18F-Radiolabeling and Evaluation of an AMD3465 Derivative for PET Imaging of CXCR4 in a Mouse Breast Tumor Model.

The exploration of pharmaceutically active agents and positron emission tomography (PET) tracers targeting CXCR4 has been a focal point in cancer research given its pivotal role in the development and progression of various cancers. While significant strides have been made in PET imaging with radiometal-labeled tracers, the landscape of 18F-labeled small molecule tracers remains relatively limited. Herein, we introduce a novel and promising derivative, [18F]SFB-AMD3465, as a targeted PET tracer for CXCR4. The compound was synthesized by modifying the pyridine ring of AMD3465, which was subsequently labeled with 18F using [18F]SFB. The study provides comprehensive insights into the design, synthesis, and biological evaluation of [18F]SFB-AMD3465. In vitro and in vivo assessments demonstrated the CXCR4-dependent, specific, and sensitive uptake of [18F]SFB-AMD3465 in the CXCR4-overexpressing 4T1 cell line and the corresponding xenograft-bearing mouse model. These findings contribute to bridging the gap in 18F-labeled PET tracers for CXCR4 and underscore the potential of [18F]SFB-AMD3465 as a PET radiotracer for in vivo CXCR4 imaging.

Hydrogen sulfide protects retinal pigment epithelium cells against ferroptosis through the AMPK- and p62-dependent non-canonical NRF2-KEAP1 pathway.

Oxidative stress-induced ferroptosis of retinal pigment epithelium (RPE) cells contributes to retinal degenerative diseases. The antioxidant molecule hydrogen sulfide (H2S) regulates oxidative stress response, but its effect on the ferroptosis of RPE cells is unclear. In this study, sodium hydrosulfide (NaHS) was used as an exogenous H2S donor to intervene tert-butyl hydroperoxide (t-BHP)-induced ferroptosis of APRE-19 cells. We found that NaHS pretreatment attenuates t-BHP-induced oxidative stress and ferroptosis. Analysis of mRNA-sequencing coupled with FerrDb database identified nuclear factor erythroid-2-related factor 2 (NRF2) as a primary target for the cytoprotective role of H2S. NRF2 inhibitor ML385 reverses the effects of H2S on ferroptosis. Biochemical analysis revealed that H2S stabilizes NRF2. H2S decreases the interaction between NRF2 and KEAP1, but enhances the interaction between KEAP1 and p62. These results suggest that H2S activates the non-canonical NRF2-KEAP1 pathway. Further study demonstrated that H2S stimulates AMPK to interact and phosphorylate p62. Additionally, inhibiting AMPK or knocking down p62 blocks the effects of H2S. We speculate that targeting the non-canonical NRF2-KEAP1 pathway by H2S-based drug may benefit the treatment of retinal degenerative diseases.

Inhibitory Effects of Myriocin on Non-Enzymatic Glycation of Bovine Serum Albumin.

Advanced glycation end products (AGEs) are the compounds produced by non-enzymatic glycation of proteins, which are involved in diabetic-related complications. To investigate the potential anti-glycation activity of Myriocin (Myr), a fungal metabolite of Cordyceps, the effect of Myr on the formation of AGEs resulted from the glycation of bovine serum albumin (BSA) and the interaction between Myr and BSA were studied by multiple spectroscopic techniques and computational simulations. We found that Myr inhibited the formation of AGEs at the end stage of glycation reaction and exhibited strong anti-fibrillation activity. Spectroscopic analysis revealed that Myr quenched the fluorescence of BSA in a static process, with the possible formation of a complex (approximate molar ratio of 1:1). The binding between BSA and Myr mainly depended on van der Waals interaction, hydrophobic interactions and hydrogen bond. The synchronous fluorescence and UV-visible (UV-vis) spectra results indicated that the conformation of BSA altered in the presence of Myr. The fluorescent probe displacement experiments and molecular docking suggested that Myr primarily bound to binding site 1 (subdomain IIA) of BSA. These findings demonstrate that Myr is a potential anti-glycation agent and provide a theoretical basis for the further functional research of Myr in the prevention and treatment of AGEs-related diseases.

Inflammatory response in lungs and extrapulmonary sites detected by [18F] fluorodeoxyglucose PET/CT in convalescing COVID-19 patients tested negative for coronavirus.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an ongoing global pandemic of coronavirus disease 2019 (COVID-19). The challenges associated with imaging infected patients have resulted, to date, in a paucity of metabolic imaging studies of patients with severe COVID-19 infection. Furthermore, it remains unclear if any abnormal metabolic events are taking place in patients who have recovered from COVID-19. PURPOSE: To use [18F] fluorodeoxyglucose ([18F] FDG) positron emission tomography/computed tomography (PET/CT) to measure metabolic activity in inflamed organs of patients convalescing post severe COVID-19 infection. MATERIALS AND METHODS: A prospective study was performed in seven convalescing patients who were recovering from severe COVID-19 infection in February 2020. Prior to [18F] FDG PET/CT, all patients had received two consecutive negative results of real-time reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 nucleic acid. Clinical intake including symptoms, treatment, laboratory test results, and follow-up was performed. The PET/CT images of COVID-19 patients were compared to a control group of patients that were matched for age and sex. RESULTS: Residual pulmonary lesions were present in all patients and maximum standard uptake value (SUVmax), average standard uptake value (SUVavg), maximum CT intensity (CTmax), and average CT intensity (CTavg) were all significantly greater than in the control group (p < 0.01 for all). In addition, SUVmax and SUVavg were significantly greater in the mediastinal lymph node and liver, and SUVmax was significantly greater in the spleen, of COVID-19 patients compared with controls (p < 0.05 for all). For the spleen, SUVmax (r2 = 0.863, p = 0.003) and SUVavg (r2 = 0.797, p = 0.007) were significantly correlated with blood lymphocyte count, and which was below the normal range in five of the seven (71.4%) patients convalescing post severe COVID-19 infection. CONCLUSION: [18F] FDG PET/CT quantitative analysis has shown that significant inflammation remained in lungs, mediastinal lymph nodes, spleen, and liver after two consecutive negative RT-PCR tests in patients convalescing post severe COVID-19 infection.

Frontal metabolic activity contributes to individual differences in vulnerability toward total sleep deprivation-induced changes in cognitive function.

Substantial individual differences characterize the changes induced by total sleep deprivation on cognitive functions. Despite some progress having been achieved, the mechanisms of individual differences in response to total sleep deprivation have not been clearly elucidated. Cerebral metabolism in the resting state is among the key physiological processes supporting the daily function of the brain, and may play an important role in these individual differences. Twenty-two right-handed participants (nine females and 13 males) between 20 and 26 years old completed a mathematical processing task both in resting wakefulness and after 24 h of total sleep deprivation. Fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography was used to investigate brain metabolism changes. The mathematical task was performed after the positron emission tomography scans were completed. Correlation analysis was used to investigate the correlations between cognitive performance changes and brain metabolism changes. Large inter-individual differences were found in the throughput changes, but these inter-individual differences were not associated with baseline or post-deprivation performance levels. Specifically, deterioration of throughput on the mathematical processing task was significantly correlated with metabolism changes in the superior frontal medial gyrus. These findings suggested that frontal metabolic activity contributes to individual differences in waking-induced impairment of cognitive performance.

[Correlation of region blood perfusion and glucose metabolism of the prefrontal lobes with clinical features in patients with first-episode depression].

OBJECTIVE: To explore the cerebral blood flow (CBF) by three-dimensional arterial spin labeling (3D-ASL) and the standardized uptake value (SUV) of 18F-fluorodeoxyglucose (18F-FDG) in the prefrontal lobe of patients with major depression disorder (MDD), and analyze their correlations with patients' depressive symptoms. METHODS: 3D-ASL and 18F-FDG positron emission tomography/computed tomography (PET/CT) were performed in 17 MDD patients and 16 healthy controls under the resting state. The depressive symptoms were classified into seven factors using Hamilton depression rating scale. Regional cerebral blood flow (CBF) and standardized uptake value (SUV) were compared between the patients and healthy controls using a two-sample t-test, and the correlation between the CBF and SUV with the patient Hamilton scores was examined using Spearman analysis. RESULTS: Decreased regional CBF values were present in the bilateral middle and the right superior frontal gyrus in patients, and decreased regional SUVs were observed in the bilateral superior, middle and inferior frontal gyrus. The significant correlation between the CBF and SUV values with the patients' Hamilton scores was mainly observed in the left middle, right middle and the right inferior frontal gyrus. CONCLUSION: 18F-FDG PET/CT is more sensitive than ASL in identifying the functional abnormalities in the prefrontal lobe. Decreased CBF and SUV in the prefrontal lobe closely correlate with the Hamilton Depression Rating Scale scores. We speculate that the left middle frontal gyrus may be a key responsible functional region in patients with MDD.

[Diagnostic role of contrast-enhanced whole-heart coronary magnetic resonance angiography in the evaluation of coronary artery disease].

OBJECTIVE: To prospectively evaluate the diagnostic effectiveness of contrast-enhanced whole-heart coronary magnetic resonance angiography (CE-CMRA) in patients with suspected coronary artery disease (CAD) with conventional coronary angiography as the reference standard. METHODS: A total of 72 subjects with suspected CAD scheduled for conventional coronary angiography underwent 3.0-T contrast-enhanced whole-heart CE-MRA. The imaging quality, diagnostic performance and accuracy of CE-MRA for detecting significant stenoses ( ≥ 50%) in coronary arteries were compared with that of quantitative coronary angiography (QCA). RESULTS: The whole-heart CE-MRA examinations were successfully completed in 65 patients. Among 809 segments with a reference luminal diameter ≥ 1.5 mm on CAG, 105 segments on CE-MRA were evaluated as nonassessable(13.0%) and 704 segments assessable.If 105 nonassessable segments on CE-MRA were considered to have significant stenoses, CE-MRA correctly identified CAD in 36/38 patients and correctly ruled out CAD in 21/27 patients. CE-MRA yielded 93.8%, 85.4%, 53.2% and 98.9% for diagnostic sensitivity, specificity, positive predicative value(PPV) and negative predicative value(NPV) on the basis of per-segment versus 94.7%, 77.8%, 85.7% and 91.3% respectively on the basis of per-patient. CONCLUSION: CE-CMRA provides sufficiently high sensitivity and NPV, but moderate specificity and PPV for the diagnosis of CAD.It may be used as an optional imaging modality for CAD screening.

Towards metal selenides: a promising anode for sodium-ion batteries.

Metal selenides have garnered significant attention as promising anode materials for sodium-ion batteries, thanks to their high theoretical capacity, excellent conductivity, and natural abundance. However, their potential is hampered by disappointing capacity retention and unsatisfactory lifespan, primarily attributed to volume expansion and unwanted structural collapse resulting from the insertion and extraction of relatively large Na+ ions during the charge and discharge processes. This feature article provides a brief overview of our endeavors to address the challenges associated with metal selenide-based anode materials, aiming to achieve high-performance electrode materials for sodium-ion batteries. Our strategy encompasses nanostructure design, materials composite engineering, heteroatoms doping, and topography and interface engineering. Additionally, future research directions are also outlined.

Zero-Strain Na3 V2 (PO4 )2 F3 @Rgo/CNT Composite as a Wide-Temperature-Tolerance Cathode for Na-Ion Batteries with Ultrahigh-Rate Performance.

Sodium-ion batteries (SIBs) are widely considered a hopeful alternative to lithium-ion battery technology. However, they still face challenges, such as low rate capability, unsatisfactory cycling stability, and inferior variable-temperature performance. In this study, a hierarchical Na3 V2 (PO4 )2 F3 (NVPF) @reduced graphene oxide (rGO)/carbon nanotube (CNT) composite (NVPF@rGO/CNT) is successfully constructed. This composite features 0D Na3 V2 (PO4 )2 F3 nanoparticles are coated by a cross-linked 3D conductive network composed of 2D rGO and 1D CNT. Furthermore, the intrinsic Na+ storage mechanism of NVPF@rGO/CNT through comprehensive characterizations is unveiled. The synthesized NVPF@rGO/CNT exhibits fast ionic/electronic transport and excellent structural stability within wide working temperatures (-40-50 °C), owing to the zero-strain NVPF and the coated rGO/CNT conductive network that reduces diffusion distance for ions and electrons. Moreover, the stable integration between NVPF and rGO/CNT enables outstanding structural stability to alleviate strain and stress induced during the cycle. Additionally, a practice full cell is assembled employing a hard carbon anode paired with an NVPF@rGO/CNT cathode, which provides a decent capacity of 105.2 mAh g-1 at 0.2 C, thereby attaining an ideal energy density of 242.7 Wh kg-1 . This work provides valuable insights into developing high-energy and power-density cathode materials for SIBs.

Scalable fabrication of free-standing and integrated electrodes with commercial level of areal capacity for aqueous zinc-ion batteries.

Aqueous zinc-ion batteries (AZIBs) present a highly promising avenue for the deployment of grid-scale energy storage systems. However, the electrodes fabricated through conventional methodologies not only suffer from insufficient mass loadings, but also are susceptible to exfoliation under deformations. Herein, a scalable and cost-effective freezing-thawing method is developed to construct free-standing and integrated electrode, comprising H11Al2V6O23.2, carboxymethyl cellulose, and carbon nanotubes. Benefiting from the synergistic effect of these components, the resultant electrode exhibits superior flexibility and robustness, large tensile strength, exceptional electrical conductivity, and favorable electrolyte wettability. Under a large mass loading of 8 mg cm-2 (corresponding to a negative/positive electrode capacity ratio of 2.09), the electrode achieves remarkable capacity of 345.2 mAh/g (2.76 mAh cm-2) at 0.2 A/g and maintains 235.2 mAh/g (1.88 mAh cm-2) at 4 A/g, while sustaining an impressive capacity retention of 97.7 % over 5000 cycles. These considerably outperform conventional electrodes employing traditional binders. Even at an elevated mass loading of 14 mg cm-2 or when operated at a low temperature of - 30 °C, the electrode continues to deliver excellent electrochemical performance (e.g., extraordinary areal capacity of 4.32 mAh cm-2). In addition, the electrode owns outstanding tolerance to external forces. This research contributes to our understanding of the pivotal challenges within the realm of AZIB technology.

Microwave-Assisted Hydrothermal Synthesis of Na3V2(PO4)2F3 Nanocuboid@Reduced Graphene Oxide as an Ultrahigh-Rate and Superlong-Lifespan Cathode for Fast-Charging Sodium-Ion Batteries.

Na3V2(PO4)2F3 (NVPF) has been regarded as a favorable cathode for sodium-ion batteries (SIBs) due to its high voltage and stable structure. However, the limited electronic conductivity restricts its rate performance. NVPF@reduced graphene oxide (rGO) was synthesized by a facile microwave-assisted hydrothermal approach with subsequent calcination to shorten the hydrothermal time. NVPF nanocuboids with sizes of 50-150 nm distributed on rGO can be obtained, delivering excellent electrochemical performance such as a longevity life (a high capacity retention of 85.6% after 7000 cycles at 10 C) and distinguished rate capability (116 mAh g-1 at 50 C with a short discharging/charging time of 1.2 min). The full battery with a Cu2Se anode represents a capacity of 116 mAh g-1 at 0.2 A g-1. The introduction of rGO can augment the electronic conductivity and advance the Na+ diffusion speed, boosting the cycling and rate capability. Besides, the small lattice change (3.3%) and high structural reversibility during the phase transition process between Na3V2(PO4)2F3 and NaV2(PO4)2F3 testified by in situ X-ray diffraction are also advantageous for Na storage behavior. This work furnishes a simple method to synthesize polyanionic cathodes with ultrahigh rate and ultralong lifespan for fast-charging SIBs.

One-step Solid-State Synthesis of V1.13Se2/V2O3 Heterostructure as a High Pseudocapacitance Anode for Fast-Charging Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) offer several benefits, including cost-efficiency and fast-charging characteristics, positioning them as attractive substitutes for lithium-ion batteries in energy storage applications. However, the inferior capacity and cycling stability of electrodes in SIBs necessitate further enhancement due to sluggish reaction kinetics. In this respect, the utilization of heterostructures, which can provide an inherent electric field and abundant active sites on the surface, has emerged as a promising strategy for augmenting the cycling stability and rate features of the electrodes. This work delves into the utilization of V1.13Se2/V2O3 heterostructure materials as anodes, initially fabricated via a simplified one-step solid-state sintering technique. The high pseudocapacitance and low characteristic relaxation time constant give the V1.13Se2/V2O3 heterostructure impressive properties, such as a high capacity of 328.5 mAh g-1 even after 1500 cycles at a high current density of 2 A g-1 and rate capability of 278.9 mAh g-1 at 5 A g-1. Moreover, the assembled sodium-ion full battery delivers a capacity of 118.5 mAh g-1 after 1000 cycles at 1 A g-1. These findings provide novel insight and guidance for the rapid synthesis of heterojunction materials and the advancement of SIBs.

Electrochemical dealloying of Al2(Au,X) (X = Pt, Pd, PtPd, Ni, Co and NiCo) alloys in NaCl aqueous solution.

The electrochemical dealloying of rapidly solidified Al2(Au,X) (X = Pt, Pd, PtPd, Ni, Co and NiCo) precursors in a 1.0 M NaCl aqueous solution has been systematically investigated using electrochemical measurements including open-circuit measurement, potentiodynamic polarization and potentiostatic polarization, and microstructural analysis. The results show that the kind of alloying element(s) has a significant influence on the open-circuit and corrosion potentials of the rapidly solidified Al2(Au,X) precursors. The bulk dealloying of the Al2(Au,X) precursors is affected by the kind of alloying element(s) and also sensitive to the applied potential (or overpotential). The addition of Ni or/and Co easily leads to passivation on the surface of precursors during potentiostatic dealloying. The potentiostatic dealloying of Al2(Au,Pt), Al2(Au,Pd) and Al2(Au,Pt,Pd) results in the formation of ultrafine nanoporous AuPt, AuPd and AuPtPd alloys, owing to the pinning effect of Pt or/and Pd on surface diffusion of Au adatoms. In comparison, the potentiostatic dealloying of Al2(Au,Ni), Al2(Au,Co) and Al2(Au,Ni,Co) leads to the formation of nanoporous Au with a ligament/channel size of ~40 nm due to the simultaneous dissolution of Al and Ni/Co. Moreover, the addition of Pt, Pd or PtPd not only inhibits surface diffusion of Au adatoms (lower diffusivities), but also improves the activation energy for the diffusion process during potentiostatic dealloying. Based upon the present results, nanoporous metals or alloys can be greenly fabricated through electrochemical dealloying in NaCl solutions.

Integrin αvß3 and EGFR dual-targeted [64Cu]Cu-NOTA-RGD-GE11 heterodimer for PET imaging in pancreatic cancer mouse model.

PURPOSE: Radiolabeled heterodimeric peptide has emerged as a highly promising targeting strategy for PET imaging due to their superior properties. RGD and GE11 are two peptides binding to receptor integrin αvß3 and EGFR, respectively, which both overexpress in many different types of tumors. This study focuses on the synthesis and evaluation of a RGD and GE11-containing heterodimeric radiotracer [64Cu]Cu-NOTA-RGD-GE11 for PET imaging of tumors that simultaneously overexpress integrin αvß3 and EGFR. PROCEDURES: [64Cu]Cu-NOTA-RGD-GE11 was prepared by the conjugation of RGD-PEG4-NOTA-N3 and GE11-PEG4-BCN via metal-free click chemistry, followed by radiolabeling with 64Cu. Cell uptake and efflux studies, saturation binding assay, the animal PET/CT and biodistribution studies were conducted to characterize the biological properties of [64Cu]Cu-NOTA-RGD-GE11. RESULTS: [64Cu]Cu-NOTA-RGD-GE11 was synthesized with a radiochemical purity of >97 % and molar activity of 23 GBq/µmol at the end of synthesis. [64Cu]Cu-NOTA-RGD-GE11 showed moderate hydrophilicity, good stability in mouse serum and high specific uptake by the human pancreatic cancer cell line (BxPC3) in the in vitro studies. Compared to the two monomeric counterparts [64Cu]Cu-NOTA-RGD and [64Cu]Cu-NOTA-GE11, [64Cu]Cu-NOTA-RGD-GE11 demonstrated significantly improved tumor uptakes (e.g. 4.63 ± 0.25 %ID/g vs 1.24 ± 0.18 %ID/g and 0.77 ± 0.13 %ID/g, 2 h after injection, p < 0.05) in the subsequent in vivo evaluation in mice bearing BxPC3 xenograft. Tumor uptake could be blocked in the presence of both non-radioactive c(RGDyK) and GE11 peptides, indicating good tumor specificity of [64Cu]Cu-NOTA-RGD-GE11 in vivo. CONCLUSION: The results suggested that the as-developed [64Cu]Cu-NOTA-RGD-GE11 could serve as a potential PET tracer for the noninvasive imaging of integrin αvß3 and EGFR expression in tumors.

Delayed 18F-FDG PET imaging provides better metabolic asymmetry in potential epileptogenic zone in temporal lobe epilepsy.

Objective: To investigate the value of 18F-FDG positron emission tomography/computed tomography (PET/CT) two time point imaging for the identification of the potential epileptogenic zone (EZ) in temporal lobe epilepsy (TLE). Methods: Fifty-two patients with TLE were prospectively enrolled in the 18F-FDG PET/CT two time point imaging study. The early imaging was obtained approximately 40 min (43.44 ± 18.04 min) after 18F-FDG injection, and the delayed imaging was obtained about 2 to 3 h (160.46 ± 28.70 min) after the injection. Visual and semi-quantitative analysis of 18F-FDG uptake were performed at the two time points in EZ and contralateral symmetrical region. The mean standardized uptake value (SUVmean) of EZ and contralateral symmetrical region was calculated to determine the asymmetry index (AI) of the early and delayed images, as well as in the MRI positive and negative patient groups. Results: Semi-quantitative analysis demonstrated that AI of the early and delayed 18F-FDG PET/CT images was 13.47 ± 6.10 and 16.43 ± 6.66, respectively. The ΔAI was 2.95 ± 3.05 in 52 TLE patients between the two time points. The AI of the EZ was significantly elevated in delayed images compared to the early images (p < 0.001). The AI of delayed imaging was also significantly elevated compared to the early imaging in both MRI positive (ΔAI = 2.81 ± 2.54, p < 0.001) and MRI negative (ΔAI = 3.21 ± 3.91, p < 0.003) groups, and more pronounced in MRI negative group. Visual analysis also showed that the delayed imaging appeared to be superior to the early imaging for identification of potential EZ. Conclusion: Delayed 18F-FDG PET imaging provided significantly better than the early imaging in the identification of potential EZ, which can be valuable during epilepsy pre-surgical evaluation in patients with TLE.

Effects of Internet Adoption on Health and Subjective Well-Being of the Internal Migrants in China.

During the past decades, the number of rural-urban migrants has dramatically increased in China. Their well-being is important for social development and has attracted the attention of researchers. This paper adopts five waves of repeated cross-sectional datasets within a nine-year span, included in the Chinese General Social Survey (CGSS 2010-2018), to evaluate the impacts and mechanisms of internet adoption on the health status and subjective well-being of rural-urban migrants. Empirical results suggest that there are significant positive correlations between internet adoption and health status as well as subjective well-being. The results of structural equation modeling suggest that the impact of the internet on well-being occurs through increasing, bridging, and bonding social capital for rural-urban migrants. The mediating impact of bonding social capital on subjective well-being is more prominent, while the mediating impact of bridging social capital on health is stronger. Furthermore, we have explored the heterogeneous effects across gender and education. This is an early study which investigates such an important topic in the context of the digital era.

Bullying Victimization, Coping Strategies, and Depression of Children of China.

It is common knowledge that bullying victimization and coping strategies significantly affect the psychological well-being of children. However, which coping strategies are more effective at a particular level of bullying victimization is underexplored. Using survey data from 1,634 children from 10 schools in Wuhan, China, this study aims to investigate the abovementioned research gap. The results of factor analysis suggest that coping strategies of children in China can be divided into three types: help-seeking, avoidance, and self-defense. The results of multilevel modeling suggest that children adopting different coping strategies have distinct levels of depression. Help seekers show a significantly lower level of depression than self-defenders and avoiders. However, with increased bullying victimization, the effectiveness of the help-seeking strategy gradually decreases to offset the negative effect of bullying victimization on psychological well-being. Instead, those who adopt the self-defense strategy display a lower level of depression. The findings of this study suggest that there is no single coping strategy that is best for children, and the more effective strategy largely relies on the level of bullying victimization. The findings also imply that without external support, it is almost impossible for children to completely overcome the negative consequences of bullying on their own.