Efficient Inhibition of wear debris-induced inflammation by locally delivered siRNA

Aseptic loosening is the most common long-term complication of total joint replacement, which is associated with the generation of wear debris. The purpose of this study was to investigate the inhibitory effect of small interfering RNA (siRNA) targeting tumor necrosis factor-α (TNF-α) on wear debris-induced inflammation. A local delivery of lentivirus-mediated TNF-α siRNA into the modified murine air pouch, which was stimulated by polymethylmethacrylate (PMMA) particles, resulted in significant blockage of TNF-α both in mRNA and protein levels for up to 4 weeks. In addition, significant down-regulation of interleukin-1 (IL-1) and interleukin-6 (IL-6) was observed in TNF-α siRNA-treated pouches. The safety profile of gene therapy was proven by Bioluminescent assay and quantitative fluorescent flux. Histological analysis revealed less inflammatory responses (thinner pouch membrane and decreased cellular infiltration) in TNF-α siRNA-treated pouches. These findings suggest that local delivery of TNF-α siRNA might be an excellent therapeutic candidate to inhibit particle-induced inflammation.     

A Passive Anti-icing Strategy Based on a Superhydrophobic Mesh with Extremely Low Ice Adhesion Strength

Although superhydrophobic materials have attracted much research interest in anti-icing,some controversy still exists.In this research,we report a cost-effective method used to verify the contribution of area fraction to ice adhesion strength.We tried to partially-embed siliea nanopnarticles into microscale fabrics of a commercial polyamide mesh.Then,the area fraction could be determined by altering the mesh size.Generally,the ice adhesion strength decreases as the area fraction decreases.An ice adhesion strength of~1.9 kPa and a delayed freezing time of~1048 s can be obtained.We attribute the low ice adhesion strength to the combination of superhydro-phobicity and stress concentration.The superhydrophobicity prohibits the water from penetrating into the voids of the meshes,and the small actual contact area leads to stress concentration which promotes interfacial crack propagation.Moreover,our superhydrophobic mesh simultaneously exhibis a micro-nano hierarchical structure and a partally-cmbedded structure.Therefore,the as-prepared superhydrophobic mesh retained the ieephobicity after 20 icingldeicing cycles,and maintained its superhydrophobicity even afier 60 sandpaper-abrasion cycles and a 220"C thermal treatment.     

Mutations in the exon 10 of prolactin receptor gene change the egg production performance in Wanjiang white goose

To select the molecular genetic markers related to egg performance of Wanjiang white goose, prolactin receptor gene (PRLR) was adopted to be a candidate gene in our study. Five pairs of primers (P1–P5) were designed to detect the SNPs of PRLR gene by PCR-SSCP method. The results revealed that polymorphisms were discovered in the PCR products amplified with P4 primers in PRLR exon 10, three genotypes were found: AA, AB and AC. The sequence of AB genotype is the same as original sequence (DQ660982) in NCBI. There are five mutations in AA genotype: C → A at 840 bp, C → T at 862 bp, T → C at 875 bp, T → A at 963 bp, A → T at 989 bp, resulting in amino acid mutations: His → Asn, Thr → Ile, Asn → Lys, Thr → Ser, and synonymous mutation at 875 bp. Sequencing revealed five mutations in AC genotype: G → T at 816 bp, A → T at 861 bp, C → T at 862 bp, T → C at 875 bp, A → G at 948 bp, causing amino acid mutations of Val → Phe, Thr → Phe, synonymous mutations at 875 and 963 bp. Besides, there are an N-glycosylation site (NQSR), three casein kinase II phosphorylation sites including SIIE, SKTE, and SLMD in AA genotype; three casein kinase II phosphorylation sites including SIIE, SKTE, and TLMD in AB genotype; three casein kinase II phosphorylation sites including SIFE, SKTE, and TLMD in AC genotype. The annual egg yielding of AB genotype geese are significantly more than those of AA and AC genotype geese on the average (P < 0.05). It is suggested for the first time that PRLR is a promising candidate gene that can affect egg performance in Wanjiang white goose.     

Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

Background

Apolipoprotein E (apoE) is a major carrier of cholesterol and essential for synaptic plasticity. In brain, it’s expressed by many cells but highly expressed by the choroid plexus and the predominant apolipoprotein in cerebrospinal fluid (CSF). The role of apoE in the CSF is unclear. Recently, the glymphatic system was described as a clearance system whereby CSF and ISF (interstitial fluid) is exchanged via the peri-arterial space and convective flow of ISF clearance is mediated by aquaporin 4 (AQP4), a water channel. We reasoned that this system also serves to distribute essential molecules in CSF into brain. The aim was to establish whether apoE in CSF, secreted by the choroid plexus, is distributed into brain, and whether this distribution pattern was altered by sleep deprivation.

Methods

We used fluorescently labeled lipidated apoE isoforms, lenti-apoE3 delivered to the choroid plexus, immunohistochemistry to map apoE brain distribution, immunolabeled cells and proteins in brain, Western blot analysis and ELISA to determine apoE levels and radiolabeled molecules to quantify CSF inflow into brain and brain clearance in mice. Data were statistically analyzed using ANOVA or Student’s t- test.

Results

We show that the glymphatic fluid transporting system contributes to the delivery of choroid plexus/CSF-derived human apoE to neurons. CSF-delivered human apoE entered brain via the perivascular space of penetrating arteries and flows radially around arteries, but not veins, in an isoform specific manner (apoE2?>?apoE3?>?apoE4). Flow of apoE around arteries was facilitated by AQP4, a characteristic feature of the glymphatic system. ApoE3, delivered by lentivirus to the choroid plexus and ependymal layer but not to the parenchymal cells, was present in the CSF, penetrating arteries and neurons. The inflow of CSF, which contains apoE, into brain and its clearance from the interstitium were severely suppressed by sleep deprivation compared to the sleep state.

Conclusions

Thus, choroid plexus/CSF provides an additional source of apoE and the glymphatic fluid transporting system delivers it to brain via the periarterial space. By implication, failure in this essential physiological role of the glymphatic fluid flow and ISF clearance may also contribute to apoE isoform-specific disorders in the long term.

     

EP300 contributes to high-altitude adaptation in Tibetans by regulating nitric oxide production

The genetic adaptation of Tibetans to high altitude hypoxia likely involves a group of genes in the hypoxic pathway,as suggested by earlier studies.To test the adaptive role of the previously reported candidate gene EP300 (histone acetyltransferase p300),we conducted resequencing of a 108.9 kb gene region of EP300 in 80 unrelated Tibetans.The allele-frequency and haplotype-based neutrality tests detected signals of positive Darwinian selection on EP300 in Tibetans,with a group of variants showing allelic divergence between Tibetans and lowland reference populations,including Han Chinese,Europeans,and Africans.Functional prediction suggested the involvement of multiple EP300 variants in gene expression regulation.More importantly,genetic association tests in 226 Tibetans indicated significant correlation of the adaptive EP300 variants with blood nitric oxide (NO) concentration.Collectively,we propose that EP300 harbors adaptive variants in Tibetans,which might contribute to high-altitude adaptation through regulating NO production.     

Role of IKK/NF-κB signaling in extinction of conditioned place aversion memory in rats

The inhibitor κB protein kinase/nuclear factor κB (IKK/NF-κB) signaling pathway is critical for synaptic plasticity. However, the role of IKK/NF-κB in drug withdrawal-associated conditioned place aversion (CPA) memory is unknown. Here, we showed that inhibition of IKK/NF-κB by sulphasalazine (SSZ; 10 mM, i.c.v.) selectively blocked the extinction but not acquisition or expression of morphine-induced CPA in rats. The blockade of CPA extinction induced by SSZ was abolished by sodium butyrate, an inhibitor of histone deacetylase. Thus, the IKK/NF-κB signaling pathway might play a critical role in the extinction of morphine-induced CPA in rats and might be a potential pharmacotherapy target for opiate addiction.     

Statin Use and the Risk of Parkinson's Disease: An Updated Meta-Analysis

Introduction

In response to the ongoing debate over the relationship between the use of statins and the risk of Parkinson''s disease (PD), we performed a systematic review and meta-analysis of observational studies to examine their association.

Methods

We conducted a review of the literature using electronic databases supplemented by a manual search to identify potentially relevant case-control or cohort studies. Summary relative risk (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Sensitivity and subgroup analyses were also conducted.

Results

Eleven studies (five case-control and six cohort) with a total of 3,513,209 participants and 21,011 PD cases were included. Statin use was associated with a lower risk of PD, with a summary RR of 0.81 (95% CI 0.71–0.92). Sensitivity analysis demonstrated the robustness of results. Subgroup analyses showed that neither study design nor study region significantly influenced the effect estimates. However, subgroup studies adjusted for age or sex had a greater inverse association than did unadjusted analyses (age-adjusted RR 0.75, 95% CI 0.60–0.95; age-unadjusted RR 0.86, 95% CI 0.75–0.99 and sex-adjusted RR 0.76, 95% CI 0.59–0.98; sex-unadjusted RR 0.85, 95% CI 0.79–0.92).

Conclusions

Results of this systematic review suggest that statin use is associated with a reduced PD risk. However, randomized controlled trials and more observational studies should be performed before strong conclusions are drawn.