Wnt-3a improves functional recovery through autophagy activation via inhibiting the mTOR signaling pathway after spinal cord injury.

Little is known about the effect of wnt-3a on motor nerve function and its specific molecular mechanisms after spinal cord injury (SCI). This study demonstrates that the downregulated expression levels of caspases-3, caspases-9 and chondroitin sulfate proteoglycan (CSPG) proteins and number of proportion of transferase UTP nick end labeling (TUNEL)-positive neurons by wnt-3a treatment. Then, Nissl and hematoxylin-eosin (HE) staining showed that wnt-3a significantly reduced the loss of spinal anterior horn motor neurons and promoted repair of injured spinal cord tissues after SCI. The above factors constructed a favorable microenvironment for the recovery of motor nerve function after SCI. To elucidate the molecular mechanism of neuroprotection of wnt-3a on SCI, the study showed that the expression levels of Beclin-1 and light chain (LC)3-II/I in spinal cord neurons were significantly improved by wnt-3a after SCI in vitro and vivo experiments, while the effect of wnt-3a was inhibited after mechanistic target of rapamycin (mTOR) signaling pathway being activated by MHY-1485. Besides, the level of p70S6K phosphorylation was inhibited by wnt-3a treatment, on the contrary, the level of p70S6K protein was elevated by wnt-3a, indicating that wnt-3a significantly activated neuronal autophagy by inhibiting mTOR signaling pathway after SCI. To further verify the correlation between neuroprotection of wnt-3a and autophagy, we found that after the rats and spinal cord neurons were combined treatment with wnt-3a and MHY-1485, the neuroprotection of wnt-3a on SCI was significantly inhibited. This study is the first to report that wnt-3a improves functional recovery through autophagy activation via inhibiting the mTOR signaling pathway after SCI.

Neuroprotection of melatonin on spinal cord injury by activating autophagy and inhibiting apoptosis via SIRT1/AMPK signaling pathway.

The effect of melatonin (MT) on spinal cord injury (SCI) has attracted increasing research attention. However, the specific role and molecular mechanism of MT on SCI have not been elucidated. An experiment was performed to investigate the effect and molecular mechanism of MT on the neuronal autophagy after SCI and its effect on the recovery of nerve function. The rats were randomly divided into four treatment groups: the SCI+MT+EX527 (SIRT1 inhibitor), SCI+MT, SCI, and sham operation groups. On the 14th day after SCI, MT significantly promoted the recovery of motor function in the hind limbs according to the results of Basso, Beattie, and Bresnahan scores. At the same time, MT treatment resulted in reduced activation of cleaved-caspase-3, cleaved-caspase-9, and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive neurons and increased the survival of motoneurons in the anterior horn of the spinal cord on the 14th day after SCI, which exerted its neuroprotection. Furthermore, western blot and immunofluorescence double staining were performed to verify the molecular mechanism of effect of MT on SCI, and results showed the significantly upregulated expressions of Beclin-1, light chain-3B, SIRT1, p-AMPK proteins in the spinal cord tissue of MT-treated rats on the 14th day after SCI, however, the effect of MT on autophagy was reversed by EX527 (SIRT1 inhibitor), which implied that MT activated autophagy via SIRT1/AMPK signaling pathway after SCI. Similarly, the neuroprotective effects of MT on SCI were also inhibited after the SIRT1/AMPK signaling pathway was suppressed by EX527. Taken together, these results suggest that MT inhibits the apoptosis and activates autophagy of nerve cells after SCI and ultimately exerts the neuroprotective effect by SIRT1/AMPK signaling pathway.

Neuroprotection of netrin-1 on neurological recovery via Wnt/ß-catenin signaling pathway after spinal cord injury.

The neuroprotective effects of netrin-1 after spinal cord injury and its specific molecular mechanisms have not been elucidated. In our study, Western blot, transferase UTP nick end labeling staining and immunofluorescence staining first showed that netrin-1 significantly decreased the expression levels of caspase-3, caspase-9, transferase UTP nick end labeling-positive neurons, nuclear factor kappa-B, and tumor necrosis factor-α after spinal cord injury, which inhibited neuronal apoptosis and inflammatory response. Using Nissl and HE staining, we also found that netrin-1 significantly increased the number of Nissl bodies in the anterior horn of spinal cord and promoted the recovery of injured tissue after spinal cord injury, consequently providing a good microenvironment for recovery of motor function. Finally, the results of Basso, Beattie, and Bresnahan score further confirmed that netrin-1 promoted the recovery of neurological function after spinal cord injury. Furthermore, netrin-1 significantly promoted the expression of ß-catenin and inhibited the expression of glycogen synthase kinase-3ß, which activated Wnt/ß-catenin signaling pathway after spinal cord injury. However, XAV939 inhibited Wnt/ß-catenin signaling pathway, which significantly inhibited the regulatory effect of netrin-1 on apoptosis, inflammation, Nissl bodies, damaged tissues, and neuroprotection. These results demonstrate for the first time the correlation between netrin-1 and Wnt/ß-catenin signaling pathway after spinal cord injury and show that netrin-1 exerts its neuroprotective effect by activating this signaling pathway after spinal cord injury.

Zinc promotes cell apoptosis via activating the Wnt-3a/ß-catenin signaling pathway in osteosarcoma.

BACKGROUND: The zinc content in the blood and tumor tissues of patients with osteosarcoma and the underlying regulation and molecular mechanism of zinc have not been reported. METHODS AND RESULTS: This study showed that the zinc content in the blood and tumor tissues of patients with osteosarcoma significantly reduced. CCK-8 and Transwell chamber assays revealed that zinc treatment significantly inhibited the proliferation and invasion abilities of osteosarcoma cells. Western blot analysis indicated that the expression levels of caspase-3 and caspase-9 were significantly increased, suggesting that zinc inhibited the growth and promoted the apoptosis of osteosarcoma cells. In addition, the expression levels of Wnt-3a and ß-catenin, the marker proteins of the Wnt/ß-catenin signaling pathways, were significantly increased in osteosarcoma cells after zinc intervention, which demonstrated that the pathway was clearly activated. However, the effect of zinc on the apoptosis, proliferation, and invasion abilities of osteosarcoma cells was reversed when the Wnt/ß-catenin signaling pathways was inhibited by XAV939 (Wnt antagonist) treatment. CONCLUSIONS: This study is the first to report the changes in zinc levels in the blood and tumor tissues of patients with osteosarcoma and to preliminarily verify that zinc inhibits the proliferation and invasion and promote the apoptosis of osteosarcoma cells by inducing the Wnt/ß-catenin signaling pathway, which ultimately inhibit cancer growth.

Knockdown of MSI1 inhibited the cell proliferation of human osteosarcoma cells by targeting p21 and p27.

Osteosarcoma is the most common type of primary bone cancer in children and adolescents, but its mechanism remains unclear. Musashi RNA-binding protein 1 (MSI1) is highly expressed in certain cancer types and functions as a putative progenitor/stem cell marker. In the present study, it was demonstrated that MSI1 expression in osteosarcoma tissue was higher compared with in the paraneoplastic tissue samples. Knockdown of MSI1 using shRNA in MG-63 and HOS cells inhibited cell proliferation in vitro and tumor formation in vivo, suggesting that MSI1 serves an essential role in osteosarcomagenesis. Further investigations demonstrated that the knockdown of MSI1 leads to the cell cycle arrest at G0/G1 phase, and the upregulation of p21 and p27 protein expression in osteosarcoma cells. Additionally, luciferase assays demonstrated that MSI1 can bind to the 3' untranslated regions of p21 and p27 mRNA. In conclusion, the results of the present study suggest that the knockdown of MSI11 can suppress cell proliferation of osteosarcoma by targeting p21 and p27 and subsequently inhibiting cell cycle progression.

Malaria control and prevention towards elimination: data from an eleven-year surveillance in Shandong Province, China.

BACKGROUND: Shandong Province experienced a declining malaria trend of local-acquired transmission, but the increasing imported malaria remains a challenge. Therefore, understanding the epidemiological characteristics of malaria and the control and elimination strategy and interventions is needed for better planning to achieve the overall elimination goal in Shandong Province. METHODS: A retrospective study was conducted and all individual cases from a web-based reporting system were reviewed and analysed to explore malaria-endemic characteristics in Shandong from 2005 to 2015. Annual malaria incidence reported in 2005-2015 were geo-coded and matched to the county-level. Spatial cluster analysis was performed to evaluate any identified spatial disease clusters for statistical significance. The space-time cluster was detected with high rates through the retrospective space-time analysis scanning using the discrete Poisson model. RESULTS: The overall malaria incidence decreased to a low level during 2005-2015. In total, 1564 confirmed malaria cases were reported, 27.1% of which (n = 424) were indigenous cases. Most of the indigenous case (n = 339, 80.0%) occurred from June to October. However, the number and scale of imported cases have been increased but no significant difference was observed during months. Shandong is endemic for both Plasmodium vivax (n = 730) and Plasmodium falciparum (n = 674). The disease is mainly distributed in Southern (n = 710) and Eastern region (n = 424) of Shandong, such as Jinning (n = 214 [13.7%]), Weihai (n = 151 [9.7%]), and Yantai (n = 107 [6.8%]). Furthermore, the spatial cluster analysis of malaria cases from 2005 to 2015 indicated that the diseased was not randomly distributed. For indigenous cases, a total of 15 and 2 high-risk counties were determined from 2005 to 2009 (control phase) and from 2010 to 2015 (elimination phase), respectively. For imported cases, a total of 26 and 29 high-risk counties were determined from 2005 to 2009 (control phase) and from 2010 to 2015 (elimination phase), respectively. The method of spatial scan statistics identified different 13 significant spatial clusters between 2005 and 2015. The space-time clustering analysis determined that the most likely cluster included 14 and 19 counties for indigenous and imported, respectively. CONCLUSIONS: In order to cope with the requirements of malaria elimination phase, the surveillance system should be strengthened particularity on the frequent migration regions as well as the effective multisectoral cooperation and coordination mechanisms. Specific response packages should be tailored among different types of cities and capacity building should also be improved mainly focus on the emergence response and case management. Fund guarantees for scientific research should be maintained both during the elimination and post-elimination phase to consolidate the achievements of malaria elimination.

Decreased Synovial Fluid α-Melanocyte-Stimulating-Hormone (α-MSH) Levels Reflect Disease Severity in Patients with Posttraumatic Ankle Osteoarthritis.

BACKGROUND: α-Melanocyte-stimulating hormone (α-MSH), an endogenous melanocortin peptide, has been demonstrated to have anti-inflammation effects and protect against cartilage damage. Objective In this study, we aimed to investigate whether α-MSH in ankle joint synovial fluid is associated with the disease severity of posttraumatic ankle osteoarthritis (PTAOA). METHODS: 66 PTAOA patients undergoing ankle arthroscopical debridement or ankle joint replacement were enrolled in the study. Synovial fluid α-MSH concentrations were explored by a special radioimmunoassay method. Cartilage degradation biomarkers such as collagen type II (CTX-II), aggrecan-1 (AGG-1), as well as inflammatory markers, interleukin-6 (IL-6) and matrix metalloproteinases-3 (MMP-3) in the synovial fluid were determined by enzyme-linked immunosorbent assay (ELISA). The symptomatic and functional severity was evaluated using Teeny-Wiss scoring and AOFAS ankle-hindfoot rating scale. The radiographic progression of PTAOA was identified according to the modified ankle osteoarthritis Kellgren-Lawrence (KL) grading system. The modified Mankin score was used for assessing the histopathological severity for cartilage lesions. Receiver operating characteristic (ROC) curve was conducted and the area under curve (AUC) was used to the evaluate the diagnostic value of α-MSH levels for the prediction of the modified K-L grading by comparing with other biomarkers examined. RESULTS: α-MSH levels in synovial fluid showed a negative correlation with, modified ankle K-L grading, Mankin scores, and degradation biomarkers CTX-II and AGG-1, as well as inflammation markers IL-6 and MMP-3. In addition, α-MSH levels were also positively associated with Teeny-Wiss scoring and AOFAS ankle-hindfoot scores. The AUC area of α-MSH was similar to CTX-II, AGG-1, IL-6, and MMP-3. CONCLUSIONS: Synovial fluid α-MSH levels showed an independent and negative correlation with disease severity in patients with PTAOA. Application of α-MSH locally may serve as a potential adjuvant therapy for delaying the process of PTAOA.

Rationally designed graphene-nanotube 3D architectures with a seamless nodal junction for efficient energy conversion and storage.

One-dimensional (1D) carbon nanotubes (CNTs) and 2D single-atomic layer graphene have superior thermal, electrical, and mechanical properties. However, these nanomaterials exhibit poor out-of-plane properties due to the weak van der Waals interaction in the transverse direction between graphitic layers. Recent theoretical studies indicate that rationally designed 3D architectures could have desirable out-of-plane properties while maintaining in-plane properties by growing CNTs and graphene into 3D architectures with a seamless nodal junction. However, the experimental realization of seamlessly-bonded architectures remains a challenge. We developed a strategy of creating 3D graphene-CNT hollow fibers with radially aligned CNTs (RACNTs) seamlessly sheathed by a cylindrical graphene layer through a one-step chemical vapor deposition using an anodized aluminum wire template. By controlling the aluminum wire diameter and anodization time, the length of the RACNTs and diameter of the graphene hollow fiber can be tuned, enabling efficient energy conversion and storage. These fibers, with a controllable surface area, meso-/micropores, and superior electrical properties, are excellent electrode materials for all-solid-state wire-shaped supercapacitors with poly(vinyl alcohol)/H2SO4 as the electrolyte and binder, exhibiting a surface-specific capacitance of 89.4 mF/cm(2) and length-specific capacitance up to 23.9 mF/cm, - one to four times the corresponding record-high capacities reported for other fiber-like supercapacitors. Dye-sensitized solar cells, fabricated using the fiber as a counter electrode, showed a power conversion efficiency of 6.8% and outperformed their counterparts with an expensive Pt wire counter electrode by a factor of 2.5. These novel fiber-shaped graphene-RACNT energy conversion and storage devices are so flexible they can be woven into fabrics as power sources.

Role of lattice defects in catalytic activities of graphene clusters for fuel cells.

Defects are common but important in graphene, which could significantly tailor the electronic structures and physical and chemical properties. In this study, the density functional theory (DFT) method was applied to study the electronic structure and catalytic properties of graphene clusters containing various point and line defects. The electron transfer processes in oxygen reduction reaction (ORR) on perfect and defective graphene clusters in fuel cells was simulated, and the free energy and reaction energy barrier of the elementary reactions were calculated to determine the reaction pathways. It was found that the graphene cluster with the point defect having pentagon rings at the zigzag edge, or line defects (grain boundaries) consisting of pentagon-pentagon-octagon or pentagon-heptagon chains also at the edges, shows the electrocatalytic capability for ORR. Four-electron and two-electron transfer processes could occur simultaneously on graphene clusters with certain types of defects. The energy barriers of the reactions are comparable to that of platinum(111). The catalytic active sites were determined on the defective graphene.

Dynamic adhesion forces between microparticles and substrates in water.

The interactions between micrometer-sized particles and substrates in aqueous environment are fundamental to numerous natural phenomena and industrial processes. Here we report a dynamically induced enhancement in adhesion interactions between microparticles and substrates immerged in water, air, and hexane. The dynamic adhesion force was measured by pulling microsized spheres off various substrate (hydrophilic/hydrophobic) surfaces at different retracting velocities. It was observed that when the pull-off velocity varies from 0.02 to 1500 µm/s, there is 100-200% increase in adhesion force in water while it has a 100% increase in nitrogen and hexane. The dynamic adhesion enhancement reduces with increasing effective contact angle defined by the average cosine of wetting angles of the substrates and the particles, and approaches the values measured in dry nitrogen and hexane as the effective contact angle is larger than 90(o). A dynamic model was developed to predict the adhesion forces resulting from this dynamic effect, and the predictions correlate well with the experimental results. The stronger dynamic adhesion enhancement in water is mainly attributed to electrical double layers and the restructuring of water in the contact area between particles and substrates.

Dynamic enhancement in adhesion forces of microparticles on substrates.

We report a dynamically induced enhancement in interfacial adhesion between microsized particles and substrates under dry and humid conditions. The adhesion force of soft (polystyrene) and hard (SiO2 and Al2O3) microparticles on soft (polystyrene) and hard (fused silica and sapphire) substrates was measured by using an atomic force microscope with retraction (z-piezo) speed ranging over 4 orders of magnitude. The adhesion is strongly enhanced by the dynamic effect. When the retraction speed varies from 0.02 to 156 µm/s, the adhesion force increases by 10% to 50% in dry nitrogen while it increases by 15% to 70% in humid air. Among the material systems tested, the soft-soft contact systems exhibit the smallest dynamic effect while the hard-hard contacts show the largest enhancement. A dynamic model was developed to predict this dynamic effect, which agrees well with the experimental results. The influence of dynamic factors related to the adhesion enhancement, such as particle inertia, viscoelastic deformations, and crack propagation, was discussed to understand the dynamic enhancement mechanisms.

Effect of microstructure of nitrogen-doped graphene on oxygen reduction activity in fuel cells.

The development of fuel cells as clean-energy technologies is largely limited by the prohibitive cost of the noble-metal catalysts needed for catalyzing the oxygen reduction reaction (ORR) in fuel cells. A fundamental understanding of catalyst design principle that links material structures to the catalytic activity can accelerate the search for highly active and abundant nonmetal catalysts to replace platinum. Here, we present a first-principles study of ORR on nitrogen-doped graphene in acidic environment. We demonstrate that the ORR activity primarily correlates to charge and spin densities of the graphene. The nitrogen doping and defects introduce high positive spin and/or charge densities that facilitate the ORR on graphene surface. The identified active sites are closely related to doping cluster size and dopant-defect interactions. Generally speaking, a large doping cluster size (number of N atoms >2) reduces the number of catalytic active sites per N atom. In combination with N clustering, Stone-Wales defects can strongly promote ORR. For four-electron transfer, the effective reversible potential ranges from 1.04 to 1.15 V/SHE, depending on the defects and cluster size. The catalytic properties of graphene could be optimized by introducing small N clusters in combination with material defects.