorten the duration of symptoms of fever, cough, and sore throat. The re-positive rate of COVID-19 test was 1.5 % in the PPQH group and 2.3 % in the LHQW group. In terms of safety, the levels of γ-GTT decreased significantly (p < 0.01); gastrointestinal reaction was the primary adverse reaction, and the reaction rate was 4.7 % in the PPQH group and 9.5 % in the LHQW group. Conclusion: PPQH can shorten the length of hospital stay and improve clinical symptoms of patients with SARS-COV-2 (Omicron), and it also has a good safety profile.

[Effects of Nutrients on the Growth of Microcystis aeruginosa and Bacteria in the Phycosphere].

The "bacteria-algae" system plays an important role in water ecosystems. The effects of bacteria in phycospheres on the growth of Microcystis aeruginosa under in-situ nutrient stimulation were studied to explore the bacteria-algae interaction during a cyanobacteria bloom. The results showed that LB medium could inhibit the growth of M. aeruginosa, and the algicidal rate was 86.49%. Sodium acetate, glucose, and sodium citrate could promote M. aeruginosa, and the growth rate was more than 50%. The addition of nutrients in M. aeruginosa could have changed the biocoenosis in the phycosphere and increased the species richness by 16S rRNA gene sequencing, and the number of bacteria in the phycosphere increased dramatically in the LB medium and peptone groups. The physiological and biochemical responses showed that algae suffered serious lipid peroxidation, and superoxide dismutase (SOD) and catalase (CAT) activities first increased significantly and subsequently decreased under the oxidative stress of LB medium or peptone. Scanning electron microscopy (SEM) indicated that the surface of algae cells appeared wrinkled, invaded, and atrophied under LB medium stimulation, whereas bacteria in the phycosphere significantly increased. Furthermore, six strains of algicidal bacteria were isolated from the LB medium and peptone groups, and the algicidal rate of Bacillus sp. A1 was 97.55%, which confirmed that the phycosphere of M. aeruginosa included algicidal bacteria. Therefore, appropriate external nutrient stimulation can produce algicidal bacteria in situ to prevent cyanobacterial blooms.

Copy Number Analyses Identified a Novel Gene: APOBEC3A Related to Lipid Metabolism in the Pathogenesis of Preeclampsia.

Background: Preeclampsia is a heterogeneous and complex disease with its pathogenesis mechanism not fully elucidated. A certain subset of patients with preeclampsia exhibit disturbances in lipid metabolism before clinical symptoms. Moreover, there is a tendency for preeclampsia to run in families. Whether genetic factors play a role in abnormal lipid metabolism during the incidence of preeclampsia has not been well investigated. Methods: Preeclampsia patients (n = 110) and healthy age- and gravidity-matched pregnant women (n = 110) were enrolled in this study. Peripheral blood specimens were used for genomic analysis (n = 10/group) or laboratory validation (n = 100/group). We retrospectively obtained the baseline clinical characteristics of 68 preeclampsia patients and 107 controls in early pregnancy (12-14 gestational weeks). Correlation analyses between differential genes and baseline lipid profiles were performed to identify candidate genes. In vitro and in vivo gain-of-function models were constructed with lentivirus and adeno-associated virus systems, respectively, to investigate the role of candidate genes in regulating lipid metabolism and the development of preeclampsia. Results: We observed that preeclampsia patients exhibited significantly elevated plasma TC (P = 0.037) and TG (P < 0.001) levels and increased body mass index (P = 0.006) before the disease onset. Within the region of 27 differential copy number variations, six genes potentially connected with lipid metabolism were identified. The aberrant copies of APOBEC3A, APOBEC3A_B, BTNL3, and LMF1 between preeclampsia patients and controls were verified by quantitative polymerase chain reaction. Especially, APOBEC3A showed a significant positive correlation with TC (P < 0.001) and LDL (P = 0.048) in early pregnancy. Then, our in vitro data revealed that overexpression of APOBEC3A disrupted lipid metabolism in HepG2 cells and affected both cholesterol and fatty acid metabolisms. Finally, in vivo study in a hepatic-specific overexpressed APOBEC3A mouse model revealed abnormal parameters related to lipid metabolism. Pregnant mice of the same model at the end of pregnancy showed changes related to preeclampsia-like symptoms, such as increases in sFlt-1 levels and sFlt-1/PLGF ratios in the placenta and decreases in fetal weight. Conclusion: Our findings established a new link between genetics and lipid metabolism in the pathogenesis of preeclampsia and could contribute to a better understanding of the molecular mechanisms of preeclampsia.

Artificial intelligence for distinguishment of hammering sound in total hip arthroplasty.

Recent studies have focused on hammering sound analysis during insertion of the cementless stem to decrease complications in total hip arthroplasty. However, the nature of the hammering sound is complex to analyse and varies widely owing to numerous possible variables. Therefore, we performed a preliminary feasibility study that aimed to clarify the accuracy of a prediction model using a machine learning algorithm to identify the final rasping hammering sound recorded during surgery. The hammering sound data of 29 primary THA without complication were assessed. The following definitions were adopted. Undersized rasping: all undersized stem rasping before the rasping of the final stem size, Final size rasping: rasping of the final stem size, Positive example: hammering sound during final size rasping, Negative example A: hammering sound during minimum size stem rasping, Negative example B: hammering sound during all undersized rasping. Three datasets for binary classification were set. Finally, binary classification was analysed in six models for the three datasets. The median values of the ROC-AUC in models A-F among each dataset were dataset a: 0.79, 0.76, 0.83, 0.90, 0.91, and 0.90, dataset B: 0.61, 0.53, 0.67, 0.69, 0.71, and 0.72, dataset C: 0.60, 0.48, 0.57, 0.63, 0.67, and 0.63, respectively. Our study demonstrated that artificial intelligence using machine learning was able to distinguish the final rasping hammering sound from the previous hammering sound with a relatively high degree of accuracy. Future studies are warranted to establish a prediction model using hammering sound analysis with machine learning to prevent complications in THA.

A synergized machine learning plus cross-species wet-lab validation approach identifies neuronal mitophagy inducers inhibiting Alzheimer disease.

Failed recognition and clearance of damaged mitochondria contributes to memory loss as well as Aß and MAPT/Tau pathologies in Alzheimer disease (AD), for which there is an unmet therapeutic need. Restoring mitophagy to eliminate damaged mitochondria could abrogate metabolic dysfunction, neurodegeneration and may subsequently inhibit or slow down cognitive decline in AD models. We have developed a high-throughput machine-learning approach combined with a cross-species screening platform to discover novel mitophagy-inducing compounds from a natural product library and further experimentally validated the potential candidates. Two lead compounds, kaempferol and rhapontigenin, induce neuronal mitophagy and reduce Aß and MAPT/Tau pathologies in a PINK1-dependent manner in both C. elegans and mouse models of AD. Our combinational approach provides a fast, cost-effective, and highly accurate method for identification of potent mitophagy inducers to maintain brain health.

Enhancing autophagy maturation with CCZ1-MON1A complex alleviates neuropathology and memory defects in Alzheimer disease models.

Rationale: Impairment of autophagy maturation has been implicated in Alzheimer's disease (AD) pathogenesis. However, the mechanism for this impairment has not been elucidated, and whether enhancing autophagy maturation is a viable therapeutic strategy for AD has not been verified. Methods: We examined the autophagosome maturation process in AD cell and mouse models by immunoblotting. To further understand the changes in autophagy in AD brains, we analyzed the transcriptome by RNA-sequencing and measured the expression of RAB7, CCZ1 and MON1A. We performed brain stereotaxic injections of AAV into 3xTg AD mouse brain and WT mouse brain to over-express MON1A/CCZ1 or knockdown MON1A. For in vitro studies, we purified autophagosomes, and determined GTP-RAB7 level in autophagosome fractions by GST-R7BD affinity-isolation assay. Results: We report that the active form of RAB7 was selectively decreased in autophagosome fractions isolated from cells and tissues of AD models, and that this decrease was accompanied by impaired activity of its guanine nucleotide exchange factor (GFE) CCZ1-MON1A. Overexpressing CCZ1-MON1A increased the active form of RAB7, enhanced autophagosome maturation, and promoted degradation of APP-CTFs, Aß and P-tau in an autophagy-dependent manner in cells and a mouse AD model. Conclusions: Our data reveals that CCZ1-MON1A-RAB7 complex dysfunction is a potential mechanism for autophagosome maturation defects in AD, and advances the possibility that enhancing autophagosome maturation is a novel therapeutic strategy against AD.

Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow.

A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer's disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-ß and tau pathologies, and improved the animals' memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational-experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.