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An unprecedented thunderstorm ground enhancement (TGE) event was recorded on May 23, 2023, at Aragats Mountain, the highest peak in Armenia. This event showcased a maximum flux intensity surpassing 3 million particles per minute per square meter for energies above 0.4 MeV. Distinctly, the fluence of the event was measured at approximately ≈700 particles/cm2. The comprehensive instrumentation at the Aragats research station, including a suite of spectrometers and detectors, enabled precise cross-correlation of measurements. The electron flux at energies exceeding 10 MeV was observed at roughly ≈55,000 particles per minute per square meter. Additional measurements, including cloud base heights and corona discharge detections, validated the intensity of the electric field, reaching approximately 2.1 kV/cm at elevations 50–100 m above ground level. Our observations confirm that TGE is a universal and significant atmospheric event, contributing a substantial flux of high-energy electrons to the global electrical circuit. Integrating such TGE phenomena into Earth's numerical models is imperative, considering their impact on aviation and aerospace operation safety. [ABSTRACT FROM AUTHOR]

Nowadays, Indian power distribution companies (PDCs) are implementing smart distribution networks. Older cities are becoming smarter as per the recent government’s policy. Existing overhead distribution lines are being replaced by underground cables as an essential criterion of a smart city. One of the main problems arising in this process is the overheating of the neutral grounding resistor (NGR) in 11 kV distribution systems, even in normal conditions. NGRs, placed inside the substations, are overloading the air conditioning and exhaust systems of the substation. Sometimes failure of the NGR occurs due to overheating. In this paper, a comprehensive investigation has been carried out to reach the roots of this problem. It is observed that long underground cables have a higher ground capacitance than overhead distribution lines. Due to the higher cable capacitance, the third harmonic current circulates through neutral, which overheats the NGR even in normal conditions. The situation becomes worse when the substation runs on diesel generators (DGs) in an isolated state under main grid failure, as a higher amount of third-harmonic current circulates depending on the type of winding and pitch factor of the DGs. Different solutions are proposed, and their advantages and disadvantages are analyzed. Finally, the rating of the NGR is modified, and louvers-cooling fan arrangement is preferred for the running substation. [ABSTRACT FROM AUTHOR]

The transformer grounding is typically inserted across a transformer or generator's ground. In a transformer and generator, this ground is often used to reduce the current of a disturbance from phase to earth. During a ground fault in a transformer, a very high current can flow, posing a danger to equipment and personnel. By connecting a resistor between the neutral point of the transformer and ground, the NGR limits this fault current. In the following paper, the protection mechanism of two high-voltage to medium-voltage transformers which connected in parallel during routine operation as well as in emergency situations will be explored. Protecting two parallel transformers with two different neutral grounding resistors involves ensuring proper coordination of protective devices to detect and isolate faults while minimizing damage to equipment and ensuring system stability. Another scenario under discussion involves a generator linked to the medium-voltage (MV) system, which distinct had a distinct ground value. A short circuit occurring in different neutral grounding resistor (NGR) systems refers to a fault scenario where more than one transformer or generator linked in parallelly, each with its own NGR of varying resistance values. This situation poses challenges for protection coordination and fault current distribution. To address this issue, a protective scheme is suggested, which modifies its configurations according to the operational status of the system. [ABSTRACT FROM AUTHOR]

Abstract The primary challenge to improving existing cancer treatment is to develop drugs that specifically target tumor cell. NGR peptide is tumor homing peptide that selectively target cancer cells while interleukin 15 is a pleiotropic cytokine with anticancer properties. This study computationally engineered a IL15-NGR fusion peptide by linking the homing peptide NGR with the targeting peptide IL-15. After evaluating and validating the chimeric peptide, we docked it to the IL-15Rα/IL-15Rβ/γc heterodimer receptor, examining the interactions and binding energy and lastly, molecular dynamics simulations were performed. The secondary and tertiary structures, along with physicochemical properties of the designed IL-15-NGR chimeric protein, were predicted using GOR IV, trRosetta and ProtParam online servers respectively. The quality and 3D structure validation were confirmed via ProSA-web and SAVES 6.0 analysis which predicted an ERRAT score of 96.72%, with 97.6% of residues in the Ramachandran plot, validating its structure. Finally, Docking, MD simulations and interaction analysis were performed using ClusPro 2.0 and GROMACS and PDBsum, which exhibited significant hydrogen bonding and salt bridges, confirming the formation of a stable docked complex. These results were further corroborated by simulation analysis, which demonstrated a stable and dynamic behavior of the docked complex in a biological environment. The predicted high expression value of fusion protein was 0.844 in E.coli using SOLUPROT tool. These findings suggest efficient expression of the IL15-NGR fusion protein if its gene is inserted into E. coli and indicates its potential as a safe and effective anticancer treatment, paving the way for targeted therapeutic interventions. Graphical abstract

The primary challenge to improving existing cancer treatment is to develop drugs that specifically target tumor cell. NGR peptide is tumor homing peptide that selectively target cancer cells while interleukin 15 is a pleiotropic cytokine with anticancer properties. This study computationally engineered a IL15-NGR fusion peptide by linking the homing peptide NGR with the targeting peptide IL-15. After evaluating and validating the chimeric peptide, we docked it to the IL-15Rα/IL-15Rβ/γc heterodimer receptor, examining the interactions and binding energy and lastly, molecular dynamics simulations were performed. The secondary and tertiary structures, along with physicochemical properties of the designed IL-15-NGR chimeric protein, were predicted using GOR IV, trRosetta and ProtParam online servers respectively. The quality and 3D structure validation were confirmed via ProSA-web and SAVES 6.0 analysis which predicted an ERRAT score of 96.72%, with 97.6% of residues in the Ramachandran plot, validating its structure. Finally, Docking, MD simulations and interaction analysis were performed using ClusPro 2.0 and GROMACS and PDBsum, which exhibited significant hydrogen bonding and salt bridges, confirming the formation of a stable docked complex. These results were further corroborated by simulation analysis, which demonstrated a stable and dynamic behavior of the docked complex in a biological environment. The predicted high expression value of fusion protein was 0.844 in E.coli using SOLUPROT tool. These findings suggest efficient expression of the IL15-NGR fusion protein if its gene is inserted into E. coli and indicates its potential as a safe and effective anticancer treatment, paving the way for targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the most common cancer for men. Current therapies such as chemotherapy or radiotherapy non-spesifically affect cancerous cells. Current therapies need more targeted delivery approaches such as peptide. Asn-Gly-Arg (NGR) is a tool for cancer targeting therapy. To mimic more natural cancer microenvironment, peptide treatment approaches are examined in 3 Dimensional (D) hydrogels. GelMA is one of the hydrogels that permits to construct 3D microenvironment of PC3 prostate cancer cells. The goal of the study was to evaluate characteristic of GelMA to model prostate cancer environment and to determine the effects of NGR peptides for PC3 line. pH values of different concentrations NGR (1 µM, 10 µM and 100 µM)-GelMA were measured. To analyze biodegradation capacity of different concentrations NGR (1 µM, 10 µM and 100 µM)-GelMA, weigth measurements were performed. Live and Dead analysis was performed on days 1, 4, and 7. The findings revealed that GelMA hydrogels created a relatively stable and neutral pH, making them potentially valuable for drug delivery systems. Furthermore, the NGR-GelMA hydrogels incorporated exhibited the capacity to absorb liquids, resulting in an increase in weight. Notably, these hydrogels allowed for the observation of the dynamic 3D microenvironment of prostate cancer, which was influenced by the concentration of the targeted drug in the GelMA matrix. This suggests promising implications for developing targeted therapies for prostate cancer using GelMA-based drug delivery systems. As a conclusion, GelMA and NGR-GelMA hyrdogels may be useful platform for further studies to progress on prostate cancer treatment.

Prostate cancer is one of the most common cancer for men. Current therapies such as chemotherapy or radiotherapy non-spesifically affect cancerous cells. Current therapies need more targeted delivery approaches such as peptide. Asn-Gly-Arg (NGR) is a tool for cancer targeting therapy. To mimic more natural cancer microenvironment, peptide treatment approaches are examined in 3 Dimensional (D) hydrogels. GelMA is one of the hydrogels that permits to construct 3D microenvironment of PC3 prostate cancer cells. The goal of the study was to evaluate characteristic of GelMA to model prostate cancer environment and to determine the effects of NGR peptides for PC3 line. pH values of different concentrations NGR (1 µM, 10 µM and 100 µM)-GelMA were measured. To analyze biodegradation capacity of different concentrations NGR (1 µM, 10 µM and 100 µM)-GelMA, weigth measurements were performed. Live and Dead analysis was performed on days 1, 4, and 7. The findings revealed that GelMA hydrogels created a relatively stable and neutral pH, making them potentially valuable for drug delivery systems. Furthermore, the NGR-GelMA hydrogels incorporated exhibited the capacity to absorb liquids, resulting in an increase in weight. Notably, these hydrogels allowed for the observation of the dynamic 3D microenvironment of prostate cancer, which was influenced by the concentration of the targeted drug in the GelMA matrix. This suggests promising implications for developing targeted therapies for prostate cancer using GelMA-based drug delivery systems. As a conclusion, GelMA and NGRGelMA hyrdogels may be useful platform for further studies to progress on prostate cancer treatment. [ABSTRACT FROM AUTHOR]

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process Umincorp (EU register number RECYC302), which uses the NGR technology. The input consists of washed and dried poly(ethylene terephthalate) (PET) flakes mainly originating from collected post‐consumer PET containers, with no more than 5% PET from non‐food consumer applications. The flakes are dried (step 2), melted in an extruder (step 3) and decontaminated during a melt‐state polycondensation step ■■■■■ (step 4). In step 5, the melt is cooled down and granulated. Having examined the challenge test provided, the Panel concluded that the melt‐state polycondensation (step 4) is critical in determining the decontamination efficiency of the process. The operating parameters to control the performance are the pressure, the temperature, the residence time (depending on the mass and throughput of the melt) and the characteristics of the reactor. It was demonstrated by the challenge test that this recycling process is able to ensure that the level of migration of potential unknown contaminants into food is below the conservatively modelled migration of 0.1 μg/kg food. Therefore, the Panel concluded that the recycled PET obtained from this process is not of safety concern when used at up to 100% for the manufacture of materials and articles for contact with all types of foodstuffs, including drinking water, for long‐term storage at room temperature, with or without hotfill. The final articles made of this recycled PET are not intended to be used in microwave and conventional ovens and such uses are not covered by this evaluation. [ABSTRACT FROM AUTHOR]

This study is a continuation of an investigation into the effect of a targeted component, a peptide with an NGR, on the properties of the previously developed doxorubicin phospholipid delivery system. The NGR peptide has an affinity for aminopeptidase N (known as the CD13 marker on the membrane surface of tumor cells) and has been extensively used to target drug delivery systems. This article presents the results of a study investigating the physical properties of the phospholipid composition with and without the peptide chain: particle size, zeta potential, stability in fluids, and dependence of doxorubicin release from nanoparticles at different pH levels (5.0, 6.5, 7.4). The cytotoxic effect of the compositions has also been shown to depend on the dose of the drug used for incubation, the presence of the targeted component in the composition, and the time of incubation time of the substances. There was a significant difference in the cytotoxic effect on HT-1080 (CD13-positive) and MCF-7 (CD13-negative) cells. Cell death pathway analysis has shown that death occurred mainly by apoptosis. We also present data on the effect of doxorubicin embedded in phospholipid nanoparticles with the targeted peptide on DNA assessed by differential pulse voltammetry, the mechanism of action being electrostatic interactions. The interactions of native dsDNA with doxorubicin encapsulated in phospholipid nanoparticles with the targeted peptide were studied electrochemically by differential pulse voltammetry. Here, we have highlighted that the targeted peptide in the doxorubicin composition moved specific interaction of the drug with dsDNA from intercalative mode to electrostatic interactions. [ABSTRACT FROM AUTHOR]

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process CCH CIRCULARPET (EU register number RECYC284), which uses the NGR technology. The input is washed and dried poly(ethylene terephthalate) (PET) flakes mainly originating from collected post‐consumer PET containers, with no more than 5% PET from non‐food consumer applications. The flakes are dried (step 2), melted in an extruder (step 3) and decontaminated during a melt‐state polycondensation step ■■■■■ (step 4). In step 5, the material is granulated. Having examined the challenge test provided, the Panel concluded that the melt‐state polycondensation (step 4) is critical in determining the decontamination efficiency of the process. The operating parameters to control the performance of the critical step are the pressure, the temperature, the residence time (depending on the mass and throughput of the melt) and the characteristics of the reactor. It was demonstrated that this recycling process is able to ensure that the level of migration of potential unknown contaminants into food is below the conservatively modelled migration of 0.1 μg/kg food. Therefore, the Panel concluded that the recycled PET obtained from this process is not of safety concern when used at up to 100% for the manufacture of materials and articles for contact with all types of foodstuffs, including drinking water, for long‐term storage at room temperature, with or without hotfill. The final articles made of this recycled PET are not intended to be used in microwave and conventional ovens and such uses are not covered by this evaluation. [ABSTRACT FROM AUTHOR]

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process Coca‐Cola HBC (EU register number RECYC285), which uses the NGR technology. The input is washed and dried poly(ethylene terephthalate) (PET) flakes mainly originating from collected post‐consumer PET containers, with no more than 5% PET from non‐food consumer applications. The flakes are dried (step 2), melted in an extruder (step 3) and decontaminated during a melt‐state polycondensation step ■■■■■ (step 4). In step 5, the material is granulated. Having examined the challenge test provided, the Panel concluded that the melt‐state polycondensation (step 4) is critical in determining the decontamination efficiency of the process. The operating parameters to control the performance of the critical step are the pressure, the temperature, the residence time (depending on the mass and throughput of the melt) and the characteristics of the reactor. It was demonstrated that this recycling process is able to ensure that the level of migration of potential unknown contaminants into food is below the conservatively modelled migration of 0.1 μg/kg food. Therefore, the Panel concluded that the recycled PET obtained from this process is not of safety concern when used at up to 100% for the manufacture of materials and articles for contact with all types of foodstuffs, including drinking water, for long‐term storage at room temperature, with or without hotfill. The final articles made of this recycled PET are not intended to be used in microwave and conventional ovens and such uses are not covered by this evaluation. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) chemoresistance presents a significant clinical challenge. This study aims to investigate the potential of using tumor vascular-targeting peptide NGR-modified cancer-associated fibroblasts (CAFs)-derived exosomes (exos) to deliver circ_0004872-encoded small peptides promoting autophagy-dependent ferroptosis to reverse chemoresistance in OS. Through combined single-cell transcriptome analysis and high-throughput sequencing, it identified circ_0004872 associated with chemoresistance. Subsequent experiments demonstrated that the small peptide encoded by this Circular RNA (circRNA) can effectively reverse chemoresistance by enhancing OS cell sensitivity to chemotherapy via the mechanism of promoting autophagy-dependent ferroptosis. Moreover, in vitro and in vivo results confirmed the efficient delivery of NGR-modified CAFs-derived exo-packaged circ_0004872-109aa to tumor cells, thereby improving targeted therapy efficacy. This study not only offers a novel strategy to overcome chemoresistance in OS but also highlights the potential application value of utilizing exos for drug delivery., (© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

In this paper, the pH-sensitive targeting functional material NGR-poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate (NGR-PEtOz-CHMC, NPC) modified quercetin (QUE) liposomes (NPC-QUE-L) was constructed. The structure of NPC was confirmed by infrared spectroscopy (IR) and nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR). Pharmacokinetic results showed that the accumulation of QUE in plasma of the NPC-QUE-L group was 1.28 times and 2.43 times that of the QUE Solution and QUE-L groups, respectively. The release amount of NPC-QUE-L in an acidic environment was significantly higher than in physiological pH value. The order of the tumor cell inhibition rate in different pH environments was NPC-QUE-L > PC-QUE-L > QUE-L. In addition, the cellular uptake of NPC-modified liposomes was higher than that of PC-modified and unmodified liposomes, indicating that NPC had good pH-sensitivity and targeting. In the triple-negative breast cancer (TNBC) model, the relative tumor proliferation rate of NPC-QUE-L is about 73%, which is better than that of the QUE solution group. Western blot results show that NPC-QUE-L can effectively reduce the expression of α-smooth actin and transforming growth factor-β1 in tumor tissues, and improve the degree of tumor fibrosis. In this study, NPC could endow QUE liposomes with good stability, pH-sensitivity, and targeting, which provides a reference for improving the solubility and targeting of poorly soluble natural drug components.

Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system. It is mainly expressed by oligodendrocytes. Although previous studies have found regulatory roles for Nogo-A in neurite outgrowth inhibition, neuronal homeostasis, precursor migration, plasticity, and neurodegeneration, its functions in the process of oxidative injury are largely uncharacterized. In this study, oligodendrocytes were extracted from the cerebral cortex of newborn Sprague-Dawley rats. We used hydrogen peroxide (H2O2) to induce an in vitro oligodendrocyte oxidative damage model and found that endogenously expressed Nogo-A is significantly upregulated in oligodendrocytes. After recombinant virus Ad-ZsGreen-rat Nogo-A infection of oligodendrocytes, Nogo-A expression was increased, and the infected oligodendrocytes were more susceptible to acute oxidative insults and exhibited a markedly elevated rate of cell death. Furthermore, knockdown of Nogo-A expression in oligodendrocytes by Ad-ZsGreen-shRNA-Nogo-A almost completely protected against oxidative stress induced by exogenous H2O2. Intervention with a Nogo-66 antibody, a LINGO1 blocker, or Y27632, an inhibitor in the Nogo-66-NgR/p75/LINGO-1-RhoA-ROCK pathway, did not affect the death of oligodendrocytes. Ad-ZsGreen-shRNA-Nogo-A also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and inhibited BCL2 expression in oligodendrocytes. In conclusion, Nogo-A aggravated reactive oxygen species damage in oligodendrocytes, and phosphorylated extracellular signal-regulated kinase 1/2 and BCL2 might be involved in this process. This study was approved by the Ethics Committee of Peking University People’s Hospital, China (approval No. 2018PHC081) on December 18, 2018.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process Indorama Ventures Recycling Verdun (IVRV) (EU register number RECYC240), which uses the NGR technology. The input is washed and dried poly(ethylene terephthalate) (PET) flakes mainly originating from collected post‐consumer PET containers, with no more than 5% PET from non‐food consumer applications. The flakes are dried (step 2), melted in an extruder (step 3) and decontaminated during a melt‐state polycondensation step under high temperature and vacuum (step 4). In step 5, the melt material is granulated. Having examined the challenge test provided, the Panel concluded that the melt‐state polycondensation (step 4) is critical in determining the decontamination efficiency of the process. The operating parameters to control the performance of the critical steps are the pressure, the temperature, the residence time (depending on the mass and throughput of the melt) and the characteristics of the reactor. It was demonstrated that this recycling process is able to ensure that the level of migration of potential unknown contaminants into food is below the conservatively modelled migration of 0.1 μg/kg food. Therefore, the Panel concluded that the recycled PET obtained from this process is not of safety concern, when used at up to 100% for the manufacture of materials and articles for contact with all types of foodstuffs, including drinking water, for long‐term storage at room temperature, with or without hotfill. The final articles made of this recycled PET are not intended to be used in microwave and conventional ovens and such uses are not covered by this evaluation. [ABSTRACT FROM AUTHOR]

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process Wellman Neufchâteau Recyclage (WNR) (EU register number RECYC233), which uses the NGR technology. The input is washed and dried poly(ethylene terephthalate) (PET) flakes mainly originating from collected post‐consumer PET containers, with no more than 5% PET from non‐food consumer applications. The flakes are dried (step 2), melted in an extruder (step 3) and decontaminated during a melt‐state polycondensation step under high temperature and vacuum (step 4). In step 5, the melt material is granulated. Having examined the challenge test provided, the Panel concluded that the melt‐state polycondensation (step 4) is critical in determining the decontamination efficiency of the process. The operating parameters to control the performance of the critical steps are the pressure, the temperature, the residence time (depending on the mass and throughput of the melt) and the characteristics of the reactor. It was demonstrated that this recycling process is able to ensure that the level of migration of potential unknown contaminants into food is below the conservatively modelled migration of 0.1 μg/kg food. Therefore, the Panel concluded that the recycled PET obtained from this process is not of safety concern, when used at up to 100% for the manufacture of materials and articles for contact with all types of foodstuffs, including drinking water, for long‐term storage at room temperature, with or without hotfill. The final articles made of this recycled PET are not intended to be used in microwave and conventional ovens and such uses are not covered by this evaluation. [ABSTRACT FROM AUTHOR]

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process rPET InWaste (EU register number RECYC231), which uses the NGR technology. The input is washed and dried poly(ethylene terephthalate) (PET) flakes mainly originating from collected post‐consumer PET containers, with no more than 5% PET from non‐food consumer applications. The flakes are dried (step 2), melted in an extruder (step 3) and decontaminated during a melt‐state polycondensation step under high temperature and vacuum (step 4). In step 5, the melt material is granulated. Having examined the challenge test provided, the Panel concluded that the melt‐state polycondensation (step 4) is critical in determining the decontamination efficiency of the process. The operating parameters to control the performance of the critical steps are the pressure, the temperature, the residence time (depending on the mass and throughput of the melt) and the characteristics of the reactor. It was demonstrated that this recycling process is able to ensure that the level of migration of potential unknown contaminants into food is below the conservatively modelled migration of 0.1 μg/kg food. Therefore, the Panel concluded that the recycled PET obtained from this process is not of safety concern, when used at up to 100% for the manufacture of materials and articles for contact with all types of foodstuffs, including drinking water, for long‐term storage at room temperature, with or without hotfill. The final articles made of this recycled PET are not intended to be used in microwave and conventional ovens and such uses are not covered by this evaluation. [ABSTRACT FROM AUTHOR]

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of the recycling process 3R (EU register number RECYC237), which uses the NGR technology. The input is washed and dried poly(ethylene terephthalate) (PET) flakes mainly originating from collected post‐consumer PET containers, with no more than 5% PET from non‐food consumer applications. The flakes are dried (step 2), melted in an extruder (step 3) and decontaminated during a melt‐state polycondensation step under high temperature and vacuum (step 4). In step 5, the melt material is granulated. Having examined the challenge test provided, the Panel concluded that the melt‐state polycondensation (step 4) is critical in determining the decontamination efficiency of the process. The operating parameters to control the performance of the critical steps are the pressure, the temperature, the residence time (depending on the mass and throughput of the melt) and the characteristics of the reactor. It was demonstrated that this recycling process is able to ensure that the level of migration of potential unknown contaminants into food is below the conservatively modelled migration of 0.1 μg/kg food. Therefore, the Panel concluded that the recycled PET obtained from this process is not of safety concern, when used at up to 100% for the manufacture of materials and articles for contact with all types of foodstuffs, including drinking water, for long‐term storage at room temperature. The final articles made of this recycled PET are not intended to be used in microwave and conventional ovens and such uses are not covered by this evaluation. [ABSTRACT FROM AUTHOR]

In the future, hybrid aluminum matrix composites, which are the second generation composites, will be replaced by solid reinforced third-generation quaternary hybrid composites in which nano- and micro-scale reinforcement particles are used together. In this study, microwave sinterability of B4C, TiO2 (nm + µm), and nGr reinforced quaternary hybrid composites that had AlCu4.5SiMg alloyed Matrix, and their microstructural and tribological properties after sintering were examined. The proportion of nGr in the composite sample was taken as 0.5 wt%, while B4C and TiO2 were used in three different proportions (3, 9, 12 wt%). After being compressed under 600 MPa pressure, the composite samples were sintered for 60 min at 550 °C by a microwave oven with a power of 2.9 kW and a frequency of 2.45 GHz. It was determined that due to its high microwave absorbency, B4C reinforcement improved the microwave sinterability more compared to TiO2. In XRD analyses, whereas Al4C3 and Al3BC reaction products were not seen as harmful, the intermetallic phase of Al2Cu was detected. It was determined that both friction coefficient and wear resistance increased as the proportion of B4C increased in composite samples. In AlCu4.5SiMg–(12 wt% B4C/3 wt% TiO2/0.5 wt% nGr) quaternary hybrid composites with the highest hardness (97.6 HV), the lowest specific wear rate (0.118 mm3 Nm × 10−3) was detected. [ABSTRACT FROM AUTHOR]

Li S, Wang X. Int J Nanomedicine. 2017;12:5797–5804. The Editor and Publisher of International Journal of Nanomedicine wish to retract the published article. Concerns were raised regarding the alleged duplication of images in Figure 7 with the same images from other unrelated articles. Specifically, Figure 7A, Liver appears to have been duplicated with the same image from Figure 5C, Liver from Zhou et al, 2017 (https://doi.org/10.2147/DDDT.S146925) and Figure 4Bc from Li & Gong, 2016 (https://doi.org/10.2147/DDDT.S113670). Figure 7A, Spleen appears to have been duplicated with the same image from Figure 5B, Spleen from Zhou et al, 2017 (https://doi.org/10.2147/DDDT.S146925). Figure 7B, Spleen appears to have been duplicated with the same image from Figure 5C, Spleen from Zhou et al, 2017 (https://doi.org/10.2147/DDDT.S146925). The authors did not respond to our queries and no explanation for the alleged image duplication was provided. The Editor requested to retract the article and the authors were notified of this. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

BACKGROUND: Hyperbaric oxygen therapy and inhibition of Nogo-A/NgR-RhoA/ROCK signaling pathways are conducive to the proliferation and differentiation of transplanted cells. OBJECTIVE: To explore the effects of hyperbaric oxygen plus rat bone marrow mesenchymal stem cells transplantation carrying miRNA silencing NgR gene on repair of rat spinal cord injury. METHODS: Rat bone marrow mesenchymal stem cells were transfected using constructed miRNA recombinant plasmid targeting NgR. The expression levels of NgR were detected by real-time quantitative PCR and western blot assay after transfection. The 15 of 80 Sprague-Dawley rats were randomly selected as sham group and the remaining 65 rats were used to construct models of spinal cord injury; and 60 successful models were randomly divided into spinal cord injury group, hyperbaric oxygen group, rat bone marrow mesenchymal stem cells group and rat bone marrow mesenchymal stem cells plus hyperbaric oxygen group. The rat bone marrow mesenchymal stem cells group and hyperbaric oxygen plus rat bone marrow mesenchymal stem cells group were injected with 5 μL rat bone marrow mesenchymal stem cells suspension (5×106 cells) after 24 hours, respectively, and the spinal cord injury and hyperbaric oxygen groups were injected with PBS of the same volume. The hyperbaric oxygen and hyperbaric oxygen plus rat bone marrow mesenchymal stem cells group received continuous treatment for 7 days. The hind limb motor function was evaluated by Basso Beattie Bresnahan score before and after the modeling, once a week, for 4 consecutive weeks. After 4 weeks of modeling, somatosensory evoked potential testing was performed to detect the recovery of neural conduction. The histopathological damage, apoptosis of cells and axon regeneration in spinal cord tissues was observed by hematoxylin-eosin staining, TUNEL staining and fluorescent gold retrograde tracing, respectively. After hyperbaric oxygen therapy, the mRNA relative expression levels of Nogo-A, NgR, RhoA, ROCK-1, Lingo-1 and p75NTR were detected by real-time quantitative PCR around the injured region. RESULTS AND CONCLUSION: (1) An obvious decrease was found in NgR expression levels after rat bone marrow mesenchymal stem cells transfection. (2) Basso Beattie Bresnahan score of 2 to 4 weeks after modeling: hyperbaric oxygen plus rat bone marrow mesenchymal stem cells group > rat bone marrow mesenchymal stem cells group and hyperbaric oxygen group > spinal cord injury group (P < 0.05). (3) The latency of somatosensory evoked potential was shortened and the amplitude of somatosensory evoked potential was increased in hyperbaric oxygen plus rat bone marrow mesenchymal stem cells group compared with other treatment groups (P < 0.05). There was no significant difference in latency and amplitude of somatosensory evoked potential between the rat bone marrow mesenchymal stem cells group and the hyperbaric oxygen group (P > 0.05). (4) Compared with the spinal cord injury group, the number of neurons increased; the number of axons increased; the regeneration effect of neurons was obvious and the apoptosis was reduced in the hyperbaric oxygen group and rat bone marrow mesenchymal stem cells group. The repair effect was better in the hyperbaric oxygen plus rat bone marrow mesenchymal stem cells group than that in other two treatment groups. (5) The mRNA relative expression of Nogo-A/NgR/RhoA-ROCK signaling pathway was significantly inhibited in hyperbaric oxygen plus rat bone marrow mesenchymal stem cells group, rat bone marrow mesenchymal stem cells group and hyperbaric oxygen group compared with the spinal cord injury group, but there was no significant difference between hyperbaric oxygen group and rat bone marrow mesenchymal stem cells group (P > 0.05). (6) In summary, hyperbaric oxygen combined with NgR gene silencing rat bone marrow mesenchymal stem cells transplantation can inhibit the gene expression of Nogo-A/NgR/RhoA-ROCK signaling pathway, promote axon regeneration and improve the electrophysiological function and locomotor function of rats. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by the progressive accumulation of β‐amyloid (Aβ)‐containing amyloid plaques, and microglia play a critical role in mediating Aβ clearance. Mounting evidence has confirmed that the ability of microglia in clearing Aβ decreased with aging and AD progress, but the underlying mechanisms are unclear. Previously, we have demonstrated that Nogo receptor (NgR), a receptor for three axon growth inhibitors associated with myelin, can decrease adhesion and migration of microglia to fibrils Aβ with aging. However, whether NgR expressed on microglia affect microglia phagocytosis of fibrils Aβ with aging remains unclear. Here, we found that aged but not young microglia showed increased NgR expression and decreased Aβ phagocytosis in APP/PS1 transgenic mice. NgR knockdown APP/PS1 mice showed simultaneous reduced amyloid burden and improved spatial learning and memory, which were associated with increased Aβ clearance. Importantly, Nogo‐P4, an agonist of NgR, enhanced the protein level of p‐Smad2/3, leading to a significant transcriptional inhibition of CD36 gene expression, which in turn decreased the microglial phagocytosis of Aβ. Moreover, ROCK accounted for Nogo‐P4‐induced activation of Smad2/3 signaling. Finally, the decreasing effect of NgR on microglial Aβ uptake was confirmed in a mouse model of intra‐hippocampal fAβ injection. Our findings suggest that NgR may play an important role in the regulation of Aβ homeostasis, and has potential as a therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Objective To prepare the new NGR-targeted shRNA-loaded liposome, and investigate its suppressing effect on orthotopic C6 glioma in rats. Methods (1) Liposome(lipo), the NGR-targeted liposome (lipo-NGR) and shBirc5-loaded lipo-NGR were prepared successively, and all kinds of products were characterized accordingly; (2) The targeting property of shBirc5-lipo-NGR was researched by immunohistochemical method in orthotopic C6 glioma rats model; (3) The tumor growth in treated rats was monitored longitudinally with MRI T2, and the survival time of each rat was recorded simultaneously. Results (1) We successfully prepared shBirc5-lipo-NGR whose size and zeta potential were (186.2±74.07)nm and (10.9±3.76)mV; (2) The Birc5 protein was significantly decreased in shBirc5-lipo-NGR group, compared with shBirc5-lipo group, shControl-lipo-NGR group and control group; (3) The control group exhibited an average tumor volume and growth rate 4.7 times greater than that in the shBirc5-lipo-NGR group on the 12th, 17th and 22th day(P < 0.05). The median survival times of the shBirc5-lipo-NGR, shBirc5-lipo, shControl-lipo-NGR and control groups were 30, 24, 22, 21 days, respectively. Conclusion We successfully prepare the new NGR-targeted shRNA-loaded liposome, and demonstrate its targeting property, obvious inhibitory effect on tumor growth and extending the survival time of orthotopic C6 glioma-bearing rats.

Xiuping Pang, Tianqi Wang, Dandan Jiang, Weiwei Mu, Bo Zhang, Na ZhangSchool of Pharmaceutical Sciences, Key Laboratory of Chemical Biology (Ministry of Education), Shandong University, Jinan, Shandong Province 250012, Peoples’ Republic of ChinaPurpose: To further enhance the antitumor efficacy through targeted delivery, DTX loaded lipid-based-nanosuspensions (DTX-LNS) were prepared and functionalized by PEGylation or NGR modification to develop DSPE-PEG2000 modified DTX-LNS (P-DTX-LNS) or DSPE-PEG2000-NGR modified DTX-LNS (N-DTX-LNS), respectively.Methods: Based on our previous work, functionalized DTX-LNS including P-DTX-LNS and N-DTX-LNS were prepared using thin-film hydration, and then characterized. Release behavior, stability in vitro, cytotoxicity and cellular uptake of functionalized LNS were observed. To demonstrate tumor targeting efficiency of functionalized DTX-LNS, in vivo real-time and ex vivo imaging study were conducted. Furthermore, therapeutic efficacy in vivo was evaluated in an H22-bearing mice model.Results: Functionalized DTX-LNS 100–110 nm in diameter were successfully prepared and exhibited good stability under various conditions. In vitro release studies demonstrated that DTX was released from functionalized DTX-LNS steadily and reached approximately 95% at 48 hrs. Functionalized DTX-LNS showed dose-dependent cytotoxicity and time-dependent internalization in human hepatocellular liver carcinoma cells (HepG2) cells. In vivo real-time and ex vivo imaging results indicated that tumor targeting efficiencies of P-DiR-LNS and N-DiR-LNS were 29.9% and 34.3%, respectively. Moreover, evaluations of in vivo antitumor efficacy indicated that functionalized DTX-LNS effectively inhibited tumor growth with low toxicity.Conclusion: The functionalized LNS exhibited suitable particle size, nearly spherical structure, enough drug loading and great potentials for large-scale production. The results in vitro and in vivo demonstrated that functionalized LNS could realize tumor targeting and antitumor efficacy. Consequently, functionalized DTX-LNS could be expected to be used for tumor targeting therapy.Keywords: docetaxel, lipid-based-nanosuspensions, NGR, PEG, nanocarriers

A combination of doxorubicin (DOX) and small interfering RNA (siRNA) is proven effective for the reverse of multidrug resistance. However, rapid degradation and poor cellular internalization of siRNA hinder their synergistic action. To improve the combination effect, asparagine–glycine–arginine peptide (NGR) -modified nanobubbles (NBs) containing cell-penetrating peptide (CPP) decorated DOX and CPP decorated c-myc siRNA were constructed. Diameters of these NBs were about 245 nm and zeta potentials were about −3 mV. Encapsulation efficiencies (EE) of DOX exceeded 80%. Release of DOX could be triggered by ultrasound (US) since above 80% DOX was released from NBs after sonication while less than 5% DOX was discharged without treatment of US. These NBs were considered stable during 24 h since the decrease of particle size was no more than 10 nm, variances of EE were less than 5%, and changes of transmission (ΔT) were less than 3%. More drugs in formulation decorated with CPP and NGR were accumulated in the tumor when combined with sonication. The evident synergistic action of DOX, siRNA, NBs, and US was verified in mice with strong antitumor efficacy. Taken together, NGR-modified NBs containing CPP-DOX and CPP-siRNA are able to realize time- and spatial-controlled drug delivery and show potential application prospects. [ABSTRACT FROM AUTHOR]

In recent years, more advanced mechanical and tribological properties have been needed in aluminum matrix composites due to the increasing variety of applications. For this purpose, second-generation aluminum matrix hybrid composites that have two or more different particle reinforcements are being developed today. In this study, in order to improve tribological and microstructural properties, nano-sized graphite and B4C-reinforced Al-4.4Cu-0.7 Mg-0.6Si aluminum alloy hybrid composites were produced. As a sintering method, the microwave sintering technique, which is one of the fast sintering methods, was preferred to prevent and/or minimize the formation of unwanted reaction products. In Al-4.4Cu-0.7 Mg-0.6Si-B4C/nGr hybrid composites, 4 different (3, 6, 9 and 12 wt %) B4C and 1 wt % nGr reinforcements were used. Raw samples, compressed by the one-way cold pressing method under 600 MPa pressure, were sintered in the microwave oven at 550 °C temperature for 60 min. In XRD analyses, whereas any unwanted reaction product (Al4C3, Al3BC, etc.) was not detected, θ-Al2Cu precipitate formations were detected. In hybrid composites where no graphite agglomeration was observed within the matrix, the highest hardness value (103.9 Hv0.05) was determined in the sample containing 6 wt % B4C and the lowest specific wear rate (0.271 × 10–3 mm3/Nm) was determined in the sample containing 12 wt % B4C. [ABSTRACT FROM AUTHOR]

Regeneration of injured peripheral nerves is an extremely complex process. Nogo-A (neurite outgrowth inhibitor-A) inhibits axonal regeneration by interacting with Nogo receptor in the myelin sheath of the central nervous system (CNS). The aim of this study was to investigate the effects of Nogo-A and its receptor on the repair of sciatic nerve injury in rats. Sprague-Dawley rats (n=96) were randomly divided into 4 groups: control group (control), sciatic nerve transection group (model), immediate repair group (immediate repair), and delayed repair group (delayed repair). The rats were euthanized 1 week and 6 weeks after operation. The injured end tissues of the spinal cord and sciatic nerve were obtained. The protein expressions of Nogo-A and Nogo-66 receptor (NgR) were detected by immunohistochemistry. The protein expressions of Nogo-A, NgR, and Ras homolog family member A (RhoA) were detected by western blot. At 1 week after operation, the pathological changes in the immediate repaired group were less, and the protein expressions of Nogo-A, NgR, and RhoA in the spinal cord and sciatic nerve tissues were decreased (P

Penetration of the blood–brain barrier (BBB) and the blood–brain tumor barrier (BBTB) remains a significant challenge for the delivery of drugs in the treatment of glioma. Therefore, the development of targeted preparations with the ability to penetrate the BBB and BBTB, and target gliomas, is an important approach if we are to improve the efficacy of glioma treatment. In the current study, an active targeting preparation based on PLGA nanoparticles coated with erythrocyte membranes (RBCNPs) and dual-modified with DWSW and NGR peptide ligands (DWSW/NGR-RBCNPs). Euphorbia factor L1 (EFL1) extracted from euphorbiae semen was used as the model drug. The final nanoparticles were characterized by in vivo and in vitro tests. In vitro results showed that EFL1-loaded DWSW/NGR-RBCNPs were taken up by cells and had the ability to penetrate the BBB and BBTB and produce cytotoxic effects. Furthermore, in vivo studies in mice showed that when injected intravenously, these specialized NPs could enter the brain, target tumor tissue, and significantly extend life span. The results showed that dual-targeting EFL1-loaded DWSW/NGR-RBCNPs have significant potential as a nanotherapeutic tool for the treatment of brain glioma.

No Abstract.

Alzheimer's disease (AD) is a chronic neurodegenerative disease that has been recognized as one of the most intractable medical problems with heavy social and economic costs. Amyloid-β (Aβ) has been identified as a major factor that participates in AD progression through its neurotoxic effects. The major mechanism of Aβ-induced neurotoxicity is by interacting with membrane receptors and subsequent triggering of aberrant cellular signaling. Besides, Aβ transporters also plays an important role by affecting Aβ homeostasis. Thus, these Aβ receptors and transporters are potential targets for the development of AD therapies. Here, we summarize the reported therapeutic strategies targeting Aβ receptors and transporters to provide a molecular basis for future rational design of anti-AD agents. [ABSTRACT FROM AUTHOR]

Penetration of the blood–brain barrier (BBB) and the blood–brain tumor barrier (BBTB) remains a significant challenge for the delivery of drugs in the treatment of glioma. Therefore, the development of targeted preparations with the ability to penetrate the BBB and BBTB, and target gliomas, is an important approach if we are to improve the efficacy of glioma treatment. In the current study, an active targeting preparation based on PLGA nanoparticles coated with erythrocyte membranes (RBCNPs) and dual-modified with DWSW and NGR peptide ligands (DWSW/NGR-RBCNPs). Euphorbia factor L1 (EFL1) extracted from euphorbiae semen was used as the model drug. The final nanoparticles were characterized by in vivo and in vitro tests. In vitro results showed that EFL1-loaded DWSW/NGR-RBCNPs were taken up by cells and had the ability to penetrate the BBB and BBTB and produce cytotoxic effects. Furthermore, in vivo studies in mice showed that when injected intravenously, these specialized NPs could enter the brain, target tumor tissue, and significantly extend life span. The results showed that dual-targeting EFL1-loaded DWSW/NGR-RBCNPs have significant potential as a nanotherapeutic tool for the treatment of brain glioma. [ABSTRACT FROM AUTHOR]

Asn-Gly-Arg (NGR) motifs have vasculature-homing properties via interactions with the aminopeptidase N (CD13) expressed on tumor neovasculature. Numerous NGR peptides with different molecular scaffolds have been exploited for targeted delivery of different compounds for imaging and therapy. When conjugated with NGR, complexes recognize the CD13 receptor expressed on the tumor vasculature, which improves the specificity to tumor and avoids systematic toxic reactions. Both preclinical and clinical studies performed with these products suggest that NGR-mediated vascular targeting is an effective strategy for delivering bioactive amounts of cytokines to tumor endothelial cells. For molecular imaging, radiolabeled peptides have been the most successful approach and have been translated into clinic. This review describes current data on radiolabeled tumor vasculature-homing NGR peptides for imaging and therapy. [ABSTRACT FROM AUTHOR]

The study presented the relationship between sudden Natural Gamma Radiation (NGR) increases related to enhanced atmospheric electric fields. We pinpoint Thunderstorm Ground Enhancements (TGEs) as the primary source of abrupt and significant NGR spikes. These TGEs, which are transient, several-minute-long increases in elementary particle fluxes, originate from natural electron accelerators within thunderclouds. The more prolonged, yet less pronounced, increases in NGR, persisting for several hours, are attributed to the gamma radiation from radon progeny and enhanced positron fluxes. This radon, emanating from terrestrial materials, is carried aloft by the Near-Surface Electric Field (NSEF). To measure NGR at Aragats Mountain, we use an ORTEC detector and custom-built large NaI (Tl) spectrometers, employing lead filters to discriminate between cosmic ray fluxes and radon progeny radiation. Our analysis differentiates between radiation enhancements during positive and negative NSEF episodes. The resultant data provide a comprehensive measurement of the intensities of principal isotopes and positron flux during thunderstorms compared to fair weather conditions. • We measure NGR at Mt. Aragats (3200 m height) during thunderstorms. • NGR was enhanced many times for minutes and ≈20% for hours. • Positive NSEF is 1.5 more effective than negative in enhancing NGR. • Atmospheric positron flux boosts twice during positive near-surface electric fields. • The negative aerosol share on Earth is larger than that of positive aerosols. Natural gamma radiation is a crucial aspect of our environment that has significance in various fields, such as radiation protection and geological exploration. Understanding and monitoring natural gamma radiation levels for human safety and scientific purposes is essential. In this context, we discuss two new sources of natural gamma radiation: thunderstorm ground enhancements and enhanced radon progeny radiation in stormy weather. Both are associated with strong atmospheric electric fields. We measured enhanced natural gamma radiation in the energy range 0.3–3 MeV at positive and negative NSEF. We found that the positive NSEF is 1.5 times more effective than the negative one. Additionally, we demonstrated that positron flux is enhanced by 2.5 times more at positive NSEF compared with negative NSEF. [ABSTRACT FROM AUTHOR]

Shu Li, Xi-Peng Wang Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China Abstract: In this study, a novel NGR (Asn-Gly-Arg) peptide-modified liposomal brucine was prepared by using spray-drying method. The surface morphology of the liposomes, encapsulation efficiency and particle size were investigated. The data showed that the addition of NGR did not produce any significant influence on brucine liposomes in terms of particle size or zeta potential. In addition, after 3 months of storage, no dramatic change such as visible aggregation, drug content changes or precipitation in the appearance of NGR-brucine liposomes occurred. The in vitro release results indicated that the release of brucine from NGR liposomes was similar to that of liposomes, demonstrating that the NGR modification did not affect brucine release. The in vitro drug-release kinetic model of NGR-brucine liposomes fitted well with the Weibull’s equation. In vivo, NGR-brucine liposomes could significantly extend the bioavailability of brucine; however, there was no significant difference observed in the pharmacokinetic parameters between liposomes and NGR liposomes after intravenous administration. Antitumor activity results showed that NGR-modified liposomes exhibited less toxicity and much higher efficacy in HepG2-bearing mice compared with non-modified liposomes. The enhanced antitumor activity might have occurred because brucine was specifically recognized by NGR receptor on the surface of tumor cells, which enhanced the intracellular uptake of drugs. Keywords: brucine, liposome, NGR, HepG2, in vivo, in vitro

Root gravitropic bending represents a fundamental aspect of terrestrial plant physiology. Gravity is perceived by sedimentation of starch-rich plastids (statoliths) to the bottom of the central root cap cells. Following gravity perception, intercellular auxin transport is redirected downwards leading to an asymmetric auxin accumulation at the lower root side causing inhibition of cell expansion, ultimately resulting in downwards bending. How gravity-induced statoliths repositioning is translated into asymmetric auxin distribution remains unclear despite PIN auxin efflux carriers and the Negative Gravitropic Response of roots (NGR) proteins polarize along statolith sedimentation, thus providing a plausible mechanism for auxin flow redirection. In this study, using a functional NGR1-GFP construct, we visualized the NGR1 localization on the statolith surface and plasma membrane (PM) domains in close proximity to the statoliths, correlating with their movements. We determined that NGR1 binding to these PM domains is indispensable for NGR1 functionality and relies on cysteine acylation and adjacent polybasic regions as well as on lipid and sterol PM composition. Detailed timing of the early events following graviperception suggested that both NGR1 repolarization and initial auxin asymmetry precede the visible PIN3 polarization. This discrepancy motivated us to unveil a rapid, NGR-dependent translocation of PIN-activating AGCVIII kinase D6PK towards lower PMs of gravity-perceiving cells, thus providing an attractive model for rapid redirection of auxin fluxes following gravistimulation., Competing Interests: IK, JS, AT, LQ, JF No competing interests declared, (© 2023, Kulich, Schmid, Teplova et al.)

The effect of miR-124 on the proliferation and differentiation of brain glioma stem cells and Nogo/NgR signaling pathway were investigated. miR-124 mimic, miR-124 inhibitor and miR-control expression vector were designed and produced to transfect U87 glioma stem cells. The results of transfection were tested via RT-qPCR and the expression of protein was detected by western blot analysis. Cell proliferation was detected by MTT proliferation and the proportion of CD133+ cells was detected by immunomagnetic beads to determine cell differentiation. The correlation between miR-124 and Nogo-A, and NgR protein expression was analyzed by Spearman correlation analysis. The relative expression of miR-124 in cells of miR-124 mimic group was significantly higher than that of miR-124 inhibitor and miR-control groups (P<0.05). The relative expression of Nogo-A and NgR protein in cells of the miR-124 mimic group was significantly lower than that of miR-124 inhibitor and miR-control groups (P<0.05). Absorbance values of the cells in the miR-124 mimic and miR-control groups were significantly lower than those in the miR-124 inhibitor group at each time point (P<0.05), while the values of the cells in the miR-124 mimic group were significantly lower than that in miR-control group (P<0.05). The level of CD133+ cells in miR-124 mimic group was significantly lower than that in miR-124 inhibitor and miR-control groups (P<0.05), while the level of CD133+ cells in miR-124 inhibitor group was higher than that in miR-control group (P<0.05). Correlation analysis revealed that there was a negative correlation between miR-124 and the expression of Nogo-A and NgR protein (P<0.05). miR-124 may participate in the differentiation of brain glioma stem cells through the Nogo/NgR pathway, which may bring a new direction for the clinical treatment of brain glioma. [ABSTRACT FROM AUTHOR]

Root tip is capable of sensing and adjusting its growth direction in response to gravity, a phenomenon known as root gravitropism. Previously, we have shown that negative gravitropic response of roots (NGR) is essential for the positive gravitropic response of roots. Here, we show that NGR, a plasma membrane protein specifically expressed in root columella and lateral root cap cells, controls the positive root gravitropic response by regulating auxin efflux carrier localization in columella cells and the direction of lateral auxin flow in response to gravity. Pharmacological and genetic studies show that the negative root gravitropic response of the ngr mutants depends on polar auxin transport in the root elongation zone. Cell biology studies further demonstrate that polar localization of the auxin efflux carrier PIN3 in root columella cells and asymmetric lateral auxin flow in the root tip in response to gravistimulation is reversed in the atngr1;2;3 triple mutant. Furthermore, simultaneous mutations of three PIN genes expressed in root columella cells impaired the negative root gravitropic response of the atngr1;2;3 triple mutant. Our work revealed a critical role of NGR in root gravitropic response and provided an insight of the early events and molecular basis of the positive root gravitropism. Early events of the gravitropic response of plant roots are still not well understood. Here, we show that previously reported negative gravitropism of Arabidopsis atngr1;2;3 triple mutant depends on root columella cell‐expressed auxin efflux carrier PIN3, PIN4, and PIN7 genes. Our cellular and genetic results indicate that the plasma membrane‐localized NGR proteins direct polar localization of PIN proteins and asymmetric auxin flow in the root tip to control root gravitropic response. Thus, our work uncovers the regulatory mechanism of NGR proteins in an early event of root gravitropism. [ABSTRACT FROM AUTHOR]

AIM: To investigate the effect of NgR mediated oxidative stress on the apoptosis of retinal ganglion cells(RGCs)induced by glucose. METHODS: RGC-5 cell were divided into 3 groups: control group(DMEM high glucose medium+10% fetal calf serum), high glucose group(DMEM high glucose medium+10% fetal calf serum+30mmol/L glucose),NEP1-40 group(DMEM high glucose medium+10% fetal calf serum+30mmol/L glucose+1μmol/L NEP1-40). Detections were performed after 3d culture: the state of cell growth was observed by microscopy. Cell viability was detected by CCK-8 kit. The apoptosis rate of RGC cells was detected by flow cytometry(FCM). The intensity of ROS of the cells were detected by fluorescence microscopy. Intracellular MDA levels and SOD activity were measured by related kits. Western blot was used to detect the expressions of Bcl-2 and Bax proteins. RESULTS: Compared with control group, high glucose group had a poor state and cell viability decreased, cell apoptosis rate significantly increased, ROS and MDA levels were significantly enhanced, SOD activity decreased, and the expression of anti-apoptotic protein Bcl-2 was decreased and the expression of pro apoptotic protein Bax was up-regulated. Compared with glucose group, after NgR expression was inhibited by NEP1-40, the oxidative stress reaction was reduced, Bcl-2/Bax was increased, the cell status was improved, the cell viability was increased, and the apoptosis rate was decreased in the NEP1-40 group(PCONCLUSION: High concentration of glucose can induce apoptosis of RGC-5 cells by NgR mediated oxidative stress reaction.

NgR, the receptor for the neurite outgrowth inhibitor Nogo-66, plays a critical role in the plasticity and regeneration of the nervous system after injury such as ischemic stroke. In the present study, we used immunohistochemistry to investigate the regional expression of NgR in rat brain following middle cerebral artery occlusion (MCAO). NgR protein expression was not observed in the center of the lesion, but was elevated in the marginal zone compared with control and sham-operated rats. The cerebral cortex and hippocampus (CA1, CA2, and CA3) showed the greatest expression of NgR. Furthermore, NgR expression was higher in the ipsilesional hemisphere than on the control side in the same coronal section. Although time-dependent changes in NgR expression across brain regions had their own characteristics, the overall trend complied with the following rules: NgR expression changes with time showed two peaks and one trough; the first peak in expression appeared between 1 and 3 days after MCAO; expression declined at 5 days; and the second peak occurred at 28 days.

Abstract The present study is aimed to investigate the molecular mechanism of miR-10 targeting NgR to regulate the proliferation and inflammatory cytokine secretion in microglia cells (MCs). The expression levels of NgR, IL-1β, and TNF-α in rat MCs were detected by QPCR and Immunoblotting assays. The proliferation of MC was detected by MTT and Soft agar clone formation assays. The target gene of miR-10 was verified by dual luciferase reporter gene assay. Overexpressed miR-10 downregulated the expression of NgR, promoted MC proliferation and inhibited inflammatory cytokine secretion. On the other hand, the inhibition of miR-10 upregulated the expression of NgR, inhibited MC proliferation and promoted inflammatory cytokine secretion. It was found that miR-10 targeted to regulate NgR. Overexpression of NgR restored the regulation effects of miR-10 on MC proliferation and inflammatory cytokine secretion. In summary, miR-10 can promote MC proliferation and inhibit the inflammatory cytokine secretion via targeting the NgR gene to down-regulate its expression. [ABSTRACT FROM AUTHOR]

Highlights • p75NTR was detected in retinal ganglion cells and their axons during the time of axon growth in the optic chiasm. • Lingo-1 was observed in RGC but not on axons at the optic disk, and was localized on axons along the optic pathway. • Lingo-1 also showed a glial localization at the optic disc and a neuronal localization in chiasmatic neurons. Abstract Our previous studies showed interaction of Nogo at the midline with its receptor (NgR) on optic axons plays a role in axon divergence at the mouse optic chiasm. Since NgR lacks a cytoplasmic domain, it needs transmembrane receptor partners for signal transduction. In this study, we examined whether the co-receptors of NgR, low-affinity neurotrophic receptor (p75NTR) and Lingo-1, are localized on axons in the mouse optic pathway. In the retina, p75NTR and Lingo-1 were observed on neuroepithelial cells at E13 and later on the retinal ganglion cells at E14 and E15. At the optic disc, p75NTR was observed on the retinal axons, whereas Lingo-1 was found on glial processes surrounding the axon fascicles. Both p75NTR and Lingo-1 were found on axons in the optic stalk, optic chiasm and optic tract. Furthermore, a transient expression of Lingo-1 was observed on the SSEA-1 positive chiasmatic neurons at E13, but not at later developmental stages. The presence of p75NTR and Lingo-1 on optic axons provides further supports to the contribution of Nogo/NgR signaling in axon divergence at the mouse optic chiasm. [ABSTRACT FROM AUTHOR]

It is well known that Arginine-Glycine-Aspartic acid (RGD) and Asparagine-Glycine-Arginine (NGR) peptides preferentially bind to integrin receptors and aminopeptidase N respectively and these two receptors play important roles in angiogenesis. Therefore ketoprofen as a non-selective cox Inhibitor was conjugated with linear RGD and NGR to take advantage of targeting capability of these two motifs and delivering ketoprofen to these cancer cells with overexpression of integrin and aminopeptidase N. In order to investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six carbon (hexanoic acid) linker was also used as a spacer. Cytotoxic effect of the synthesized compounds was evaluated against a group of cancer cell lines, including MCF-7, A2780 (αvβ3 positive), OVCAR3 (high αvβ3), HT-1-80 (high CD13) and SKOV-3 (CD13 positive). Both NGR and RGD conjugated forms of ketoprofen showed higher cytotoxic activity against OVCAR3 and HT-1-80 respectively. [ABSTRACT FROM AUTHOR]

Identification of fluorescent biomarkers with peptide ligand-directed receptors for diagnosis or theranostic of pancreatic ductal adenocarcinoma (PDAC) is still challenging. As potential prognostic/predictive bioimaging targets, both aminopeptidase N (APN, known as CD13) and Caveolin-1 are found as upregulation on the cell membrane surface of PDAC, in which APN is the principal receptor of the cyclic peptide cNGR (Asn-Gly-Arg, NGR) and Caveolin-1 can synergistically mediate endocytosis in this receptor-targeted process. Herein, we conjugate cNGR to dicyanomethylene-4 H-pyran (DCM) chromophore to develop a synergistic-targeted near-infrared (NIR) fluorescent probe DCM-cNGR with strongly intrinsic NIR fluorescence, stable optical performance, low cytotoxicity, and rapid accumulation in PANC-1 cells with the synergistic overexpressed APN receptor-targeted and Caveolin-1-mediated endocytosis. As demonstrated, DCM-cNGR can realize noninvasive NIR imaging for targeting PANC-1 tumor in vivo after intravenous injection into PANC-1 xenograft tumor of nude mice, making a great promise to improve the precision diagnosis and therapy of pancreatic cancer with real time tracing and bioimaging of PDAC in vitro and in vivo. [ABSTRACT FROM AUTHOR]

As current tumor chemotherapy faces many challenges, it is important to develop drug delivery systems with increased tumor-targeting ability, enhanced therapeutic effects and reduced side effects. In this study, a pH-sensitive liposome was constructed containing CHEMS-anchored PEG2000 for extended circulation and NGR peptide as the targeting moiety. The NGR-modified docetaxel-loaded pH-sensitive extended-circulation liposomes (DTX/NGR-PLL) prepared possess suitable physiochemical properties, including particle size of approximately 200 nm, drug encapsulation efficiency of approximately 70%, and pH-sensitive drug release properties. Experiments performed in vitro and in vivo on human fibrosarcoma cells (HT-1080) and human breast adenocarcinoma cells (MCF-7) verified the specific targeting ability and enhanced antitumor activity to HT-1080 cells. The results of intravenous administration demonstrated that NGR-modified liposomes can significantly and safely accumulate in tumor tissue in xenografted nude mice. In conclusion, the liposomes constructed hold promise as a safe and efficient drug delivery system for specific tumor treatment. [ABSTRACT FROM AUTHOR]

Introduction: Nogo-A and Nogo receptor (NgR) are expressed in the subventricular zone (SVZ) stem cells. NgR plays critical inhibitory roles in axonal regeneration and remyelination. However, the role of NgR in SVZ niche behaviors in demyelination context is still uncertain. Here we investigated the effects of NgR inhibition on SVZ niche reaction in a local model of demyelination in adult mouse optic chiasm. Methods: Demyelination was induced in adult mouse optic chiasm by microinjection of lysolecithin. We injected siRNAs against NgR intracerebroventricularly via a permanent cannula over 14 days to knockdown NgR. To trace SVZ stem cells and assess the effect of NgR inhibition on their reaction, BrdU was injected to the animals prior to the demyelination induction. Immunohistochemistry and histological analysis was carried out 3, 7 and 14 days post demyelination lesion. Results: NgR inhibition significantly increased the numbers of proliferating cells in SVZ in response to demeylination. The number of BrdU+/Olig2+progenitor cells in the neurogenic zone of the lateral ventricles was enhanced when NgR was blocked. These progenitor cells (Olig2+, GFAP+ or PSA-NCAM) were mobilized away from this SVZ as a function of time. Inhibition of NgR significantly reduced demyelination extension in optic chiasm. Conclusion: Our findings reveal that inhibition of NgR potentiates adult SVZ progenitor cells proliferation and differentiation in demyelination condition and facilitates remyelination in the optic chiasm. Therefore, inhibition of NgR function could have therapeutic potential for demyelinating disease like multiple sclerosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mild hypothermia can effectively ease secondary brain and spinal cord injuries, which has a definite protective effect on the central nervous system. Meanwhile, mild hypothermia is conducive to the proliferation, activation and growth of transplanted cells by improving the microenvironment of the injured spinal cord. OBJECTIVE: To investigate whether mild hypothermia intervention can regulate the proliferation and apoptosis of neural stem cells through the RhoA/ROCK pathway. METHODS: The neural stem cell injury model was prepared and randomly divided into two groups: normothermia group and mild hypothermia group. The mild hypothermia group was treated with mild hypothermia [(32.0±0.5) ℃] for 4 hours. Expression of RhoA, RHOCK, Nogo-A and NgR in neural stem cells was detected by RT-PCR and western blot assay. RhoA/RHOCK positive cells were observed by fluorescence microscope. The intracellular Ca2+ concentration in neurons was measured by laser scanning confocal microscopy. RESULTS AND CONCLUSION: The expression of RhoA, RHOCK, Nogo-A and NgR in neural stem cells at mRNA and protein levels was significantly lower in mild hypothermia group than in the normothermia group (P < 0.05). The intracellular Ca2+ concentration in the neural stem cells was lower in the mild hypothermia group than in the normothermia group (P < 0.05). The number of RhoA/RHOCK positive cells in the brain tissue of rats was significantly lower in the mild hypothermia group than in the in the mild hypothermia group (P < 0.05). To conclude, mild hypothermia regulates the proliferation and apoptosis of neural stem cells by inhibiting the RhoA/ROCK pathway. [ABSTRACT FROM AUTHOR]