Ultrahigh-Flux Water Nanopumps Generated by Asymmetric Terahertz Absorption.

Controlling active transport of water through membrane channels is essential for advanced nanofluidic devices. Despite advancements in water nanopump design using techniques like short-range invasion and subnanometer-level control, challenges remain facilely and remotely realizing massive waters active transport. Herein, using molecular dynamic simulations, we propose an ultrahigh-flux nanopump, powered by frequency-specific terahertz stimulation, capable of unidirectionally transporting massive water through asymmetric-wettability membrane channels at room temperature without any external pressure. The key physics behind this terahertz-powered water nanopump is revealed to be the energy flow resulting from the asymmetric optical absorption of water.

Coagulation/co-catalytic membrane integrated system for fouling-resistant and efficient water purification.

Low-pressure catalytic membranes allow efficient rejection of particulates and simultaneously removing organics pollutant in water, but the accumulation of dissolved organic matters (DOM) on membrane surface, which cover the catalytic sites and cause membrane fouling, challenges their stable operation in practical wastewater treatment. Here we propose a ferric salt-based coagulation/co-catalytic membrane integrated system that can effectively mitigate the detrimental effects of DOM. Ferric salt (Fe3+) serving both as a DOM coagulant to lower the membrane fouling and as a co-catalyst with the membrane-embedded MoS2 nanosheets to drive perxymonosulfate (PMS) activation and pollutant degradation. The membrane functionalized with 2H-phased MoS2 nanosheets showed improved hydrophilicity and fouling resistance relative to the blank polysulfone membrane. Attributed to the DOM coagulation and co-catalytic generation of surface-bound radicals for decontamination at membrane surface, the catalytic membrane/PMS/ Fe3+ system showed much less membrane fouling and 2.6 times higher pollutant degradation rate in wastewater treatment than the catalytic membrane alone. Our work imply a great potential of coagulation/co-catalytic membrane integrated system for water purification application.

Heavy-metal resistant bio-hybrid with biogenic ferrous sulfide nanoparticles: pH-regulated self-assembly and wastewater treatment application.

Self-assembled bio-hybrids with biogenic ferrous sulfide nanoparticles (bio-FeS) on the cell surface are attractive for reduction of toxic heavy metals due to higher activity than bare bacteria, but they still suffer from slow synthesis and regeneration of bio-FeS and bacterial activity decay for removal of high-concentration heavy metals. A further optimization of the bio-FeS synthesis process and properties is of vital importance to address this challenge. Herein, we present a simple pH-regulation strategy to enhance bio-FeS synthesis and elucidated the underlying regulatory mechanisms. Slightly raising the pH from 7.4 to 8.3 led to 1.5-fold higher sulfide generation rate due to upregulated expression of thiosulfate reduction-related genes, and triggered the formation of fine-sized bio-FeS (29.4 ± 6.1 nm). The resulting bio-hybrid exhibited significantly improved extracellular reduction activity and was successfully used for treatment of high-concentration chromium -containing wastewater (Cr(VI), 80 mg/L) at satisfactory efficiency and stability. Its feasibility for bio-augmented treatment of real Cr(VI)-rich electroplating wastewater was also demonstrated, showing no obvious activity decline during 7-day operation. Overall, our work provides new insights into the environmental-responses of bio-hybrid self-assembly process, and may have important implications for optimized application of bio-hybrid for wastewater treatment and environmental remediation.

The prognostic role of M2 tumor-associated macrophages in non-small-cell lung cancer.

Lung cancer is a high-risk tumor and is a main cause of death worldwide. The tumor aggressiveness and degree of malignancy depend not only on the tumor itself, but also on the microenvironment. The inflammatory microenvironment is one of the key factors in promoting the progression of lung cancer. It has been found that macrophages are the most abundant immune cells in the tumor microenvironment, with strong plasticity and heterogeneity. Tumor-Associated Macrophages (TAMs) are important components of the tumor immune microenvironment. TAMs are thought to be polarized into two main phenotypes: inflammatory or classically activated (M1) and antiinflammatory or alternatively activated (M2) macrophages. Their phenotype and function change according to environment and the appearance of tumor cells. M2 macrophages have been reported to be protumorigenic, because they can promote the formation of blood vessels in the tumor microenvironment, helping tumor cells escape the body's immune defense and promote their growth, by releasing a variety of cytokines, including chemokines, inflammatory factors and growth factor. However, the prognostic impact of TAMs and their phenotypes in non-small-cell lung cancer (NSCLC) remains to be fully elucidated. Some reports of the association between the characteristics of macrophages in lung tumor and patients' survival outcomes show contradicting results. In order to explore the prognostic role of TAMs in NSCLS, the association between the phenotype, density and distribution of macrophages and the prognosis of human NSCLC, as well as the potential mechanisms of M2 macrophages leading to poor prognosis in NSCLC, are reviewed in this study.

Author Correction: The natural product 4,10-aromadendranediol induces neuritogenesis in neuronal cells in vitro through activation of the ERK pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Comparison of Awake and Asleep Deep Brain Stimulation for Parkinson's Disease: A Detailed Analysis Through Literature Review.

OBJECTIVES: Deep brain stimulation (DBS) for Parkinson's disease (PD) has been applied to clinic for approximately 30 years. The goal of this review is to explore the similarities and differences between "awake" and "asleep" DBS techniques. METHODS: A comprehensive literature review was carried out to identify relevant studies and review articles describing applications of "awake" or "asleep" DBS for Parkinson's disease. The surgical procedures, clinical outcomes, costs and complications of each technique were compared in detail through literature review. RESULTS: The surgical procedures of awake and asleep DBS surgeries rely upon different methods for verification of intended target acquisition. The existing research results demonstrated that the stereotactic targeting accuracy of lead placement obtained by either method is reliable. There were no significant differences in clinical outcomes, costs, or complications between the two techniques. CONCLUSION: The surgical and clinical outcomes of asleep DBS for PD are comparable to those of awake DBS.

Modification of forward osmosis membrane with naturally-available humic acid: Towards simultaneously improved filtration performance and antifouling properties.

In this work, a thin-film composite forward osmosis (FO) membrane was fabricated on polyethersulfone substrate by interfacial polymerization with naturally-available humic acid (HA) as a stable membrane additive in the support layer. Compared with the pristine polyethersulfone substrate, the incorporation of HA significantly altered the cross-section structure, increased average pore size and porosity of the substrate, leading to a thinner polyamide layer, further increasing the water flux (permeability). Specifically, the FO membrane showed a higher water flux (~20 L m-2 h-1) with the introduction of HA than the membrane synthesized without HA (~15 L m-2 h-1) in the FO mode with 2 M NaCl as draw solution. Moreover, the selectivity of the membrane was improved ~45% by dosing 0.8 wt% HA into the substrate, in comparation to the pristine membrane without HA doped. Besides, the average roughness of the polyamide layer was reduced by up to 68% when HA was present in the substrate, which mitigated the fouling potential. Thus, a slower flux decline ratio (~60%) was observed for the membrane modified with 0.8 wt% HA than the pristine membrane (~80%). Taken together, our findings shed light on using natural-available HA for effectively and efficiently modifying membrane substrate to simultaneously enhance the permeate-selectivity performance and the anti-fouling behavior in FO membrane process. The fundamental causes of these differences in membrane separation performance and fouling behavior are considered and related to the physical and chemical characteristics of support layer (i.e., porosity and pore size) and polyamide layer (i.e., active layer thickness and roughness) of membranes.

Interactions between chlorophenols and peroxymonosulfate: pH dependency and reaction pathways.

A non-radical reaction between peroxysulfates and phenolic compounds, as important structural moieties of natural organic matters, has been reported recently, implying new opportunities for environmental remediation without need for catalyst or energy input. However, this approach seems to be ineffective for halogenated aromatic compounds, an important disinfection by-products (DBPs). Here, we shed light on the interactions between peroxymonosulfate (PMS) and chlorophenols and the influential factors. The results show that the chlorophenols transformation kinetics were highly dependent on the solution pH and chlorophenol species: raising the pH significantly accelerated the chlorophenols degradation, and at alkaline pH the removal rates of different chlorophenols were in the order of trichlorophenol > dichlorophenol > chlorophenol > tetrachlorophenol. The faster degradation of pollutants with more chlorine groups was mainly due to their relatively higher dissociation degree, which favors a direct pollutant-PMS interaction to generate radicals for their degradation. The chlorophenol degradation intermediate (i.e. benzoquinone) further mediated the generation of singlet oxygen at alkaline pH, thereby contributing to accelerated pollutant removal. The slower degradation of tetrachlorophenol than other chlorophenols was likely due to its strong electrostatic epulsion to PMS which restricted the reaction. Our work unveils the chlorophenols degradation mechanisms in PMS reaction system, which may facilitate a better understanding and optimization of advanced oxidation processes for pollution control to reduce potential DBPs accumulation.

Astrocytoma progression scoring system based on the WHO 2016 criteria.

Diffuse astrocytoma (including glioblastoma) is morbid with a worse prognosis than other types of glioma. Therefore, we sought to build a progression-associated score to improve malignancy and prognostic predictions for astrocytoma. The astrocytoma progression (AP) score was constructed through bioinformatics analyses of the training cohort (TCGA RNA-seq) and included 18 genes representing distinct aspects of regulation during astrocytoma progression. This classifier could successfully discriminate patients with distinct prognoses in the training and validation (REMBRANDT, GSE16011 and TCGA-GBM Microarray) cohorts (P < 0.05 in all cohorts) and in different clinicopathological subgroups. Distinct patterns of somatic mutations and copy number variation were also observed. The bioinformatics analyses suggested that genes associated with a higher AP score were significantly involved in cancer progression-related biological processes, such as the cell cycle and immune/inflammatory responses, whereas genes associated with a lower AP score were associated with relatively normal nervous system biological processes. The analyses indicated that the AP score was a robust predictor of patient survival, and its ability to predict astrocytoma malignancy was well elucidated. Therefore, this bioinformatics-based scoring system suggested that astrocytoma progression could distinguish patients with different underlying biological processes and clinical outcomes, facilitate more precise tumour grading and possibly shed light on future classification strategies and therapeutics for astrocytoma patients.

Interaction between humic acid and protein in membrane fouling process: A spectroscopic insight.

Membrane fouling remains a major challenge for applying membrane technology to water treatment and, therefore, new tools to recognize the key foulants are essential for characterizing and evaluating the membrane fouling process. In this work, fluorescence excitation emission matrix coupled with parallel factor framework-clustering analysis was used to investigate the membrane fouling during the filtration process of humic acid (HA) and bovine serum albumin (BSA) solution by polyvinylidene fluoride membrane. Interestingly, the interaction between BSA and HA in the membrane fouling process was observed, and was further confirmed by infrared microspectroscopy and two-dimensional correlation spectroscopic analysis. In addition, the HA-induced membrane fouling was observed to be initially relieved, but became aggravated when a certain amount of BSA was added. Furthermore, with such an integrated approach, the OH groups in HA and amide bands in BSA were found to be mainly responsible for the membrane fouling and the HA-BSA interaction was mainly caused by the encapsulation of BSA with HA. This work develops a new method for probing membrane fouling and demonstrates the interaction between membrane foulants and its roles in membrane fouling process. Furthermore, the integrated approach developed in this work has a potential to explore other types of interfacial interactions.

Downregulation of adult and neonatal Nav1.5 in the dorsal root ganglia and axon of peripheral sensory neurons of rats with spared nerve injury.

Previous studies demonstrated that Nav1.5 splice variants, including Nav1.5a and Nav1.5c, were expressed in dorsal root ganglia (DRG) neurons. However, since nine Nav1.5 isoforms have been identified, whether other Nav1.5 splice variants, especially the neonatal Nav1.5 splice variant, express in the DRG neurons is still unknown. In this study, we systematically investigated the expression of adult and neonatal Nav1.5 isoforms in the DRG neurons and axon of peripheral sensory neurons of rats with spared nerve injury (SNI) by RT-PCR, DNA sequencing, restriction enzyme digestion, immunohistochemistry and immunofluorescence methods. The results demonstrated that both adult and neonatal Nav1.5 isoforms were expressed in the DRG neurons, but their expression ratio was ~2.5:1. In SNI rat models, the expression of both adult and neonatal Nav1.5 decreased by approximately a half in both mRNA and protein levels. In contrast, the expression of protein kinase C (PKC)-γ, one of the negative modulators for sodium currents, increased by ~1-fold. Taken together, this study first confirmed the expression of both adult and neonatal Nav1.5 isoforms in the DRG neurons and axon of peripheral sensory neurons of rat, but their expression level decreased in pain models. The upregulation of PKC-γ may directly or indirectly downregulate the expression of Nav1.5 isoforms in SNI rat models, which may further involve in the pathological process of neuropathic pain.

Discovery of N-cyclobutylaminoethoxyisoxazole derivatives as novel sigma-1 receptor ligands with neurite outgrowth efficacy in cells.

Herein we reported a series of 14 novel derivatives based on the N-cyclobutylaminoethoxyisoxazole scaffold. In vitro binding studies of these compounds demonstrated their low nanomolar to subnanomolar potencies as σ1 receptor ligands, with moderate to excellent selectivity over the σ2 receptor as represented by compounds 17-30. The majority of the derivatives scored high (>4.7) in the CNS MPO appraisal system, indicating their high likelihood in penetrating the blood-brain barrier. A number of these compounds exhibited significant neurite outgrowth efficacy in N1E-115 neuronal cells and displayed excellent selectivity for σ1 receptors over the selected endogenous neurotransmitter transporters, such as DAT, NET and SERT. Among the mini-series, compound 28 (K i σ1 = 0.2 nM, K i σ2 = 198 nM, CNS MPO score = 5.4) emerged as a promising selective σ1 receptor ligand that warrants its further evaluation as a potential therapeutic for neurodegenerative diseases.

Molecular expression of multiple Nav1.5 splice variants in the frontal lobe of the human brain.

Voltage-gated sodium channels serve an essential role in the initiation and propagation of action potentials for central neurons. Previous studies have demonstrated that two novel variants of Nav1.5, designated Nav1.5e and Nav1.5f, were expressed in the human brain cortex. To date, nine distinct sodium channel isoforms of Nav1.5 have been identified. In the present study, the expression of Nav1.5 splice variants in the frontal lobe of the human brain cortex was systematically investigated. The results demonstrated that wild Nav1.5 and its splice variants, Nav1.5c and Nav1.5e, were expressed in the frontal lobe of the human brain cortex. Nav1.5a, Nav1.5b and Nav1.5d splice variants were not detected. However, the expression level of different Nav1.5 variants was revealed to vary. The expression ratio of wild Nav1.5 vs. Nav1.5c and Nav1.5e was approximately 5:1 and 1:5, respectively. Immunochemistry results revealed that Nav1.5 immunoreactivity was predominantly in neuronal cell bodies and processes, including axons and dendrites, whereas little immunoreactivity was detected in the glial components. These results revealed that a minimum of four Nav1.5 splice variants are expressed in the frontal lobe of the human brain cortex. This indicates that the previously reported tetrodotoxin­resistant sodium current was a compound product of different Nav1.5 variants. The present study revealed that Nav1.5 channels have a more abundant expression in the human brain than previously considered. It also provided further insight into the complexity and functional significance of Nav1.5 channels in human brain neurons.

Distribution and function of voltage-gated sodium channels in the nervous system.

Voltage-gated sodium channels (VGSCs) are the basic ion channels for neuronal excitability, which are crucial for the resting potential and the generation and propagation of action potentials in neurons. To date, at least nine distinct sodium channel isoforms have been detected in the nervous system. Recent studies have identified that voltage-gated sodium channels not only play an essential role in the normal electrophysiological activities of neurons but also have a close relationship with neurological diseases. In this study, the latest research findings regarding the structure, type, distribution, and function of VGSCs in the nervous system and their relationship to neurological diseases, such as epilepsy, neuropathic pain, brain tumors, neural trauma, and multiple sclerosis, are reviewed in detail.

Multiple Nav1.5 isoforms are functionally expressed in the brain and present distinct expression patterns compared with cardiac Nav1.5.

It has previously been demonstrated that there are various voltage gated sodium channel (Nav) 1.5 splice variants expressed in brain tissue. A total of nine Nav1.5 isoforms have been identified, however, the potential presence of further Nav1.5 variants expressed in brain neurons remains to be elucidated. The present study systematically investigated the expression of various Nav1.5 splice variants and their associated electrophysiological properties in the rat brain tissue, via biochemical analyses and whole­cell patch clamp recording. The results demonstrated that adult Nav1.5 was expressed in the rat, in addition to the neonatal Nav1.5, Nav1.5a and Nav1.5f isoforms. Further studies indicated that the expression level ratio of neonatal Nav1.5 compared with adult Nav1.5 decreased from 1:1 to 1:3 with age development from postnatal (P) day 0 to 90. This differed from the ratios observed in the developing rat hearts, in which the expression level ratio decreased from 1:4 to 1:19 from P0 to 90. The immunohistochemistry results revealed that Nav1.5 immunoreactivity was predominantly observed in neuronal cell bodies and processes, whereas decreased immunoreactivity was detected in the glial components. Electrophysiological analysis of Nav1.5 in the rat brain slices revealed that an Na current was detected in the presence of 300 nM tetrodotoxin (TTX), however this was inhibited by ~1 µM TTX. The TTX­resistant Na current was activated at ­40 mV and reached the maximum amplitude at 0 mV. The results of the present study demonstrated that neonatal and adult Nav1.5 were expressed in the rat brain and electrophysiological analysis further confirmed the functional expression of Nav1.5 in brain neurons.

The natural product 4,10-aromadendranediol induces neuritogenesis in neuronal cells in vitro through activation of the ERK pathway.

Recent studies focus on promoting neurite outgrowth to remodel the central nervous network after brain injury. Currently, however, there are few drugs treating brain diseases in the clinic by enhancing neurite outgrowth. In this study, we established an NGF-induced PC12 differentiation model to screen novel compounds that have the potential to induce neuronal differentiation, and further characterized 4,10-Aromadendranediol (ARDD) isolated from the dried twigs of the Baccharis gaudichaudiana plant, which exhibited the capability of promoting neurite outgrowth in neuronal cells in vitro. ARDD (1, 10 µmol/L) significantly enhanced neurite outgrowth in NGF-treated PC12 cells and N1E115 cells in a time-dependent manner. In cultured primary cortical neurons, ARDD (5, 10 µmol/L) not only significantly increased neurite outgrowth but also increased the number of neurites on the soma and the number of bifurcations. Further analyses showed that ARDD (10 µmol/L) significantly increased the phosphorylation of ERK1/2 and the downstream GSK-3ß, subsequently induced ß-catenin expression and up-regulated the gene expression of the Wnt ligands Fzd1 and Wnt3a in neuronal cells. The neurite outgrowth-promoting effect of ARDD in neuronal cells was abolished by pretreatment with the specific ERK1/2 inhibitor PD98059, but was partially reversed by XAV939, an inhibitor of the Wnt/ß-catenin pathway. ARDD also increased the expression of BDNF, CREB and GAP-43 in N1E115 cells, which was reversed by pretreatment with PD98059. In N1E115 cells subjected to oxygen and glucose deprivation (OGD), pretreatment with ARDD (1-10 µmol/L) significantly enhanced the phosphorylation of ERK1/2 and induced neurite outgrowth. These results demonstrated that the natural product ARDD exhibits neurite outgrowth-inducing activity in neurons via activation of the ERK signaling pathway, which may be beneficial to the treatment of brain diseases.

A novel GSK-3ß inhibitor YQ138 prevents neuronal injury induced by glutamate and brain ischemia through activation of the Nrf2 signaling pathway.

AIM: To discover neuroprotective compounds and to characterize the discovered active compound YQ138 as a novel GSK-3ß inhibitor. METHODS: Primary rat cerebellar granule cells (CGCs) were treated with glutamate, and cell viability was analyzed with MTT assay, which was used as in vitro model for screening neuroprotective compounds. Active compound was further tested in OGD- or serum deprivation-induced neuronal injury models. The expression levels of GSK-3ß downstream proteins (Nrf2, HO-1, NQO1, Tau and ß-catenin) were detected with Western blotting. For evaluating the neuroprotective effects in vivo, adult male rats were subjected to transient middle cerebral artery occlusion (tMCAO), then treated with YQ138 (10 mg/kg, iv) at 2, 4 and 6 h after ischemia onset. RESULTS: From a compound library consisting of about 2000 potential kinase inhibitors, YQ138 was found to exert neuroprotective effects: pretreatment with YQ138 (0.1-40 µmol/L) dose-dependently inhibited glutamate-induced neuronal death. Furthermore, pretreatment with YQ138 (10 µmol/L) significantly inhibited OGD- or serum deprivation-induced neuronal death. Among a panel of seven kinases tested, YQ138 selectively inhibited the activity of GSK-3ß (IC50=0.52 nmol/L). Furthermore, YQ138 dose-dependently increased the expression of ß-catenin, and decreased the phosphorylation of Tau in CGCs. Moreover, YQ138 significantly increased the expression of GSK-3ß downstream antioxidative proteins Nrf2, HO-1, NQO1, GSH and SOD in CGCs. In rats with tMCAO, administration of YQ138 significantly decreased infarct volume, improved the neurological deficit, and increased the expression of Nrf2 and HO-1 and the activities of SOD and GSH in the cerebral cortex. CONCLUSION: A novel GSK-3ß inhibitor YQ138 effectively suppresses brain ischemic injury in vitro and in vivo.

Microsurgical Outcomes of Secondary Epilepsy from Hippocampal Lesions: A Report of 56 Cases and Literature Review.

AIM: To explore the treatment efficacy of microsurgery for secondary epilepsy from hippocampal lesions. MATERIAL AND METHODS: The clinical data, pathological findings, surgical methods and surgical outcomes of 56 patients with secondary epilepsy from hippocampal lesions were retrospectively analyzed. RESULTS: Postoperative pathological examinations confirmed that 27 patients had gliomas, 17 patients had vascular malformations and 12 patients had hippocampal sclerosis. Twenty-nine patients underwent selective resection of the lesioned tissue and the surrounding infiltrated tissue, and 26 patients underwent a more generous removal of the anterior temporal lobe, lesioned tissue, infiltrated tissue and medial structures of the temporal lobe. Fifty patients were followed up with an average follow-up duration of 25.5 months. At postoperative one year, the remission rate of epilepsy that achieved Engel grade I was 80.8% (21/26) and 83.3% (20/24) for the selective resection and more generous resection, respectively, indicating that the difference between the two methods was insignificant. CONCLUSION: Microsurgery is the first choice for the treatment of secondary epilepsy from hippocampal lesions. Various operative routes and methods can be selected based on the lesion natures. Long-term favorable outcome of seizure control following microsurgery can be achieved in most of the patients.

Design, synthesis and biological evaluation of tricyclic diterpene derivatives as novel neuroprotective agents against ischemic brain injury.

Lead compound 7 has neuroprotective effects, and it was discovered by screening a small synthetic natural product-like (NPL) library. Based on the lead, a series of tricyclic diterpene derivatives was designed and synthesized, and their neuroprotective effects were further evaluated against glutamate-, oxygen and glucose deprivation (OGD)- and nutrient deprivation-induced neuronal injury using cell-based assays. To our delight, most of these synthetic compounds exhibited increased neuroprotective effects and blood-brain barrier (BBB) permeability without cellular toxicity. The most potent compound, compound 30, showed significantly improved neuroprotection against neuronal injury in primary neurons. Furthermore, compound 30 exhibited remarkable neuroprotection in transient middle cerebral artery occlusion (tMCAO) rats by reducing their infarct sizes and neurological deficit scores. A mechanistic exploration using in vitro and in vivo experiments showed that the neuroprotection of these compounds was at least partly mediated by improving the levels of glutathione (GSH), superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) protein. Therefore, these tricyclic diterpene derivatives could be used as promising leads for the development of a new type of neuroprotective agents against ischemic brain injury.