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The PTEN/AKT signaling pathway is involved in the pathogenesis of febrile convulsion (FC), a convulsion caused by abnormal electrical activity in the brain. The objective of the present study was to evaluate the therapeutic effect of melatonin (MT) on FC and the according underlying molecular mechanisms. Reverse transcription‑quantitative PCR and western blot analysis were used to explore the effects of MT on the expression levels of MEG3, microRNA (miRNA/miR)‑223, phosphatase and tensin homolog (PTEN) and protein kinase B (AKT). Luciferase assay was performed to verify the downstream targets of MEG3 and miR‑223. An animal model was established to evaluate the effects of MT on the MEG3/miR‑223/PTEN/AKT pathway. TUNEL staining was carried out to assess the effect of MT on neuronal apoptosis. Finally, the duration of seizure/convulsion was recorded to determine the effect of MT on FC. In both cell and animal models, mRNA levels of MEG3 and PTEN increased in the apoptosis group, while treatment with MT decreased the expression levels of MEG3 and PTEN. miR‑223 expression was decreased in the apoptosis group, whereas treatment with MT increased the expression level of miR‑223. Protein levels of PTEN and cleaved caspase‑3 increased in the apoptosis group, whereas treatment with MT decreased the protein level of PTEN. Phosphorylated (p)‑AKT expression was decreased in the apoptosis group and treatment with MT reversed this effect. miR‑223 could directly bind to MEG3, and PTEN was a direct target of miR‑223. MT could decrease the duration of seizure/convulsion. In all experimental groups, treatment with MT could decrease the ratio of β waves, while increasing the ratios of α, θ and δ waves. Therefore, the results from the present study collectively suggested that treatment with MT alleviated FC via the MEG3/miR‑223/PTEN/AKT pathway, which also indicated that MT could be considered as a novel strategy for the treatment of FC disease.

Background: Benign Childhood Epilepsy with Centro-temporal Spikes (BECTS) is the most common form of idiopathic epilepsy in children, accounting for up to 23% of pediatric epilepsy. The pathogenesis of BECTS is unknown, but it is thought that genetic factors play a role in susceptibility to the disease. Methods: To investigate the role of common genetic variants in BECTS pathogenesis, a 2-stage genome-wide association study (GWAS) was performed in 1,800 Chinese Han BECTS patients, and 7,090 healthy controls. Genetic findings were used in a Mendelian Randomization study in the UK Biobank dataset to investigate the potential role of smoking in BECTS. Findings: Definitive evidence of a role for common-variant heritability was demonstrated, with heritability of BECTS of >10% observed even with conservative disease prevalence assumptions. Although no individual locus achieved genome-wide significance, twelve loci achieved suggestive evidence of association (5 × 10-8

Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive inherited neurodegenerative disorders mainly affecting children, and at least 13 causative genes (CLN1 to CLN8 and CLN10 to CLN14) have been identified. Here, we reported a novel homozygous missense mutation (c.434G > C, p.Arg145Pro) identified in CLN5 gene via whole exome sequencing in a 5-year-old girl. The patient first presented paroxysmal epilepsy associated with vomiting, followed by progressive regression in walking, vision, intelligence and speaking. Combining the molecular and clinical analysis, the diagnosis of NCL could be made, although the missense mutation (c.434G > C, p.Arg145Pro) in CLN5 was evaluated to be a variant of uncertain significance according to American College of Medical Genetics and Genomics (ACMG) standard. We further performed expression and localization studies and our results provide evidence of impaired cellular trafficking of CLN5 to lysosome, indicating that this mutation might be deleterious to the function of CLN5 for its mislocalization. Our study demonstrated the efficacy of next generation sequencing in molecular diagnosis, and a deleterious effect of the variant discovered in our patient on CLN5, triggering the NCL disease.

To investigate the flow field evolution and resultant aerodynamic characteristics of a square cylinder during flow acceleration, large-eddy simulations were undertaken to simulate flow with a dimensionless acceleration rate ap of 0.0048. The adopted ap resembles that is likely to be experienced during a severe downburst wind storm. The tested incidence angle α ranges from 0° to 45° and the time-dependent Reynolds number Re [Re = U(t)D/v, where U(t) is the time-dependent inflow velocity and D and v are the cylinder length and the kinematic viscosity, respectively] varies from 0 to 5 × 104 throughout the simulation. Results revealed that the flow around a square cylinder in accelerated flow evolves through three distinct temporal flow phases: namely, Phase I (Ia and Ib) where no vortex shedding (the instantaneous lift force through this period is zero) is observed, Phase II, where periodic vortex shedding and associated lift force oscillations are initiated and enhanced, and Phase III where stable vortex shedding occurs. Phase I can be further broken down into Phase Ia, which is characterized by laminar shear layer separation and the existence of steady recirculation vortices in the near wake region, and Phase Ib (only present at α = 0° and 45°) which is distinguished by the presence of quasi-steady recirculation vortices behind the cylinder. Aside from the variation of flow patterns, the transient lift and drag coefficients and the wind pressure distributions, as well as the spatial evolution of three-dimensional flow structures and pressure distributions, are also elucidated in detail.

Benign Childhood Epilepsy with Centro-temporal Spikes (BECTS) is the most common form of idiopathic epilepsy in children. To explore the genetic susceptibility loci in children with BECTS, we conducted 2stage genome-wide association study (GWAS) in over 1,800 Chinese Han patients with BECTS, and 7,090 healthy controls. We combined the datasets of the two stages by meta-analysis to identify the SNPs associated to BECTS. Significant common variant heritability of BECTS was observed. Heritability in the combined phase 1 and 2 datasets was > 10% even for assumed prevalence as low as 0.00025 on the liability scale. Twelve loci achieved suggestive evidence of association (5x10-8 < P < 10-5). In addition, the intersection between the GWAS findings and gene expression in brain tissue was analyzed by Summary-data-based Mendelian Randomization (SMR). We found association of t3603436 transcripts in CHRNA5 gene with SNP rs1948, which is suggestively associated with BECTS (Peqtl = 2.10x10-12, Psmr = 7.9x10-5), suggesting that rs1948 is significantly associated with BECTS through effects on expression of CHRNA5 in brain tissue. These findings suggest involvements of KALRN and CHRNA5-A3-B4 cluster in BECTS, give new directions to biological understanding of pediatric epilepsy, and opens avenues for investigation of prognostic factors and possible prevention of epilepsy in children. Funding: The study was funded by the National Key R&D Program of China (No. 2016YFC1000707), the National Natural Science Foundation of China (No. 81771389 and No. 81471329), and China Ministry of Science and technology (973 Program of China 2014CB541800). The study was also funded by Australian Research Council grant LPl10200926, and by the Queensland Premier’s Fellowship for Science (awarded to MAB, 2013). MAB was funded by Electronic copy available at: https://ssrn.com/abstract=3384897 a National Health and Medical Research Council Senior Principal Research Fellowship (APP1024879). Declaration of Interest: The authors have no conflict of interest. Ethical Approval: Written informed consent was obtained from all the parents or guardians, and the study was approved by the relevant ethics committees of the hospitals and institutions involved.

Many protected areas around the world are struggling to achieve financial stability and meet management costs, which is a difficult challenge. This difficulty is particularly acute in China, even though protected area conservation has been increasingly stressed upon in recent central policy announcements. The practice of providing supplemental funding for protected areas has been going on for years, but there is a lack of theoretical research on why and how landowners in protected areas could be compensated. This paper aims to fill the gap and make two contributions to the literature by explaining why landowners in protected areas should be compensated and who should pay for protected areas. The theoretical arguments on compensation for protected areas are first reviewed before we derive the theoretical framework of value capture for protected areas in China based on the principle of symmetry between burden and compensation. We conclude that local residents should be compensated according to the principle of equal public burden because the spatial regulation of protected areas has seriously restricted their land development rights. Furthermore, the beneficiaries of added land value in the process of the spatial regulation of protected areas can be categorized into three groups: the general public, residents around protected areas and some residents in protected areas (along the infrastructure site or in the upzoning area). Therefore, we structure a three-level value capture framework for protected areas. This is the first attempt to study compensation for protected areas based on value capture theory, which can provide guidance on protected area management for government leaders and researchers across the world.

This paper presents a numerical study of the flow around two static staggered circular cylinders at a high subcritical Reynolds number of Re = 1.4 × 105. The center-to-center pitch ratio (P/D) varied from 1.5 to 4, and the incidence angle (β) increased from 0° to 90°. Three critical aerodynamic phenomena at the downstream cylinder—negative drag force, inner lift force, and outer lift force—are successfully simulated. New explanations for the phenomena are proposed. The negative drag force appears at approximately P/D = 1.5–2 and β = 0°–10°, which is ascribed to a recirculation pair with opposite directions and a high-speed gap flow between the cylinders in the tandem and staggered configurations, respectively. The inner lift force happens at about P/D = 1.5–3 and β = 10°, which is due to the combined effects of a stagnation point shift, high-speed gap flow, and rising of the gap-side unsteady separation bubble at the downstream cylinder. The outer lift force occurs at about β = 20° and P/D = 3–4, which is attributed to a gap-side separation point shift from windward to leeward and interactions between the vortices shed from the upstream cylinder and the shear layer of the downstream cylinder.

Value capture has been shown to be an innovative instrument to solve the dilemma of funding shortfalls for protected areas. However, value capture mechanisms are often ineffective even though financing from the domestic budget is sufficient. This paper structures a theoretical framework to compare two value capture mechanisms (ecological compensation and ecological migration) based on implementation effects (heritage protection and welfare promotion) and transaction costs (the costs of information, bargaining, and policing). Sanjiangyuan National Park in China is adopted as an empirical case. Based on multi-source data collection and in-depth interviews, we review the ecological compensation in multiple functions and ecological migration in multiple forms for this case. Our results suggest that value capture tools have attained great achievements and dramatically changed the lives of aborigines. We then evaluate implementation effects separately: compensation for ecological regulation, bonuses for incentives, and transfer payments to the poor could all contribute to better ecological restoration and increased resident income. However, although ecological engineering accounts for the largest expenditures, it has little influence on heritage protection and welfare promotion. We also find that the transaction costs of ecological migration are significantly higher than those of ecological compensation. To our knowledge, this investigation is the first attempt to understand domestic funds for protected areas from a novel value capture perspective, and the results of this study can provide guidance for both protected area finances and policy evaluation.

This multicenter clinical trial was conducted to examine current practice of benign epilepsy with centrotemporal spikes and especially address the question that in what circumstances 1 antiepileptic drug (AED) should be preferred. Twenty-five medical centers participate in this clinical trial. The general information, clinical information, and treatment status were collected under the guidance of clinicians and then analyzed. Difference between different treatment groups was compared, and usefulness of the most commonly used AEDs was evaluated. A total of 1817 subjects were collected. The average age of the subject was 8.81 years. The average age of onset is 6.85 years (1–14 years). Male-to-female ratio is 1.13:1. A total of 62.9% of the patients are receiving monotherapies, and 10.6% are receiving multidrug therapy. Both age and course of disease of treated rolandic epilepsy (RE) patients are significantly different from those of untreated patients. Bilateral findings on electroencephalography (EEG) are less seen in patients with monotherapy compared with patients with multidrug therapy. Except for 25.4% patients not taking any AEDs, oxcarbazepine (OXC), sodium valproate (VPA), and levetiracetam (LEV) are the most commonly used 3 AEDs. VPA and LEV are commonly used in add-on therapy. OXC and LEV are more effective as monotherapy than VPA. Age of onset of Chinese RE patients is 6.85 years. Bilateral findings on EEG could be a risk factor to require multidrug therapy. In Chinese patients, OXC, VPA, and LEV are most commonly used AEDs as monotherapy and OXC and LEV are more effective than VPA.

Wind tunnel tests are conducted to investigate the wake-induced vibrations (WIVs) of two circular cylinders with a centre-to-centre spacing of 4 times the diameter and attack angles varying from 0°to 20°for Reynolds numbers between 18,000 and 168,800. Two types of circular cylinders with different surface roughnesses are adopted, and the effects of the surface roughness and Reynolds number on the WIVs are examined. The results show that increasing the surface roughness of a cylinder changes the dynamic characteristic of the WIVs significantly. Two divergent types of wake-induced instability phenomena of distinct dynamic characteristics, namely oscillation trajectories, maximum amplitudes, and evolution of the vibrations, are observed. Changing the roughness of the upstream cylinder only has a smaller effect on wake-induced instabilities than changing the roughness of the downstream cylinder only. For a downstream cylinder with a rough surface, the cylinder only oscillates in a limited velocity range and exhibits “velocity-restrained vibrations” rather than divergent vibrations. Furthermore, it is found that the Reynolds number has strong effects on the wake-induced instabilities of the downstream cylinder, and the possibility that a cylinder experience instabilities is much lower at higher Reynolds numbers (Re>80,000) than at lower Reynolds numbers (Re

The rheological behaviors of the nanotube-in-oil dispersions stabilized by polyisobutylene succinimide (PIBSI) dispersants are studied at different temperatures. Abnormal viscosity increase happens in the nanotube dispersion containing long chain dispersant (molecular weight 1000) at high temperature due to flocculation of the nanoparticles. Desorption of the dispersant molecules from solid surface is proved not to be the reason by FTIR measurement. Short chain polymer dispersant (molecular weight 550) cannot disperse nanotube well at room temperature which indicates that the shorter dispersant chain lead to the flocculation of nanotubes in the dispersions. Long chain dispersant molecules shrink at high temperature, however, the change of the dispersant conformation at high temperature is not the only reason for the flocculation behaviors. The long chain polymer may also contribute to the creation of the network structure in the dispersion at high temperature. Dispersant concentration and dispersing energy are the important factors to affect the flocculation process of the dispersion at high temperature.

The convective heat transfer coefficients of several nanoparticle-in-liquid dispersions (nanofluids) have been measured under laminar flow in a horizontal tube heat exchanger. The nanoparticles used in this research were graphitic in nature, with aspect ratios significantly different from one ( l / d ≈ 0.02). The graphite nanoparticles increased the static thermal conductivities of the fluid significantly at low weight fraction loadings. However, the experimental heat transfer coefficients showed lower increases than predicted by either the conventional heat transfer correlations for homogeneous fluids, or the correlations developed from the particle suspensions with aspect ratios close to one. New correlations on heat transfer need to be developed for nanofluid systems.

Originally five candidates of nano material were chosen for making stable nano dispersions. Nano graphite particles remain a practical choice for nanofluids thermal application after taking divergent performance attributes into full account: significant thermal conductivity increases, minimal viscosity increase, low density for better dispersion stability, and relatively low cost, among others. Three different types of commercial antifreeze coolants were chosen for the integration with graphite nano fluids. Without corrosion inhibitors our nano coolants typically fail both ASTM D15 engine coolant corrosion tests: D1384 and D4340. Yet, heating up and adding in electrolytes are two common ways to destroy a nano particle dispersion. After making adjustments in particle loading, choosing an effective dispersant, and establishing proper dispersant levels, two nano graphite coolants made from two different nano sources passed both engine coolant corrosion tests plus the CID AA-52624A compatibility and storage stability tests. Compared with the base fluid, the nano graphite coolant's thermal conductivity has more than a 25% increase at 2 volume percent particle loading, which is a significant enhancement.

Dispersions containing nanoparticles (nanofluids) are mixtures with unique properties, and their transport properties depend on the three-dimensional network or microstructure of the nanoparticles, which can be affected by various factors including shear stress, particle loading, and temperature. In this research, we studied the rheological behaviors of dispersions containing two different carbon morphologies: multiwalled carbon nanotubes (rodlike nanoparticles with L/D = 30), and graphite particles (disklike nanoparticles with L/D = 0.025). All nanofluids showed shear thinning behavior in steady shear measurements and those containing nanotubes had lower power law indices than graphite dispersions. Shear stress broke down the microstructure network and oriented both rodlike and disklike nanoparticles in the dispersions. The presence of a modest amount of nanotubes in the graphite nanofluid affected the microstructure of the dispersion and caused a remarkable decrease in its power law index. Microstructures of nanofluids strongly depended on the dispersant chemistry used to stabilize the particles, and high temperature may cause dispersant failure. Mechanical methods for dispersing the particles affected the geometry of the nanoparticles and therefore the rheological properties of the nanofluids. In the creep recovery tests, the compliance of graphite nanofluids quickly returned to zero when the stress was removed, while nanotube dispersion with high nanotube loading showed an elastic response during recovery. These results suggest that the microstructure in the dispersions is affected by nanoparticle morphology, dispersant chemistry, and shear stress.

Polymer-drug conjugates (polymer therapeutics) are finding increasing use as novel anticancer agents. Here a series of poly(ethylene glycol) PEG-doxorubicin (Dox) conjugates were synthesized using polymers of linear or branched architecture (molecular weight 5000-20000 g/mol) and with different peptidyl linkers (GFLG, GLFG, GLG, GGRR, and RGLG). The resultant conjugates had a drug loading of 2.7-8.0 wt % Dox and contained2.0% free drug (% total drug). All conjugates containing a GFLG linker showed approximately 30% release of Dox at 5 h irrespective of PEG molecular weight or architecture. The GLFG linker was degraded more quickly (approximately 57% Dox release at 5 h), and the other linkers more slowly (16% release at 5 h), by lysosomal enzymes in vitro. In vitro there was no clear relationship between cytotoxicity toward B16F10 cells and the observed Dox release rate. All PEG conjugates were more than 10-fold less toxic (IC50 values2 microg/mL) than free Dox (IC50 value = 0.24 microg/mL). Biodistribution in mice bearing sc B16F10 tumors was assessed after administration of PEGs (5000, 10000, or 20000 g/mol) radioiodinated using the Bolton and Hunter reagent or PEG-Dox conjugates by HPLC. The 125I-labeled PEGs showed a clear relationship between Mw and blood clearance and tumor accumulation. The highest Mw PEG had the longest plasma residence time and consequently the greatest tumor targeting. The PEG-Dox conjugates showed a markedly prolonged plasma clearance and greater tumor targeting compared to free Dox, but there was no clear molecular weight-dependence on biodistribution. This was consistent with the observation that the PEG-Dox conjugates formed micelles in aqueous solution comprising 2-20 PEG-Dox molecules depending on polymer Mw and architecture. Although PEG-Dox showed greater tumor targeting than free Dox, PEG conjugation led to significantly lower anthracycline levels in heart. Preliminary experiments to assess antitumor activity against sc B16F10 in vivo showed the PEG5000linear (L)-GFLG-Dox and PEG10000branched (B)-GLFG-Dox (both 5 mg/kg Dox-equiv) to be the most active with T/C values of 146 and 143%, respectively. Free Dox did not show significant activity in this model (T/C = 121%). Dose escalation of PEG5000(L)-GFLG-Dox to 10 mg/kg Dox-equiv prolonged further animal survival (T/C = 161%). Using the Dox-sensitive model ip L1210 (where Dox displayed a T/C = 150% after single ip dose), the PEG5000(L)-GFLG-Dox displayed a maximum T/C of 141% (10 mg/kg Dox-equiv) using a once a day (x3) schedule. Further studies are warranted with PEG5000(L)-GFLG-Dox to determine its spectrum of antitumor activity and also the optimum dosing schedule before clinical testing.

Water soluble polymer anticancer conjugates can improve the pharmacokinetics of covalently bound drugs by limiting cellular uptake to the endocytic route, thus prolonging plasma circulation time and consequently facilitating tumor targeting by the enhanced permeability and retention (EPR) effect. Many of the first generation antitumor polymer conjugates used nonbiodegradable polymeric carriers which limits the molecular weight that can be safely used to40,000 g/mol. The aim of this ambitious study was to synthesize and evaluate a novel, prototype biodegradable polymeric system based on high molecular weight, water-soluble functionalized polyesters. The main polymeric platform was prepared from bis(4-hydroxy)butyl maleate (DBM) and poly(ethylene glycol) (PEG4000) blocks to give the polymer DBM2-PEG4000 containing biodegradable carbonate bonds and having a M(w) of 100,000-190,000 g/mol; M(n) of 37,000-53,000 g/mol, and M(w)/M(n) of 3.0-3.7. Using thioether linkages, this polymer was then grafted with HS-PEG3000-Gly-Phe-Lue-Gly doxorubicin (HS-PEG3000-GFLG-Dox) pendant side chains ( approximately 30 per DBM2-PEG chain). The final construct, DBM2-PEG4000-S-PEG3000-GFLG-Dox had a total Dox content of 3-4 wt % and a free Dox content ofor = 0.7% total Dox. During incubation with isolated lysosomal enzymes, the rate of Dox release from the polymer backbone was relatively slow (5% release over 5 h) compared to that seen for PEG5000-GFLG-Dox alone (20% over 5 h). The in vitro cytotoxicity was assessed using B16F10 murine melanoma (MTT assay). DBM2-PEG4000-S-PEG3000-GFLG-Dox was 10-20-fold less toxic than free Dox. In vivo antitumor activity of the DBM2-PEG4000-S-PEG3000-GFLG-Dox conjugates was assessed using a subcutaneous (s.c.) B16F10 murine melanoma model, and an intraperitoneal (i.p.) L1210 leukaemia model. The increased toxicity (attributed to poor solubility) and low antitumor activity of DBM2-PEG4000-S-PEG3000-GFLG-Dox conjugates compared to PEG5000-GFLG-Dox and HPMA copolymer-Dox conjugates was attributed to the slow rate of Dox release. The DBM2-PEG4000-S-PEG3000-GFLG-Dox conjugates were considered unfavorable as candidates for further development. However, the successful scale-up synthesis of DBM2-PEG4000-S-PEG3000 constructs suggest that they are worthy of further investigation as carriers for controlled release and targeting of less hydrophobic agents.

Prior work on asymmetric thermally conducting nanoparticle dispersions has shown that it is possible to raise the thermal conductivity of low thermal conductivity liquids at modest volume fractions of nanoparticles. Stable and reproducible nanotube dispersions require careful control of the dispersant chemistry as well as an understanding of their response to input energy. This paper addresses the effects of dispersant concentration, dispersing energy, and nanoparticle loading on thermal conductivity and steady shear viscosity of nanotube-in-oil dispersions. The thermal conductivity and viscosity of these dispersions correlate with each other and vary with the size of large scale agglomerates, or clustered nanoparticles, in the fluids. Fluids with large scale agglomerates have high thermal conductivities. Dispersion energy, applied by sonication, can decrease agglomerate size, but also breaks the nanotubes, decreasing both the thermal conductivity and viscosity of nanotube dispersions. Developing practica...