Effects of Low-Salinity Stress on Histology and Metabolomics in the Intestine of Fenneropenaeus chinensis.

Metabolomics has been used extensively to identify crucial molecules and biochemical effects induced by environmental factors. To understand the effects of acute low-salinity stress on Fenneropenaeus chinensis, intestinal histological examination and untargeted metabonomic analysis of F. chinensis were performed after exposure to a salinity of 15 ppt for 3, 7, and 14 d. The histological examination revealed that acute stress resulted in most epithelial cells rupturing, leading to the dispersion of nuclei in the intestinal lumen after 14 days. Metabolomics analysis identified numerous differentially expressed metabolites (DEMs) at different time points after exposure to low-salinity stress, in which some DEMs were steadily downregulated at the early stage of stress and then gradually upregulated. We further screened 14 overlapping DEMs, in which other DEMs decreased significantly during low-salinity stress, apart from L-palmitoylcarnitine and vitamin A, with enrichments in phenylalanine, tyrosine and tryptophan biosynthesis, fatty acid and retinol metabolism, and ABC transporters. ABC transporters exhibit significant abnormalities and play a vital role in low-salinity stress. This study provides valuable insights into the molecular mechanisms underlying the responses of F. chinensis to acute salinity stress.

Haplotype-resolved assembly of the mule duck genome using high-fidelity sequencing technology.

Mule duck is vitally important to the production of global duck meat. Here, we present two high-quality haplotypes of a female mule duck (haplotype 1 (H1):1.28 Gb, haplotype 2 (H2): 1.40 Gb). The continuity (H1: contig N50 = 14.90 Mb, H2: contig N50 = 15.70 Mb) and completeness (BUSCO: H1 = 96.9%, H2 = 97.3%) are substantially better than those of other duck genomes. We detected the structural variations (SVs) in H1 and H2. We observed a positive correlation between autosome length and the number of SVs. Z chromosome was some deficient in deletions and insertions, but W chromosome was some excessive. A total of 1,451 genes were haplotype specific expression (HSEs). Among them, 737 specifically expressed in H1, and 714 specifically expressed in H2. We found that H1 and H2 HSEs tended to be involved in similar biological processes, such as myometrial relaxation and contraction pathways, muscle structure development and phosphorylation. Our haplotype-resolved genome assembly provides a powerful platform for future functional genomics, molecular breeding, and genome editing in mule duck.

The effects of reward and punishment on the performance of ping-pong ball bouncing.

Introduction: Reward and punishment modulate behavior. In real-world motor skill learning, reward and punishment have been found to have dissociable effects on optimizing motor skill learning, but the scientific basis for these effects is largely unknown. Methods: In the present study, we investigated the effects of reward and punishment on the performance of real-world motor skill learning. Specifically, three groups of participants were trained and tested on a ping-pong ball bouncing task for three consecutive days. The training and testing sessions were identical across the three days: participants were trained with their right (dominant) hand each day under conditions of either reward, punishment, or a neutral control condition (neither). Before and after the training session, all participants were tested with their right and left hands without any feedback. Results: We found that punishment promoted early learning, while reward promoted late learning. Reward facilitated short-term memory, while punishment impaired long-term memory. Both reward and punishment interfered with long-term memory gains. Interestingly, the effects of reward and punishment transferred to the left hand. Discussion: The results show that reward and punishment have different effects on real-world motor skill learning. The effects change with training and transfer readily to novel contexts. The results suggest that reward and punishment may act on different learning processes and engage different neural mechanisms during real-world motor skill learning. In addition, high-level metacognitive processes may be enabled by the additional reinforcement feedback during real-world motor skill learning. Our findings provide new insights into the mechanisms underlying motor learning, and may have important implications for practical applications such as sports training and motor rehabilitation.

NFIC mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to represses malignant phenotype of non-small cell lung cancer cells.

BACKGROUND: Multiple genetic and epigenetic regulatory mechanisms are crucial in the development and tumorigenesis process. Transcriptional regulation often involves intricate relationships and networks with post-transcriptional regulatory molecules, impacting the spatial and temporal expression of genes. However, the synergistic relationship between transcription factors and N6-methyladenosine (m6A) modification in regulating gene expression, as well as their influence on the mechanisms underlying the occurrence and progression of non-small cell lung cancer (NSCLC), requires further investigation. The present study aimed to investigate the synergistic relationship between transcription factors and m6A modification on NSCLC. METHODS: The transcription factor NFIC and its potential genes was screened by analyzing publicly available datasets (ATAC-seq, DNase-seq, and RNA-seq). The association of NFIC and its potential target genes were validated through ChIP-qPCR and dual-luciferase reporter assays. Additionally, the roles of NFIC and its potential genes in NSCLC were detected in vitro and in vivo through silencing and overexpression assays. RESULTS: Based on multi-omics data, the transcription factor NFIC was identified as a potential tumor suppressor of NSCLC. NFIC was significantly downregulated in both NSCLC tissues and cells, and when NFIC was overexpressed, the malignant phenotype and total m6A content of NSCLC cells was suppressed, while the PI3K/AKT pathway was inactivated. Additionally, we discovered that NFIC inhibits the expression of METTL3 by directly binding to its promoter region, and METTL3 regulates the expression of KAT2A, a histone acetyltransferase, by methylating the m6A site in the 3'UTR of KAT2A mRNA in NSCLC cells. Intriguingly, NFIC was also found to negatively regulate the expression of KAT2A by directly binding to its promoter region. CONCLUSIONS: Our findings demonstrated that NFIC suppresses the malignant phenotype of NSCLC cells by regulating gene expression at both the transcriptional and post-transcriptional levels. A deeper comprehension of the genetic and epigenetic regulatory mechanisms in tumorigenesis would be beneficial for the development of personalized treatment strategies.

Nab-paclitaxel, cisplatin, and capecitabine versus cisplatin and gemcitabine as first line chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma: randomised phase 3 clinical trial.

OBJECTIVE: To compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment option for recurrent or metastatic nasopharyngeal carcinoma. DESIGN: Phase 3, open label, multicentre, randomised trial. SETTING: Four hospitals located in China between September 2019 and August 2022. PARTICIPANTS: Adults (≥18 years) with recurrent or metastatic nasopharyngeal carcinoma. INTERVENTIONS: Patients were randomised in a 1:1 ratio to treatment with either nab-paclitaxel (200 g/m2 on day 1), cisplatin (60 mg/m2 on day 1), and capecitabine (1000 mg/m2 twice on days 1-14) or gemcitabine (1 g/m2 on days 1 and 8) and cisplatin (80 mg/m2 on day 1). MAIN OUTCOME MEASURES: Progression-free survival was evaluated by the independent review committee as the primary endpoint in the intention-to-treat population. RESULTS: The median follow-up was 15.8 months in the prespecified interim analysis (31 October 2022). As assessed by the independent review committee, the median progression-free survival was 11.3 (95% confidence interval 9.7 to 12.9) months in the nab-TPC cohort compared with 7.7 (6.5 to 9.0) months in the gemcitabine and cisplatin cohort. The hazard ratio was 0.43 (95% confidence interval 0.25 to 0.73; P=0.002). The objective response rate in the nab-TPC cohort was 83% (34/41) versus 63% (25/40) in the gemcitabine and cisplatin cohort (P=0.05), and the duration of response was 10.8 months in the nab-TPC cohort compared with 6.9 months in the gemcitabine and cisplatin cohort (P=0.009). Treatment related grade 3 or 4 adverse events, including leukopenia (4/41 (10%) v 13/40 (33%); P=0.02), neutropenia (6/41 (15%) v 16/40 (40%); P=0.01), and anaemia (1/41 (2%) v 8/40 (20%); P=0.01), were higher in the gemcitabine and cisplatin cohort than in the nab-TPC cohort. No deaths related to treatment occurred in either treatment group. Survival and long term toxicity are still being evaluated with longer follow-up. CONCLUSION: The nab-TPC regimen showed a superior antitumoural efficacy and favourable safety profile compared with gemcitabine and cisplatin for recurrent or metastatic nasopharyngeal carcinoma. Nab-TPC should be considered the standard first line treatment for recurrent or metastatic nasopharyngeal carcinoma. Longer follow-up is needed to confirm the benefits for overall survival. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900027112.

Identification of Prospective Ebola Virus VP35 and VP40 Protein Inhibitors from Myxobacterial Natural Products.

The Ebola virus (EBOV) is a lethal pathogen causing hemorrhagic fever syndrome which remains a global health challenge. In the EBOV, two multifunctional proteins, VP35 and VP40, have significant roles in replication, virion assembly, and budding from the cell and have been identified as druggable targets. In this study, we employed in silico methods comprising molecular docking, molecular dynamic simulations, and pharmacological properties to identify prospective drugs for inhibiting VP35 and VP40 proteins from the myxobacterial bioactive natural product repertoire. Cystobactamid 934-2, Cystobactamid 919-1, and Cittilin A bound firmly to VP35. Meanwhile, 2-Hydroxysorangiadenosine, Enhypyrazinone B, and Sorangiadenosine showed strong binding to the matrix protein VP40. Molecular dynamic simulations revealed that, among these compounds, Cystobactamid 919-1 and 2-Hydroxysorangiadenosine had stable interactions with their respective targets. Similarly, molecular mechanics Poisson-Boltzmann surface area (MMPBSA) calculations indicated close-fitting receptor binding with VP35 or VP40. These two compounds also exhibited good pharmacological properties. In conclusion, we identified Cystobactamid 919-1 and 2-Hydroxysorangiadenosine as potential ligands for EBOV that target VP35 and VP40 proteins. These findings signify an essential step in vitro and in vivo to validate their potential for EBOV inhibition.

A Prelimbic Cortex-Thalamus Circuit Bidirectionally Regulates Innate and Stress-Induced Anxiety-Like Behavior.

Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.

Associations between smoking, sex steroid hormones, trouble sleeping, and depression among U.S. adults: a cross-sectional study from NHANES (2013-2016).

BACKGROUND: Dose-response and nonlinear relationships of cigarette exposure with sleep disturbances and depression are warranted, and the potential mechanism of sex hormones in such associations remains unclear. METHODS: Cigarette exposure, trouble sleeping, and depression were assessed by standard questionnaires, and the levels of cotinine and sex steroid hormones were determined among 9900 adults from the National Health and Nutrition Examination Survey (NHANES). Multiple linear regression, logistic regression, and mediation models were conducted to evaluate the associations between smoking, sex steroid hormones, trouble sleeping, and depression. RESULTS: With never smokers as a reference, current smokers had a higher prevalence of trouble sleeping (OR = 1.931, 95% CI: 1.680, 2.219) and depression (OR = 2.525, 95% CI: 1.936, 3.293) as well as testosterone level (ß = 0.083, 95% CI: 0.028, 0.140). Pack-years of smoking and cigarettes per day were positively associated with the prevalence of trouble sleeping and depression as well as testosterone level (Ptrend <0.05). The restricted cubic spline model showed linear relationships of cotinine with trouble sleeping, depression, and testosterone. The positive associations of cigarettes per day with trouble sleeping and depression were greater in females than that in males (Pmodification <0.05). However, the potential role of sex hormones was not observed in the association of cotinine with trouble sleeping or depression (Pmediation >0.05). CONCLUSION: Smoking may induce sex hormone disturbance and increase the risk of sleep problems and depression symptoms, and ceasing smoking may reduce the risk of such complications.

Identification and Root Cause Analysis of the Visible Particles Commonly Encountered in the Biopharmaceutical Industry.

Visible particle is an important issue in the biopharmaceutical industry, and it may occur across all the stages in the life cycle of biologics. Upon the occurrence of visible particles, it is often necessary to conduct chemical identification and root cause analysis to safeguard the safety and efficacy of the biotherapeutic products. In this article, we present a number of typical particles and relevant root cause analysis in the categories of extrinsic, intrinsic and inherent particles that are commonly encountered in the biopharma industry. In particular, the optical images of particles obtained both in situ and after isolation are provided, along with the spectral and elemental information. The particle identification was carried out with multiple microscopic and microspectroscopic techniques, including stereo optical microscopy, Fourier transform infrared microscopy, confocal Raman microscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy. Both commercial and in-house spectral databases were used for comparison and identification. In addition to particle identification, our significant efforts are placed on the root cause analysis of the addressed particles with the intention to provide a relatively whole picture of the particle related issues and practical references to particle mitigation for our peers in the biopharmaceutical industry.

ROS-Responsive Injectable Hydrogel Loaded with SLC7A11-modRNA Inhibits Ferroptosis and Mitigates Intervertebral Disc Degeneration in Rats.

Intervertebral disc degeneration (IVDD) is the primary cause of low back pain, with oxidative stress being a recognized factor that causes its development. Presently, low back pain imposes a significant global economic burden. However, the effectiveness of treatments for IVDD remains extremely limited. Therefore, this study aims to explore innovative and effective IVDD treatments by focusing on oxidative stress as a starting point. In this study, an injectable reactive oxygen species-responsive hydrogel (PVA-tsPBA@SLC7A11 modRNA) is developed, designed to achieve rapid loading and selective release of chemically synthesized modified mRNA (modRNA). SLC7A11 modRNA is specifically used to upregulate the expression of the ferroptosis marker SLC7A11. The local injection of PVA-tsPBA@SLC7A11 modRNA into the degenerated intervertebral disc (IVD) results in the cleavage of PVA-tsPBA, leading to the release of enclosed SLC7A11 modRNA. The extent of SLC7A11 modRNA release is directly proportional to the severity of IVDD, ultimately ameliorating IVDD by inhibiting ferroptosis in nucleus pulposus cells (NPCs). This study proposes an innovative system of PVA-tsPBA hydrogel-encapsulated modRNA, representing a potential novel treatment strategy for patients with early-stage IVDD.

HIF-1α-induced expression of the m6A reader YTHDF1 inhibits the ferroptosis of nucleus pulposus cells by promoting SLC7A11 translation.

The nucleus pulposus is in a hypoxic environment in the human body, and when intervertebral disc degeneration (IVDD) occurs, the hypoxic environment is disrupted. Nucleus pulposus cell (NPC) ferroptosis is one of the causes of IVDD. N6-methyladenosine (m6A) and its reader protein YTHDF1 regulate cellular activities by affecting RNA metabolism. However, the regulation of ferroptosis in NPCs by m6A-modified RNAs under hypoxic conditions has not been as well studied. In this study, through in vitro and in vivo experiments, we explored the underlying mechanism of HIF-1α and YTHDF1 in regulating ferroptosis in NPCs. The results indicated that the overexpression of HIF-1α or YTHDF1 suppressed NPC ferroptosis; conversely, the knockdown of HIF-1α or YTHDF1 increased ferroptosis levels in NPCs. Luciferase reporter assays and chromatin immunoprecipitation demonstrated that HIF-1α regulated YTHDF1 transcription by directly binding to its promoter region. Polysome profiling results showed that YTHDF1 promoted the translation of SLC7A11 and consequently the expression of the anti-ferroptosis protein GPX4 by binding to m6A-modified SLC7A11 mRNA. In conclusion, HIF-1α-induced YTHDF1 expression reduces NPC ferroptosis and delays IVDD by promoting SLC7A11 translation in a m6A-dependent manner.

Augmented Central Pain Processing Occurs after Osteoporotic Vertebral Compression Fractures and Is Associated with Residual Back Pain after Percutaneous Vertebroplasty.

STUDY DESIGN: A retrospective analysis. PURPOSE: To investigate the occurrence of central sensitization (CS) in patients with osteoporotic vertebral compression fractures (OVCFs) and identify the association between CS and residual back pain (RBP). OVERVIEW OF LITERATURE: RBP is a vexing complication that affects 6.3%-17.0% of patients with OVCFs who underwent percutaneous vertebroplasty (PVP). Given the negative effect of RBP on patients' psychological and physiological statuses, efforts to preoperatively select patients who are at risk for RBP development have a high priority to offer additional treatment and minimize this complication. METHODS: Preoperatively, all 160 patients with OVCFs underwent pressure-pain threshold (PPT), temporal summation (TS), conditioned pain modulation (CPM), and imaging assessments. Pain intensity and pain-related disability were evaluated before and after PVP. RESULTS: Preoperatively, patients with OVCFs had lower PPTs in both local pain and pain-free areas and lower CPM and higher TS in pain-free areas than healthy participants (p<0.05). Unlike patients with acute fractures, patients with subacute/chronic OVCFs showed higher TS with or without lower CPM in the pain-free area compared with healthy participants (p<0.05). Postoperatively, RBP occurred in 17 of 160 patients (10.6%). All preoperative covariates with significant differences between the RBP and non-RBP groups were subjected to multivariate logistic regression, showing that intravertebral vacuum cleft, posterior fascia edema, numeric rating pain scale scores for low back pain at rest, and TS were independently associated with RBP (p<0.05). CONCLUSIONS: Augmented central pain processing may occur in patients with OVCFs, even in the subacute stage, and this preexisting CS may be associated with RBP. Preoperative assessment of TS in pain-free areas may provide additional information for identifying patients who may be at risk of RBP development, which may be beneficial for preventing this complication.

Nuclear factor-κB p65 subunit determines the fate of aging epithelial cells.

Nuclear factor (NF)-κB signaling is not only important for the immune and inflammatory responses but also for the normal development of epithelial cells, such as those in the skin and tooth. Here, we generated epithelial cell-specific p65-deficient (p65Δepi-/-) mice to analyze the roles of NF-κB signaling in epithelial cell developent. Notably, p65Δepi-/- mice exhibited no abnormalities in their appearance compared to the control (p65flox/flox) littermates. Furthermore, no major changes were observed in the skin, hair growth, and shape and color of the incisors and molars. However, 65 % of p65Δepi-/- mice exhibited corneal thickening after 8 weeks of age, and 30 % of p65Δepi-/- mice exhibited hair growth from the mandibular incisors around 24 weeks of age. No hair growth was observed at 36 and 42 weeks of age. However, micro-computed tomography images revealed a large cavity below the mandibular incisors extending to the root of the incisor. Histological analysis revealed that the cavity was occupied by a connective tissue containing hair-like structures with many dark brown granules that disappeared after melanin bleaching, confirming the presence of hair. Although inflammatory cells were also observed near the eruption site of the incisor teeth of p65Δepi-/- mice, no major disturbance was observed in the arrangement of enamel epithelial cells. Overall, these results highlight the role of p65 in the maintenance of epithelial cell homeostasis during aging.

Mature astrocytes as source for astrocyte repopulation after deletion in the medial prefrontal cortex: Implications for depression.

The adult brain retains a high repopulation capacity of astrocytes after deletion, and both mature astrocytes in the neocortex and neural stem cells in neurogenic regions possess the potential to generate astrocytes. However, the origin and the repopulation dynamics of the repopulating astrocytes after deletion remain largely unclear. The number of astrocytes is reduced in the medial prefrontal cortex (mPFC) of patients with depression, and selective elimination of mPFC astrocytes is sufficient to induce depression-like behaviors in rodents. However, whether astrocyte repopulation capacity is impaired in depression is unknown. In this study, we used different transgenic mouse lines to genetically label different cell types and demonstrated that in the mPFC of normal adult mice of both sexes, mature astrocytes were a major source of the repopulating astrocytes after acute deletion induced by an astrocyte-specific toxin, L-alpha-aminoadipic acid (L-AAA), and astrocyte regeneration was accomplished within two weeks accompanied by reversal of depression-like behaviors. Furthermore, re-ablation of mPFC astrocytes post repopulation led to reappearance of depression-like behaviors. In adult male mice subjected to 14-day chronic restraint stress, a well-validated mouse model of depression, the number of mPFC astrocytes was reduced; however, the ability of mPFC astrocytes to repopulate after L-AAA-induced deletion was largely unaltered. Our study highlights a potentially beneficial role for repopulating astrocytes in depression and provides novel therapeutic insights into enhancing local mature astrocyte generation in depression.

Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice.

Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients' blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.

Nanofiber-induced hierarchically-porous magnesium phosphate bone cements accelerate bone regeneration by inhibiting Notch signaling.

Magnesium phosphate bone cements (MPC) have been recognized as a viable alternative for bone defect repair due to their high mechanical strength and biodegradability. However, their poor porosity and permeability limit osteogenic cell ingrowth and vascularization, which is critical for bone regeneration. In the current study, we constructed a novel hierarchically-porous magnesium phosphate bone cement by incorporating extracellular matrix (ECM)-mimicking electrospun silk fibroin (SF) nanofibers. The SF-embedded MPC (SM) exhibited a heterogeneous and hierarchical structure, which effectively facilitated the rapid infiltration of oxygen and nutrients as well as cell ingrowth. Besides, the SF fibers improved the mechanical properties of MPC and neutralized the highly alkaline environment caused by excess magnesium oxide. Bone marrow stem cells (BMSCs) adhered excellently on SM, as illustrated by formation of more pseudopodia. CCK8 assay showed that SM promoted early proliferation of BMSCs. Our study also verified that SM increased the expression of OPN, RUNX2 and BMP2, suggesting enhanced osteogenic differentiation of BMSCs. We screened for osteogenesis-related pathways, including FAK signaing, Wnt signaling and Notch signaling, and found that SM aided in the process of bone regeneration by suppressing the Notch signaling pathway, proved by the downregulation of NICD1, Hes1 and Hey2. In addition, using a bone defect model of rat calvaria, the study revealed that SM exhibited enhanced osteogenesis, bone ingrowth and vascularization compared with MPC alone. No adverse effect was found after implantation of SM in vivo. Overall, our novel SM exhibited promising prospects for the treatment of critical-sized bone defects.

Artemisinic acid attenuates osteoclast formation and titanium particle-induced osteolysis via inhibition of RANKL-induced ROS accumulation and MAPK and NF-κB signaling pathways.

Periprosthetic osteolysis (PPO) is the most common cause of joint arthroplasty failure. Its progression involves both biological and mechanical factors. Osteoclastogenesis induced by wear from debris-cell interactions, ultimately leading to excessive bone erosion, is considered the primary cause of PPO; therefore, targeting osteoclasts is a promising treatment approach. Currently available drugs have various side effects and limitations. Artemisinic acid (ArA) is a sesquiterpene isolated from the traditional herb Artemisia annua L. that has various pharmacological effects, such as antimalarial, anti-inflammatory, and antioxidant activities. Therefore, this study was aimed at investigating the effect of ArA on osteoclast formation and bone resorption function in vitro, as well as wear particle-induced osteolysis in vivo, and to explore its molecular mechanism of action. Here, we report that ArA inhibits RANKL-stimulated osteoclast formation and function. Mechanistically, ArA suppresses intracellular reactive oxygen species levels by activating the antioxidant response via nuclear factor erythroid-2-related factor 2 (Nrf2) pathway upregulation. It also inhibits the mitogen-activated kinases (MAPK) and nuclear factor-κB (NF-κB) pathways, as well as the transcription and expression of NFATc1 and c-Fos. In vivo experiments demonstrated that ArA reduces osteoclast formation and alleviates titanium particle-induced calvarial osteolysis. Collectively, our study highlights that ArA, with its osteoprotective and antioxidant effects, is a promising therapeutic agent for preventing and treating PPO and other osteoclast-mediated osteolytic diseases.

Applicability of the generalized wind profile model over mountainous forests.

The analytical equation based on Monin-Obukhov (M-O) similarity theory (i.e., wind profile equation) has been adopted since 1970s for using in the prediction of wind vertical profile over flat terrains, which is mature and accurate. However, its applicability over complex terrains remains unknown. This applicability signifies the accuracy of the estimations of aerodynamic parameters for the boundary layer of non-flat terrain, such as zero-displacement height (d) and aerodynamic roughness length (z0), which will determine the accuracy of frequency correction and source area analysis in calculating carbon, water, and trace gas fluxes based on vorticity covariance method. Therefore, the validation of wind profile model in non-flat terrain is the first step to test whether the flux model needs improvement. We measured three-dimensional wind speed data by using the Ker Towers (three towers in a watershed) at Qingyuan Forest CERN in the Mountainous Region of east Liaoning Province, and compared them with data from Panjin Agricultural Station in the Liaohe Plain, to evaluate the applicability of a generalized wind profile model based on the Monin-Obukhov similarity theory on non-flat terrain. The results showed that the generalized wind profile model could not predict wind speeds accurately of three flux towers separately located in different sites, indicating that wind profile model was not suitable for predicting wind speeds in complex terrains. In the leaf-off and leaf-on periods, the coefficient of determination (R2) between observed and predicted wind speeds ranged from 0.12 to 0.30. Compared to measured values, the standard error of the predicted wind speeds was high up to 2 m·s-1. The predicted wind speeds were high as twice as field-measured wind speed, indicating substantial overestimation. Nevertheless, this model correctly predicted wind speeds in flat agricultural landscape in Panjin Agricultural Station. The R2 between observed wind speeds and predicted wind speed ranged from 0.90 to 0.93. The standard error between observed and predicted values was only 0.5 m·s-1. Results of the F-test showed that the root-mean-square error of the observed and predicted wind speeds in each secondary forest complex terrain was much greater than that in flat agricultural landscape. Terrain was the primary factor affecting the applicability of wind profile model, followed by seasonality (leaf or leafless canopy). The wind profile model was not applicable to the boundary-layer flows over forest canopies in complex terrains, because the d was underestimated or both the d and z0 were underestimated, resulting in inaccurate estimation of aerodynamic height.

Extracellular ATP Is a Homeostatic Messenger That Mediates Cell-Cell Communication in Physiological Processes and Psychiatric Diseases.

Neuronal activity is the basis of information encoding and processing in the brain. During neuronal activation, intracellular ATP (adenosine triphosphate) is generated to meet the high-energy demands. Simultaneously, ATP is secreted, increasing the extracellular ATP concentration and acting as a homeostatic messenger that mediates cell-cell communication to prevent aberrant hyperexcitability of the nervous system. In addition to the confined release and fast synaptic signaling of classic neurotransmitters within synaptic clefts, ATP can be released by all brain cells, diffuses widely, and targets different types of purinergic receptors on neurons and glial cells, making it possible to orchestrate brain neuronal activity and participate in various physiological processes, such as sleep and wakefulness, learning and memory, and feeding. Dysregulation of extracellular ATP leads to a destabilizing effect on the neural network, as found in the etiopathology of many psychiatric diseases, including depression, anxiety, schizophrenia, and autism spectrum disorder. In this review, we summarize advances in the understanding of the mechanisms by which extracellular ATP serves as an intercellular signaling molecule to regulate neural activity, with a focus on how it maintains the homeostasis of neural networks. In particular, we also focus on neural activity issues that result from dysregulation of extracellular ATP and propose that aberrant levels of extracellular ATP may play a role in the etiopathology of some psychiatric diseases, highlighting the potential therapeutic targets of ATP signaling in the treatment of these psychiatric diseases. Finally, we suggest potential avenues to further elucidate the role of extracellular ATP in intercellular communication and psychiatric diseases.