Dysfunction of STING Autophagy Degradation in Senescent Nucleus Pulposus Cells Accelerates Intervertebral Disc Degeneration.

The pathogenesis of Intervertebral Disc Degeneration (IDD) is complex and multifactorial, with cellular senescence of nucleus pulposus (NP) cells and inflammation playing major roles in the progression of IDD. The stimulator of interferon genes (STING) axis is a key mediator of inflammation during infection, cellular stress, and tissue damage. Here, we present a progressive increase in STING in senescent NP cells with the degradation disorder. The STING degradation function in normal NP cells can prevent IDD. However, the dysfunction of STING degradation through autophagy causes the accumulation and high expression of STING in senescent NP cells as well as inflammation continuous activation together significantly promotes IDD. In senescent NP cells and intervertebral discs (IVDs), we found that STING autophagy degradation was significantly lower than that of normal NP cells and IVDs when STING was activated by 2'3'-cGAMP. Also, the above phenomenon was found in STINGgt/gt, cGAS-/- mice with models of age-induced, lumbar instability-induced IDD as well as found in the rat caudal IVD puncture models. Taken together, we suggested that the promotion of STING autophagy degradation in senescent NP Cells demonstrated a potential therapeutic modality for the treatment of IDD.

The effect of developmental care on the length of hospital stay and family centered care practice for very low birth weight infants in neonatal intensive care units: A cluster randomized controlled trial.

BACKGROUND: Despite previous studies suggesting that developmental care can provide benign stimulation to promote neural development of newborns, more evidence is needed regarding the other clinical benefits of developmental care. OBJECTIVE: To evaluate the effect of implementing developmental care on the length of hospital stay, the improvement of care practice in neonatal intensive care units, as well as the short-term outcome of very low birth weight infants. DESIGN: Cluster-randomized controlled trial. SETTING(S) AND PARTICIPANTS: From March 1, 2021 to March 1, 2022, 1400 very low birth weight infants were recruited from 14 tertiary neonatal intensive care units in China. METHODS: We assigned 14 neonatal intensive care units to either developmental care or standard care. The length of hospital stay of the infants was the primary outcome analyzed at the individual level. Secondary outcomes were family centered care practice including parental involvement, the skin to skin care, exclusive breast milk, oral immune therapy and breastfeeding. The environmental management (noise and light) and the short-term outcomes were also evaluated. RESULTS: The length of hospital stay for the developmental care group was 65 % as long as that for the control group (HR: 0.65, 95 % CI, 0.451-0936, p = 0.021). After controlling the covariables, the adjusted HR = 0.755 (95 % CI, 0.515 to 1.107, p = 0.150). When compared to the control group, the developmental care group had greater access to SSC, with 22 infants (3.8 %) in the developmental care group compared to 13 infants (1.7 %) in the standard care group (p = 0.013). A greater proportion of infants in the developmental care group were fed at the breast, than those in the standard care group (136 [23.6 %] vs 9 [1.1 %]; p = 0.029). Compared to the control group, exclusively breast milk was significantly more favorable in the developmental care group (435 [75.6 %] vs 114 [15.0 %]; p = 0.001). The difference remained significant even after adjusting for covariates. However, the rate of oral immune therapy and parental involvement was similar in the two groups. The average noise and light levels in the developmental care group were significantly lower than those in the standard care group. After adjusting for confounders, the difference remained significant. There were no significant differences among groups in the mortality and major morbidity. CONCLUSIONS: Developmental care might have developed an accumulated effect over time on the length of hospital stay among very low birth weight infants. The implementation of developmental care can greatly improve family centered care practices and the neonatal intensive care unit environment. REGISTRATION: ClinicalTrials.govNCT05166720. Registration date: 1 March, 2021.

Cryo-EM structure of human sphingomyelin synthase and its mechanistic implications for sphingomyelin synthesis.

Sphingomyelin (SM) has key roles in modulating mammalian membrane properties and serves as an important pool for bioactive molecules. SM biosynthesis is mediated by the sphingomyelin synthase (SMS) family, comprising SMS1, SMS2 and SMS-related (SMSr) members. Although SMS1 and SMS2 exhibit SMS activity, SMSr possesses ceramide phosphoethanolamine synthase activity. Here we determined the cryo-electron microscopic structures of human SMSr in complexes with ceramide, diacylglycerol/phosphoethanolamine and ceramide/phosphoethanolamine (CPE). The structures revealed a hexameric arrangement with a reaction chamber located between the transmembrane helices. Within this structure, a catalytic pentad E-H/D-H-D was identified, situated at the interface between the lipophilic and hydrophilic segments of the reaction chamber. Additionally, the study unveiled the two-step synthesis process catalyzed by SMSr, involving PE-PLC (phosphatidylethanolamine-phospholipase C) hydrolysis and the subsequent transfer of the phosphoethanolamine moiety to ceramide. This research provides insights into the catalytic mechanism of SMSr and expands our understanding of sphingolipid metabolism.

Loss of DDRGK1 impairs IRE1α UFMylation in spondyloepiphyseal dysplasia.

Spondyloepiphyseal dysplasia (SEMD) is a rare disease in which cartilage growth is disrupted, and the DDRGK1 mutation is one of the causative genes. In our study, we established Ddrgk1fl/fl, Col2a1-ERT Cre mice, which showed a thickened hypertrophic zone (HZ) in the growth plate, simulating the previous reported SEMD pathology in vivo. Instead of the classical modulation mechanism towards SOX9, our further mechanism study found that DDRGK1 stabilizes the stress sensor endoplasmic reticulum-to-nucleus signaling 1 (IRE1α) to maintain endoplasmic reticulum (ER) homoeostasis. The loss of DDRGK1 decreased the UFMylation and subsequently led to increased ubiquitylation-mediated IRE1α degradation, causing ER dysfunction and activating the PERK/CHOP/Caspase3 apoptosis pathway. Further DDRGK1 K268R-mutant mice revealed the importance of K268 UFMylation site in IRE1α degradation and subsequent ER dysfunction. In conclusion, DDRGK1 stabilizes IRE1α to ameliorate ER stress and following apoptosis in chondrocytes, which finally promote the normal chondrogenesis.

SE-VisionTransformer: Hybrid Network for Diagnosing Sugarcane Leaf Diseases Based on Attention Mechanism.

Sugarcane is an important raw material for sugar and chemical production. However, in recent years, various sugarcane diseases have emerged, severely impacting the national economy. To address the issue of identifying diseases in sugarcane leaf sections, this paper proposes the SE-VIT hybrid network. Unlike traditional methods that directly use models for classification, this paper compares threshold, K-means, and support vector machine (SVM) algorithms for extracting leaf lesions from images. Due to SVM's ability to accurately segment these lesions, it is ultimately selected for the task. The paper introduces the SE attention module into ResNet-18 (CNN), enhancing the learning of inter-channel weights. After the pooling layer, multi-head self-attention (MHSA) is incorporated. Finally, with the inclusion of 2D relative positional encoding, the accuracy is improved by 5.1%, precision by 3.23%, and recall by 5.17%. The SE-VIT hybrid network model achieves an accuracy of 97.26% on the PlantVillage dataset. Additionally, when compared to four existing classical neural network models, SE-VIT demonstrates significantly higher accuracy and precision, reaching 89.57% accuracy. Therefore, the method proposed in this paper can provide technical support for intelligent management of sugarcane plantations and offer insights for addressing plant diseases with limited datasets.

The cryo-EM structure of the human ERAD retrotranslocation complex.

Endoplasmic reticulum-associated degradation (ERAD) maintains protein homeostasis by retrieving misfolded proteins from the endoplasmic reticulum (ER) lumen into the cytosol for degradation. The retrotranslocation of misfolded proteins across the ER membrane is an energy-consuming process, with the detailed transportation mechanism still needing clarification. We determined the cryo-EM structures of the hetero-decameric complex formed by the Derlin-1 tetramer and the p97 hexamer. It showed an intriguing asymmetric complex and a putative coordinated squeezing movement in Derlin-1 and p97 parts. With the conformational changes of p97 induced by its ATP hydrolysis activities, the Derlin-1 channel could be torn into a "U" shape with a large opening to the lipidic environment, thereby forming an entry for the substrates in the ER membrane. The EM analysis showed that p97 formed a functional protein complex with Derlin-1, revealing the coupling mechanism between the ERAD retrotranslocation and the ATP hydrolysis activities.

Aminooxyacetic acid hemihydrochloride leads to decreased intracellular ATP levels and altered cell cycle of prostate cancer cells by suppressing energy metabolism.

The second most common cancer among men is prostate cancer, which is also the fifth leading reason for male cancer deaths worldwide. Bone metastases are the main factor affecting the prognosis of prostate cancer. Consequently, antitumor and anti-prostate cancer-induced bone destruction medicines are urgently needed. We previously discovered that aminooxyacetic acid hemihydrochloride (AOAA) suppressed bone resorption and osteoclast growth by decreasing adenosine triphosphate (ATP) production and limiting oxidative phosphorylation (OXPHOS). Here, we evaluated the impacts of AOAA on prostate cancer RM-1 cells in vitro. It's found that AOAA significantly inhibited cell proliferation, migration, and invasiveness, decreased ATP levels, increased ROS, halted the cell cycle phase, and triggered apoptosis. AOAA also decreased mitochondrial membrane potential and the ability to uptake glucose, suggesting that the antitumor effects of AOAA were expressed through the inhibition of OXPHOS and glycolysis. Furthermore, we assessed the effects of AOAA in vivo using a prostate cancer-induced bone osteolysis mice model. AOAA also delayed tumor growth and bone destruction in vivo. On the whole, our findings imply that AOAA may potentially have therapeutic effects on prostate cancer and prostate cancer-induced osteolysis.

Dlk2 interacts with Syap1 to activate Akt signaling pathway during osteoclast formation.

Excessive osteoclast formation and bone resorption are related to osteolytic diseases. Delta drosophila homolog-like 2 (Dlk2), a member of the epidermal growth factor (EGF)-like superfamily, reportedly regulates adipocyte differentiation, but its roles in bone homeostasis are unclear. In this study, we demonstrated that Dlk2 deletion in osteoclasts significantly inhibited osteoclast formation in vitro and contributed to a high-bone-mass phenotype in vivo. Importantly, Dlk2 was shown to interact with synapse-associated protein 1 (Syap1), which regulates Akt phosphorylation at Ser473. Dlk2 deletion inhibited Syap1-mediated activation of the AktSer473, ERK1/2 and p38 signaling cascades. Additionally, Dlk2 deficiency exhibits increased bone mass in ovariectomized mice. Our results reveal the important roles of the Dlk2-Syap1 signaling pathway in osteoclast differentiation and osteoclast-related bone disorders.

Cynarin alleviates intervertebral disc degeneration via protecting nucleus pulposus cells from ferroptosis.

Intervertebral disc degeneration (IVDD) leads to a series of degenerative spine diseases. Clinical treatment of IVDD is mainly surgery, lacking effective drugs to alleviate intervertebral disc degeneration. In this study, we analysed the mRNA sequencing dataset of human degenerative intervertebral disc tissues and revealed the participation of ferroptosis in IVDD. Furthermore, we confirmed that TNF-α, an important cytokine in IVDD, induces ferroptosis in nucleus pulposus cells. Subsequently, a ferroptosis inhibitors screening strategy using multiple ferroptosis indicators was developed. Through the screen of various natural compounds, cynarin, a natural product enriched in Artichoke, was discovered to inhibit ferroptosis of nucleus pulposus cells. Cynarin can dose-dependently inhibit the catabolism of nucleus pulposus cells, increase the expression of key ferroptosis-inhibiting genes (GPX4 and NRF2), inhibit the increment of cellular Fe2+, lipid peroxides, and reactive oxygen species. It can also prevent mitochondria shrinkage, reduce mitochondria cristae density in ferroptosis, and prevent IVDD in the rat model. In conclusion, cynarin is a potential candidate for the drug development for IVDD.

Verapamil attenuates intervertebral disc degeneration by suppressing ROS overproduction and pyroptosis via targeting the Nrf2/TXNIP/NLRP3 axis in four-week puncture-induced rat models both in vivo and in vitro.

Low back pain is usually caused by intervertebral disc degeneration (IVDD), during which the involvement of oxidation system imbalance and inflammasome activation cannot be neglected. In this study, we aimed to validate the expression level of TXNIP in IVDD and investigate the function and potential mechanism of action of verapamil. TXNIP is upregulated in the degenerate nucleus pulposus in both humans and rats, as well as in tert-butyl hydroperoxide (TBHP)-stimulated nucleus pulposus cells. Administration of verapamil, a classic clinical drug, mitigated the TBHP-induced overproduction of reactive oxygen species and activation of the NLRP3 inflammasome, thus protecting cells from pyroptosis, apoptosis, and extracellular matrix degradation. The Nrf2/TXNIP/NLRP3 axis plays a major role in verapamail-mediated protection. In vivo, a puncture-induced IVDD rat model was constructed, and we found that verapamil delayed the development of IVDD at both the imaging and histological levels. In summary, our results indicate the potential therapeutic effects and mechanisms of action of verapamil in the treatment of IVDD.

Challenges and applications of volatile organic compounds monitoring technology in plant disease diagnosis.

Biotic and abiotic stresses are well known to increase the emission of volatile organic compounds (VOCs) from plants. The analysis of VOCs emissions from plants enables timely diagnostic of plant diseases, which is critical for prompting sustainable agriculture. Previous studies have predominantly focused on the utilization of commercially available devices, such as electronic noses, for diagnosing plant diseases. However, recent advancements in nanomaterials research have significantly contributed to the development of novel VOCs sensors featuring exceptional sensitivity and selectivity. This comprehensive review presents a systematic analysis of VOCs monitoring technologies for plant diseases diagnosis, providing insights into their distinct advantages and limitations. Special emphasis is placed on custom-made VOCs sensors, with detailed discussions on their design, working principles, and detection performance. It is noteworthy that the application of VOCs monitoring technologies in the diagnostic process of plant diseases is still in its emerging stage, and several critical challenges demand attention and improvement. Specifically, the identification of specific stress factors using a single VOC sensor remains a formidable task, while environmental factors like humidity can potentially interfere with sensor readings, leading to inaccuracies. Future advancements should primarily focus on addressing these challenges to enhance the overall efficacy and reliability of VOCs monitoring technologies in the field of plant disease diagnosis.

The structural pathology for hypophosphatasia caused by malfunctional tissue non-specific alkaline phosphatase.

Hypophosphatasia (HPP) is a metabolic bone disease that manifests as developmental abnormalities in bone and dental tissues. HPP patients exhibit hypo-mineralization and osteopenia due to the deficiency or malfunction of tissue non-specific alkaline phosphatase (TNAP), which catalyzes the hydrolysis of phosphate-containing molecules outside the cells, promoting the deposition of hydroxyapatite in the extracellular matrix. Despite the identification of hundreds of pathogenic TNAP mutations, the detailed molecular pathology of HPP remains unclear. Here, to address this issue, we determine the crystal structures of human TNAP at near-atomic resolution and map the major pathogenic mutations onto the structure. Our study reveals an unexpected octameric architecture for TNAP, which is generated by the tetramerization of dimeric TNAPs, potentially stabilizing the TNAPs in the extracellular environments. Moreover, we use cryo-electron microscopy to demonstrate that the TNAP agonist antibody (JTALP001) forms a stable complex with TNAP by binding to the octameric interface. The administration of JTALP001 enhances osteoblast mineralization and promoted recombinant TNAP-rescued mineralization in TNAP knockout osteoblasts. Our findings elucidate the structural pathology of HPP and highlight the therapeutic potential of the TNAP agonist antibody for osteoblast-associated bone disorders.

Micron-resolution Imaging of Cortical Bone under 14 T Ultrahigh Magnetic Field.

Compact, mineralized cortical bone tissues are often concealed on magnetic resonance (MR) images. Recent development of MR instruments and pulse techniques has yielded significant advances in acquiring anatomical and physiological information from cortical bone despite its poor 1 H signals. This work demonstrates the first MR research on cortical bones under an ultrahigh magnetic field of 14 T. The 1 H signals of different mammalian species exhibit multi-exponential decays of three characteristic T2 or T2 * values: 0.1-0.5 ms, 1-4 ms, and 4-8 ms. Systematic sample comparisons attribute these T2 /T2 * value ranges to collagen-bound water, pore water, and lipids, respectively. Ultrashort echo time (UTE) imaging under 14 T yielded spatial resolutions of 20-80 microns, which resolves the 3D anatomy of the Haversian canals. The T2 * relaxation characteristics further allow spatial classifications of collagen, pore water and lipids in human specimens. The study achieves a record of the spatial resolution for MR imaging in bone and shows that ultrahigh-field MR has the unique ability to differentiate the soft and organic compartments in bone tissues.

The structural basis of the pH-homeostasis mediated by the Cl-/HCO3- exchanger, AE2.

The cell maintains its intracellular pH in a narrow physiological range and disrupting the pH-homeostasis could cause dysfunctional metabolic states. Anion exchanger 2 (AE2) works at high cellular pH to catalyze the exchange between the intracellular HCO3- and extracellular Cl-, thereby maintaining the pH-homeostasis. Here, we determine the cryo-EM structures of human AE2 in five major operating states and one transitional hybrid state. Among those states, the AE2 shows the inward-facing, outward-facing, and intermediate conformations, as well as the substrate-binding pockets at two sides of the cell membrane. Furthermore, critical structural features were identified showing an interlock mechanism for interactions among the cytoplasmic N-terminal domain and the transmembrane domain and the self-inhibitory effect of the C-terminal loop. The structural and cell-based functional assay collectively demonstrate the dynamic process of the anion exchange across membranes and provide the structural basis for the pH-sensitive pH-rebalancing activity of AE2.

DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination.

Chemoresistance is the main obstacle in osteosarcoma (OS) treatment; however, the underlying mechanism remains unclear. In this study, it is discovered that DDRGK domain-containing protein 1 (DDRGK1) plays a fundamental role in chemoresistance induced in OS. Bioinformatic and tissue analyses indicate that higher expression of DDRGK1 correlates with advanced tumor stage and poor clinical prognosis of OS. Quantitative proteomic analyses suggest that DDRGK1 plays a critical role in mitochondrial oxidative phosphorylation. DDRGK1 knockout trigger the accumulation of reactive oxygen species (ROS) and attenuate the stability of nuclear factor erythroid-2-related factor 2 (NRF2), a major antioxidant response element. Furthermore, DDRGK1 inhibits ubiquitin-proteasome-mediated degradation of NRF2 via competitive binding to the Kelch-like ECH-associated protein 1 (KEAP1) protein, which recruits NRF2 to CULLIN(CUL3). DDRGK1 knockout attenuates NRF2 stability, contributing to ROS accumulation, which promotes apoptosis and enhanced chemosensitivity to doxorubicin (DOX) and etoposide in cancer cells. Indeed, DDRGK1 knockout significantly enhances osteosarcoma chemosensitivity to DOX in vivo. The combination of DDRGK1 knockdown and DOX treatment provides a promising new avenue for the effective treatment of OS.

Metabolite asymmetric dimethylarginine (ADMA) functions as a destabilization enhancer of SOX9 mediated by DDAH1 in osteoarthritis.

Osteoarthritis (OA) is a degenerative disease with a series of metabolic changes accompanied by many altered enzymes. Here, we report that the down-regulated dimethylarginine dimethylaminohydrolase-1 (DDAH1) is accompanied by increased asymmetric dimethylarginine (ADMA) in degenerated chondrocytes and in OA samples. Global or chondrocyte-conditional knockout of ADMA hydrolase DDAH1 accelerated OA development in mice. ADMA induces the degeneration and senescence of chondrocytes and reduces the extracellular matrix deposition, thereby accelerating OA progression. ADMA simultaneously binds to SOX9 and its deubiquitinating enzyme USP7, blocking the deubiquitination effects of USP7 on SOX9 and therefore leads to SOX9 degradation. The ADMA level in synovial fluids of patients with OA is increased and has predictive value for OA diagnosis with good sensitivity and specificity. Therefore, activating DDAH1 to reduce ADMA level might be a potential therapeutic strategy for OA treatment.

Relationship between dietary fruit intake and overweight and obesity in children / 中国学校卫生

Objective@#To explore the relationship between fruit intake and the risk of overweight with obesity in children, so as to provide references for the prevention of childhood obesity.@*Methods@#From September to November 2014, a stratified cluster sampling method was used to select 6 369 children aged 6-12 from two elementary schools of a country in rural Chongqing for physical examinations and questionnaire surveys, and 1 814 children in grades 1-2 at baseline were followed up from March to May 2019. The relationship between fruit intake and the prevalence of overweight and obesity was analyzed.@*Results@#According to the percentile of fruit intake, the 6 369 children at baseline were assigned to three groups: Q 1 (< P 33.3 , fruit intake <100 g/d), Q 2 ( P 33.3 - P 66.7 , fruit intake:100-214.3 g/d), and Q 3 (> P 66.7 , fruit intake >214.3 g/d). For the baseline survey results, children in the Q 2 group had a lower weight and Body Mass Index (BMI) ( P <0.05); the prevalence of overweight and obesity among children in the Q 1 group was the highest (32.03%), and the prevalence of overweight and obesity among boys in the Q 2 group was the lowest (31.94%) after gender stratification ( P <0.05). The follow up survey results showed no significant differences between the three groups in terms of changes in height, weight, and BMI ( P >0.05); but the prevalence of obesity among youth in the Q 2 group was the lowest (5.07%, P <0.05). Compared with youth in the Q 2 group, the risk of obesity was higher among those in the Q 1 group at baseline survey ( OR=1.41, 95%CI=1.10-1.81, P <0.05), and was higher among those in the Q 3 group at follow up survey ( RR= 1.83, 95%CI=1.21-2.75, P <0.05).@*Conclusion@#Deviating from moderate fruit intake may increase the likelihood of overweight and obesity in children, and it is recommended that children are encouraged to consume fruits as part of a well balanced diet to prevent the occurrence of obesity.

Ceritinib (LDK378) prevents bone loss via suppressing Akt and NF-κB-induced osteoclast formation.

Background: Ceritinib is used for the treatment of patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), who are at the risk of developing bone metastasis. During bone metastasis, tumor cells release factors that induce osteoclast formation, resulting in osteolysis. However, the effect of ceritinib on osteoclast formation remains unclear. Methods: Osteoclastogenesis was induced to assess the effect of ceritinib on osteoclast formation and osteoclast-specific gene expression. Western blotting was used to examine the molecular mechanisms underlying the effect of ceritinib on osteoclast differentiation. An in vivo ovariectomized mouse model was established to validate the effect of ceritinib in suppressing osteoclast formation and preventing bone loss. Results: The differentiation of osteoclasts and the expression of osteoclast-specific genes were inhibited upon ceritinib stimulation. Ceritinib suppressed Akt and p65 phosphorylation during the receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis. The administration of ceritinib to ovariectomized mice ameliorated trabecular bone loss by inhibiting osteoclast formation. Conclusions: Ceritinib is beneficial in preventing bone loss by suppressing osteoclastic Akt and nuclear factor κB (NF-κB) signaling.

MR-based synthetic CT image for intensity-modulated proton treatment planning of nasopharyngeal carcinoma patients.

PURPOSE: To develop an advanced deep convolutional neural network (DCNN) architecture to generate synthetic CT (SCT) images from MR images for intensity-modulated proton therapy (IMPT) treatment planning of nasopharyngeal cancer (NPC) patients. METHODS: T1-weighted MR images and paired CT (PCT) images were obtained from 206 NPC patients. For each patient, deformable image registration was performed between MR and PCT images to create an MR-CT image pair. Thirty pairs were randomly chosen as the independent test set and the remaining 176 pairs (14 for validation and 162 for training) were used to build two conditional generative adversarial networks (GANs): 1) GAN3D: using a 3D U-net enhanced with residual connections and attentional mechanism as the generator and 2) GAN2D: using a 2D U-net as the generator. For each test patient, SCT images were generated using the generators with the MR images as input and were compared with respect to the corresponding PCT image. A clinical IMPT plan was created and optimized on the PCT image. The dose was recalculated on the SCT images and compared with the one calculated on the PCT image. RESULTS: The mean absolute errors (MAEs) between the PCT and SCT, within the body, were (64.89 ± 5.31) HU and (64.31 ± 4.61) HU for the GAN2D and GAN3D. Within the high-density bone (HU > 600), the GAN3D achieved a smaller MAE compared with the GAN2D (p < 0.001). Within the body, the absolute point dose deviation was reduced from (0.58 ± 1.61) Gy for the GAN2D to (0.47 ± 0.94) Gy for the GAN3D. The (3 mm/3%) gamma passing rates were above 97.32% for all SCT images. CONCLUSIONS: The SCT images generated using GANs achieved clinical acceptable dosimetric accuracy for IMPT of NPC patients. Using advanced DCNN architecture design, such as residual connections and attention mechanism, SCT image quality was further improved and resulted in a small dosimetric improvement.

Aminooxyacetic acid hemihydrochloride inhibits osteoclast differentiation and bone resorption by attenuating oxidative phosphorylation.

Osteoclasts undergo active metabolic reprogramming to acquire the energy needed during differentiation and bone resorption. Compared with immature osteoclasts, mature osteoclasts comprise higher levels of electron transport chain enzymes and more metabolically active mitochondria. Of all energy metabolism pathways, oxidative phosphorylation is considered to be the most efficient in supplying energy to osteoclasts. We found that the malate-aspartate shuttle inhibitor aminooxyacetic acid hemihydrochloride inhibits osteoclastogenesis and bone resorption by inhibiting exchange of reducing equivalents between the cytosol and the mitochondrial matrix and attenuating mitochondrial oxidative phosphorylation in vitro. The weakening of the oxidative phosphorylation pathway resulted in reduced mitochondrial function and inadequate energy supply along with reduced reactive oxygen species production. Furthermore, treatment with aminooxyacetic acid hemihydrochloride helped recover bone loss in ovariectomized mice. Our findings highlight the potential of interfering with the osteoclast intrinsic energy metabolism pathway as a treatment for osteoclast-mediated osteolytic diseases.