ß-Ga2O3 Air-Channel Field-Emission Nanodiode with Ultrahigh Current Density and Low Turn-On Voltage.

Field-emission nanodiodes with air-gap channels based on single ß-Ga2O3 nanowires have been investigated in this work. With a gap of ∼50 nm and an asymmetric device structure, the proposed nanodiode achieves good diode characteristics through field emission in air at room temperature. Measurement results show that the nanodiode exhibits an ultrahigh emission current density, a high enhancement factor of >2300, and a low turn-on voltage of 0.46 V. More impressively, the emission current almost keeps constant over a wide range (8 orders of magnitude) of air pressures below 1 atm. Meanwhile, the fluctuation in field-emission current is below 8.7% during long-time monitoring, which is better than the best reported field-emission device based on ß-Ga2O3 nanostructures. All of these results indicate that ß-Ga2O3 air-gapped nanodiodes are promising candidates for vacuum electronics that can also operate in air.

Knockdown of UBE2I inhibits tumorigenesis and enhances chemosensitivity of cholangiocarcinoma via modulating p27kip1 nuclear export.

The asymptomatic nature of cholangiocarcinoma (CCA), particularly during its early stages, in combination with its high aggressiveness and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. As a tumor suppressor that inhibits the cell cycle, abnormal cytoplasmic p27kip1 localization is related to chemotherapy resistance and often occurs in various cancers, including CCA. Nevertheless, the underlying mechanism is unclear. SUMOylation, which is involved in regulating subcellular localization and the cell cycle, is a posttranslational modification that regulates p27kip1 activity. Here, we confirmed that UBE2I, as the only key enzyme for SUMOylation, was highly expressed and p27kip1 was downregulated in CCA tissues, which were associated with poor outcomes in CCA. Moreover, UBE2I silencing inhibited CCA cell proliferation, delayed xenograft tumor growth in vivo, and sensitized CCA cells to the chemotherapeutics, which may be due to cell cycle arrest induced by p27kip1 nuclear accumulation. According to the immunoprecipitation result, we found that UBE2I could bind p27kip1, and the binding amount of p27kip1 and SUMO-1 decreased after UBE2I silencing. Moreover, nuclear retention of p27kip1 was induced by UBE2I knockdown and SUMOylation or CRM1 inhibition, further suggesting that UBE2I could cooperate with CRM1 in the nuclear export of p27kip1. These data indicate that UBE2I-mediated SUMOylation is a novel regulatory mechanism that underlies p27kip1 export and controls CCA tumorigenesis, providing a therapeutic option for CCA treatment.

RNF4 promotes tumorigenesis, therapy resistance of cholangiocarcinoma and affects cell cycle by regulating the ubiquitination degradation of p27kip1 in the nucleus.

Among the hallmarks of cholangiocarcinoma (CCA) progression and unresponsiveness to therapy is impaired ubiquitin-dependent degradation of nuclear tumor suppressor protein. In the previous stage, our research group found that as a key tumor suppressor, nuclear dysfunction of p27kip1 is closely related to chemotherapy resistance of CCA, but the specific mechanism is unclear. It was recently shown that p27kip1-driven tumors were strongly dependent on the SUMO pathway. RNF4, as the SUMO-targeted ubiquitin ligase (STUbL), identifies SUMOylated proteins as a substrate through sumo-interacting motifs (SIM) and causes its degradation via the ubiquitin proteasome pathway. Here we described that the expression of RNF4 was upregulated in CCA tissues and related to malignant features. Silencing RNF4 arrested human CCA cells at the G1 phase, which was associated with the upregulation of p27kip1 and the downregulation of its downstream cycle-related proteins. Silencing RNF4 inhibited cell proliferation and migration, increased cell apoptosis, and sensitized CCA cells to treatment of chemotherapeutic drugs in vitro. Immunofluorescence showed that p27kip1 and RNF4 were mainly co-located in the nucleus. Immunoprecipitation and Western blot showed that p27kip1 was a target protein for SUMOylation and high expression of RNF4 decreased the levels of nuclear p27kip1, enhanced the levels of ubiquitinated and SUMOylated p27kip1, indicating that RNF4 could regulate cell cycle progression via recognizing SUMOylated p27kip1 and facilitating its ubiquitination degradation. These data indicate that RNF4-mediated ubiquitination degradation of SUMOylated proteins is a novel regulatory mechanism of p27kip1 dysfunction and CCA tumorigenesis, which provides a potential option for therapeutic intervention of CCA.

H19 Promotes HCC Bone Metastasis Through Reducing Osteoprotegerin Expression in a Protein Phosphatase 1 Catalytic Subunit Alpha/p38 Mitogen-Activated Protein Kinase-Dependent Manner and Sponging microRNA 200b-3p.

BACKGROUND AND AIMS: Bone is the second most frequent site of metastasis for HCC, which leads to an extremely poor prognosis. HCC bone metastasis is typically osteolytic, involving the activation of osteoclasts. Long noncoding RNA H19 plays an important role in the pathogenesis of human cancers. Nonetheless, the mechanism underlying the participation of H19 in HCC bone metastasis remains unclear. APPROACH AND RESULTS: The current study established a mouse HCC bone metastasis model by using serial intracardiac injection and cell isolation to obtain cells with distinct bone metastasis ability. H19 was highly expressed in these cells and in clinical HCC bone metastasis specimens. Both osteoclastogenesis in vitro and HCC bone metastasis in vivo were promoted by H19 overexpression, whereas these processes were suppressed by H19 knockdown. H19 overexpression attenuated p38 phosphorylation and further down-regulated the expression of osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor. However, up-regulated OPG expression as well as suppressed osteoclastogenesis caused by H19 knockdown were recovered by p38 interference, indicating that p38 mitogen-activated protein kinase (MAPK)-OPG contributed to H19-promoted HCC bone metastasis. Furthermore, we demonstrated that H19 inhibited the expression of OPG by binding with protein phosphatase 1 catalytic subunit alpha (PPP1CA), which dephosphorylates p38. SB-203580-mediated inactivation of p38MAPK reversed the down-regulation of HCC bone metastasis caused by H19 knockdown in vivo. Additionally, H19 enhanced cell migration and invasion by up-regulating zinc finger E-box binding homeobox 1 through the sequestration of microRNA (miR) 200b-3p. CONCLUSIONS: H19 plays a critical role in HCC bone metastasis by reducing OPG expression, which is mediated by the PPP1CA-induced inactivation of the p38MAPK pathway; and H19 also functions as a sponge for miR-200b-3p.

PTPRε Acts as a Metastatic Promoter in Hepatocellular Carcinoma by Facilitating Recruitment of SMAD3 to TGF-ß Receptor 1.

BACKGROUND AND AIMS: Transforming growth factor beta (TGF-ß) suppresses early stages of tumorigenesis, but contributes to the migration and metastasis of cancer cells. However, the role of TGF-ß signaling in invasive prometastatic hepatocellular carcinoma (HCC) is poorly understood. In this study, we investigated the roles of canonical TGF-ß/mothers against decapentaplegic homolog 3 (SMAD3) signaling and identified downstream effectors on HCC migration and metastasis. APPROACH AND RESULTS: By using in vitro trans-well migration and invasion assays and in vivo metastasis models, we demonstrated that SMAD3 and protein tyrosine phosphatase receptor epsilon (PTPRε) promote migration, invasion, and metastasis of HCC cells in vitro and in vivo. Further mechanistic studies revealed that, following TGF-ß stimulation, SMAD3 binds directly to PTPRε promoters to activate its expression. PTPRε interacts with TGFBR1/SMAD3 and facilitates recruitment of SMAD3 to TGFBR1, resulting in a sustained SMAD3 activation status. The tyrosine phosphatase activity of PTPRε is important for binding with TGFBR1, recruitment and activation of SMAD3, and its prometastatic role in vitro. A positive correlation between pSMAD3/SMAD3 and PTPRε expression was determined in HCC samples, and high expression of SMAD3 or PTPRε was associated with poor prognosis of patients with HCC. CONCLUSIONS: PTPRε positive feedback regulates TGF-ß/SMAD3 signaling to promote HCC metastasis.

Regulatory Mechanism for Absence Seizures in Bidirectional Interactive Thalamocortical Model via Different Targeted Therapy Schemes.

Recent clinical practice has found that the spike-wave discharge (SWD) scopes of absence seizures change from small cortical region to large thalamocortical networks, which has also been proved by theoretical simulation. The best biophysics explanation is that there are interactions between coupled cortico-thalamic and thalamocortical circuits. To agree with experiment results and describe the phenomena better, we constructed a coupled thalamocortical model with bidirectional channel (CTMBC) to account for the causes of absence seizures which are connected by the principle of two-way communication of neural pathways. By adjusting the coupling strength of bidirectional pathways, the spike-wave discharges are reproduced. Regulatory mechanism for absence seizures is further applied to CTMBC via four different targeted therapy schemes, such as deep brain stimulation (DBS), charge-balanced biphasic pulse (CBBP), coordinated reset stimulation (CRS) 1 : 0, and (CRS) 3 : 2. The new CTMBC model shows that neurodiversity in bidirectional interactive channel could supply theory reference for the bidirectional communication mode of thalamocortical networks and the hypothesis validation of pathogenesis.

Analysis of the genetic architecture of maize kernel size traits by combined linkage and association mapping.

Kernel size-related traits are the most direct traits correlating with grain yield. The genetic basis of three kernel traits of maize, kernel length (KL), kernel width (KW) and kernel thickness (KT), was investigated in an association panel and a biparental population. A total of 21 single nucleotide polymorphisms (SNPs) were detected to be most significantly (P < 2.25 × 10-6 ) associated with these three traits in the association panel under four environments. Furthermore, 50 quantitative trait loci (QTL) controlling these traits were detected in seven environments in the intermated B73 × Mo17 (IBM) Syn10 doubled haploid (DH) population, of which eight were repetitively identified in at least three environments. Combining the two mapping populations revealed that 56 SNPs (P < 1 × 10-3 ) fell within 18 of the QTL confidence intervals. According to the top significant SNPs, stable-effect SNPs and the co-localized SNPs by association analysis and linkage mapping, a total of 73 candidate genes were identified, regulating seed development. Additionally, seven miRNAs were found to situate within the linkage disequilibrium (LD) regions of the co-localized SNPs, of which zma-miR164e was demonstrated to cleave the mRNAs of Arabidopsis CUC1, CUC2 and NAC6 in vitro. Overexpression of zma-miR164e resulted in the down-regulation of these genes above and the failure of seed formation in Arabidopsis pods, with the increased branch number. These findings provide insights into the mechanism of seed development and the improvement of molecular marker-assisted selection (MAS) for high-yield breeding in maize.

Antiwetting and Antifouling Performances of Different Lubricant-Infused Slippery Surfaces.

The concept of slippery lubricant-infused surfaces has shown promising potential in antifouling for controlling detrimental biofilm growth. In this study, nontoxic silicone oil was either impregnated into porous surface nanostructures, referred to as liquid-infused surfaces (LIS), or diffused into a polydimethylsiloxane (PDMS) matrix, referred to as a swollen PDMS (S-PDMS), making two kinds of slippery surfaces. The slippery lubricant layers have extremely low contact angle hysteresis, and both slippery surfaces showed superior antiwetting performances with droplets bouncing off or rolling transiently after impacting the surfaces. We further demonstrated that water droplets can remove dust from the slippery surfaces, thus showing a "cleaning effect". Moreover, "coffee-ring" effects were inhibited on these slippery surfaces after droplet evaporation, and deposits could be easily removed. The clinically biofilm-forming species P. aeruginosa (as a model system) was used to further evaluate the antifouling potential of the slippery surfaces. The dried biofilm stains could still be easily removed from the slippery surfaces. Additionally, both slippery surfaces prevented around 90% of bacterial biofilm growth after 6 days compared to the unmodified control PDMS surfaces. This investigation also extended across another clinical pathogen, S. epidermidis, and showed similar results. The antiwetting and antifouling analysis in this study will facilitate the development of more efficient slippery platforms for controlling biofouling.

Hierarchical Rose Petal Surfaces Delay the Early-Stage Bacterial Biofilm Growth.

A variety of natural surfaces exhibit antibacterial properties; as a result, significant efforts in the past decade have been dedicated toward fabrication of biomimetic surfaces that can help control biofilm growth. Examples of such surfaces include rose petals, which possess hierarchical structures like the micropapillae measuring tens of microns and nanofolds that range in the size of 700 ± 100 nm. We duplicated the natural structures on rose petal surfaces via a simple UV-curable nanocasting technique and tested the efficacy of these artificial surfaces in preventing biofilm growth using clinically relevant bacteria strains. The rose petal-structured surfaces exhibited hydrophobicity (contact angle (CA) ≈ 130.8° ± 4.3°) and high CA hysteresis (∼91.0° ± 4.9°). Water droplets on rose petal replicas evaporated following the constant contact line mode, indicating the likely coexistence of both Cassie and Wenzel states (Cassie-Baxter impregnating the wetting state). Fluorescence microscopy and image analysis revealed the significantly lower attachment of Staphylococcus epidermidis (86.1 ± 6.2% less) and Pseudomonas aeruginosa (85.9 ± 3.2% less) on the rose petal-structured surfaces, compared with flat surfaces over a period of 2 h. An extensive biofilm matrix was observed in biofilms formed by both species on flat surfaces after prolonged growth (several days), but was less apparent on rose petal-biomimetic surfaces. In addition, the biomass of S. epidermidis (63.2 ± 9.4% less) and P. aeruginosa (76.0 ± 10.0% less) biofilms were significantly reduced on the rose petal-structured surfaces, in comparison to the flat surfaces. By comparing P. aeruginosa growth on representative unitary nanopillars, we demonstrated that hierarchical structures are more effective in delaying biofilm growth. The mechanisms are two-fold: (1) the nanofolds across the hemispherical micropapillae restrict initial attachment of bacterial cells and delay the direct contact of cells via cell alignment and (2) the hemispherical micropapillae arrays isolate bacterial clusters and inhibit the formation of a fibrous network. The hierarchical features on rose petal surfaces may be useful for developing strategies to control biofilm formation in medical and industrial contexts.

Plasmon-modulated bistable four-wave mixing signals from a metal nanoparticle-monolayer MoS2 nanoresonator hybrid system.

We present a study for the impact of exciton-phonon and exciton-plasmon interactions on bistable four-wave mixing (FWM) signals in a metal nanoparticle (MNP)-monolayer MoS2 nanoresonator hybrid system. Via tracing the FWM response we predict that, depending on the excitation conditions and the system parameters, such a system exhibits 'U-shaped' bistable FWM signals. We also map out bistability phase diagrams within the system's parameter space. Especially, we show that compared with the exciton-phonon interaction, a strong exciton-plasmon interaction plays a dominant role in the generation of optical bistability, and the bistable region will be greatly broadened by shortening the distance between the MNP and the monolayer MoS2 nanoresonator. In the weak exciton-plasmon coupling regime, the impact of exciton-phonon interaction on optical bistability will become obvious. The scheme proposed may be used for building optical switches and logic-gate devices for optical computing and quantum information processing.

Bidirectional correlation between gastroesophageal reflux disease and sleep problems: a systematic review and meta-analysis.

Objectives: Gastroesophageal reflux disease (GERD) and sleep problems are highly prevalent among the general population. Both them are associated with a variety of psychiatric disorders such as depression and anxiety, which is highlighting an underexplored connection between them. This meta-analysis aims to explore the association between sleep problems and GERD. Methods: We conducted a comprehensive search on PubMed, Cochrane Library, Embase, and Web of Science, using Medical Subject Headings (MeSH) and keywords, covering articles from the inception of the databases until August 2023. Stata statistical software, version 14.0, was utilized for all statistical analyses. A fixed-effects model was applied when p > 0.1 and I2 ≤ 50%, while a random-effects model was employed for high heterogeneity (p < 0.1 and I2 > 50%). Funnel plots and Egger's test were used to assess publication bias. Results: Involving 22 studies, our meta-analysis revealed that insomnia, sleep disturbance, or short sleep duration significantly increased the risk of GERD (OR = 2.02, 95% CI [1.64-2.49], p < 0.001; I2 = 66.4%; OR = 1.98, 95% CI [1.58-2.50], p < 0.001, I2 = 50.1%; OR = 2.66, 95% CI [2.02-3.15], p < 0.001; I2 = 62.5%, respectively). GERD was associated with an elevated risk of poor sleep quality (OR = 1.47, 95% CI [1.47-1.79], p < 0.001, I2 = 72.4%), sleep disturbance (OR = 1.47, 95% CI [1.24-1.74], p < 0.001, I2 = 71.6%), or short sleep duration (OR = 1.17, 95% CI [1.12-1.21], p < 0.001, I2 = 0). Conclusion: This meta-analysis establishes a bidirectional relationship between four distinct types of sleep problems and GERD. The findings offer insights for the development of innovative approaches in the treatment of both GERD and sleep problems.

Xiezhuo Tiaozhi formula inhibits macrophage pyroptosis in the non-alcoholic fatty liver disease by targeting the SIRT1 pathway.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a challenging disease to interfere with and represents a potential long-term risk factor for hepatic fibrosis and liver cancer. The Xiezhuo Tiaozhi (XZTZ) formula, a water extract from crude herbs, has been widely used as an anti-NAFLD agent through clinical observation. However, the underlying pharmacological mechanisms of the XZTZ formula and its impact on the potential pathways against NAFLD have not been elucidated. PURPOSE: Our study aims to investigate the pharmacological effects and underlying regulatory mechanisms of the XZTZ formula to treat NAFLD. METHODS: The possible active components and pharmacological mechanisms of the XZTZ formula against NAFLD were identified using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) and molecular docking. To further explore the potential mechanisms, forty-eight 6-week-old male C57BL/6 J mice were given individual attention with high-fat and high-sugar diet (HFHSD) or relevant control (Ctrl) diets for 16 weeks to successfully construct a NAFLD mouse model. Subsequently, the levels of serum biochemicals, pathological changes in the liver, and pyroptosis levels were assessed in mice to investigate the therapeutic effects of the XZTZ formula. Further, LPS-induced RAW264.7 cells and Immortalized Mouse Kupffer cells (ImKC) were used to verify the potential mechanisms of the XZTZ formula against NAFLD in vitro. RESULTS: We identified 7 chemical compounds and 2 potential therapeutic targets as plausible therapeutic points for the treatment of NAFLD using the XZTZ formula. Subsequent histopathological analysis revealed marked hepatic steatosis and lipid accumulation in the HFHSD mice liver, while conditions were effectively ameliorated by administration of the XZTZ formula. Additionally, our work demonstrated that the XZTZ formula could attenuate M1 polarization, promote M2 polarization, and suppress pyroptosis via the SIRT1 pathway in tissue samples. Moreover, validation performed through LPS-induced RAW264.7 and ImKC cells by showing that silencing SIRT1 weaken the effects of the XZTZ formula on relative pyroptosis affirmed that its role was associated with the SIRT1 pathway in macrophage. CONCLUSION: These findings suggest that the XZTZ formula alleviated hepatic steatosis and lipid accumulation in NAFLD mice. These ameliorations are associated with mechanisms involving the attenuation of M1 polarization, promotion of M2 polarization, and anti-pyroptosis effects through the SIRT1 pathway.

Suppression of absence seizures by using different stimulations in a reduced corticothalamic-basal ganglion-pedunculopontine nucleus model.

Coupled neural network models are playing an increasingly important part in the modulation of absence seizures today. However, it is currently unclear how basal ganglia, corticothalamic network and pedunculopontine nucleus can coordinate with each other to develop a whole coupling circuit, theoretically. In addition, it is still difficult to select effective parameters of electrical stimulation on the regulation of absence seizures in clinical trials. Therefore, to develop a coupled model and reduce computation cost, a new model constructed by a simplified basal ganglion, two corticothalamic circuits and a pedunculopontine nucleus was proposed. Further, to seek better inhibition therapy, three electrical stimulations, high frequency stimulation (HFS), 1:0 coordinate reset stimulation (CRS) and 3:2 CRS, were applied to the thalamic reticular nucleus (RE) in the first corticothalamic circuit in the coupled model. The simulation results revealed that increasing the frequency and pulse width of an electrical stimulation within a certain range can also suppress seizures. Under the same parameters of electrical stimulation, the inhibitory effect of HFS on seizures was better than that of 1:0 CRS and 3:2 CRS. The research established a reduced corticothalamic-basal ganglion-pedunculopontine nucleus model, which lays a theoretical foundation for future optimal parameters selection of electrical stimulation. We hope that the findings will provide new insights into the role of theoretical models in absence seizures.

Lubrication and drug release behaviors of mesoporous silica nanoparticles grafted with sulfobetaine-based zwitterionic polymer.

Osteoarthritis, which is characterized by irreversible destruction of articular cartilage and severe inflammation of joint capsule, may be effectively treated via the synergistic therapy of lubrication restoration and local drug intervention. In this study, zwitterionic polymer-grafted mesoporous silica nanoparticles (MSNs@pSBMA) with the property of enhanced lubrication and sustained drug release were successfully synthesized via photopolymerization of 3-[dimethyl-[2-(2-methylprop-2-enoyloxy) ethyl] azaniumyl] propane-1-sulfonate polymer (pSBMA) on the surface of MSNs. The tribiological test showed that the lubrication performance of MSNs@pSBMA was remarkably improved, with a reduction of 80% in friction coefficient compared with MSNs. It was attributed to hydration lubrication mechanism by which a tenacious hydration layer was formed surrounding the N+(CH2)2(CH3)2 and SO3- headgroups in the pSBMA polyelectrolyte polymer. Additionally, the surface morphology analysis of the tribopairs demonstrated that MSNs@pSBMA were endowed with excellent anti-wear performance. Importantly, the drug release test illustrated that, compared with MSNs, MSNs@pSBMA achieved good sustained drug release behavior. In summary, the MSNs@pSBMA nanoparticles developed herein, as an injectable lubricant with enhanced lubrication and drug delivery, may represent a promising approach for the treatment of osteoarthritis.

TPX2 as a Novel Prognostic Indicator and Promising Therapeutic Target in Triple-negative Breast Cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC), which lacks endocrine therapies and targeted therapies, has the worst prognosis of all breast cancers which remain the most common malignancy in women worldwide. Targeting protein for xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein that is strongly correlated with chromosomal instability, resulting in the development of different human tumors. Herein, we investigated the relationship between the clinical outcome of TNBC and the expression level of the TPX2 protein. MATERIALS AND METHODS: Patients initially treated at Tongji Hospital for confirmed TNBC were evaluated by immunohistochemical staining and retrospectively recruited into our study. The immunohistochemical staining evaluation of TPX2 was based on the staining intensity and extent. STATA was used to analyze all the data. RESULTS: In total, 97 patients with TNBC were recruited into our study. The TPX2 protein was overexpressed in almost all patients with TNBC. Our study demonstrated that an elevated TPX2 protein level was significantly associated with worse outcomes in the patients with TNBC, including worse progression-free survival (PFS) and overall survival (OS) (log-rank test, P < .001). Our model also indicated that TPX2 expression was an independent predictor of OS (hazard ratio, 2.20; 95% confidence interval, 1.13-4.28; P = .020) but not of PFS (P = .639). CONCLUSION: In conclusion, we demonstrated that TPX2 could be a novel prognostic marker of PFS and OS after the initial treatment of TNBC. We also revealed that TPX2 expression could serve as an independent predictor of OS but not of PFS and a promising therapeutic target in patients with TNBC.

Mechanised lubricating silica nanoparticles for on-command cargo release on simulated surfaces of joint cavities.

We describe a type of supramolecular host-guest function silica nanoparticle activated by energy conversion from joint movement. The high coefficient of friction from damaged joints causes more energy conversion, weakening the surface host-guest interaction and resulting in target cargo release. Additionally, the hydrated layer on the nanoparticle surface plays a role in lubrication enhancement.

Crossing the blood-brain-barrier with nanoligand drug carriers self-assembled from a phage display peptide.

The filamentous bacteriophage fd bind a cell target with exquisite specificity through its few copies of display peptides, whereas nanoparticles functionalized with hundreds to thousands of synthetically generated phage display peptides exhibit variable and often-weak target binding. We hypothesise that some phage peptides in a hierarchical structure rather than in monomeric form recognise and bind their target. Here we show hierarchial forms of a brain-specific phage-derived peptide (herein as NanoLigand Carriers, NLCs) target cerebral endothelial cells through transferrin receptor and the receptor for advanced glycation-end products, cross the blood-brain-barrier and reach neurons and microglial cells. Through intravenous delivery of NLC-ß-secretase 1 (BACE1) siRNA complexes we show effective BACE1 down-regulation in the brain without toxicity and inflammation. Therefore, NLCs act as safe multifunctional nanocarriers, overcome efficacy and specificity limitations in active targeting with nanoparticles bearing phage display peptides or cell-penetrating peptides and expand the receptor repertoire of the display peptide.

miRNA-448 inhibits cell growth by targeting BCL-2 in hepatocellular carcinoma.

BACKGROUND: Increasing evidence indicates that aberrant micro (mi)RNA-448 expression plays a critical role in the progression of several human cancers. However, the function of miRNA-448 in hepatocellular carcinoma (HCC) has not been fully investigated. METHODS: miRNA-448 expression levels in HCC tissues, adjacent non-cancerous tissues (ANTs), and HCC cell lines were examined by quantitative real-time polymerase chain reaction (qRT-PCR). HCC cells were treated with a miRNA-448 mimic or inhibitor, followed by cell viability measurements with the CCK-8 assay. Venn diagram analysis predicted, and dual luciferase reporter assays verified, the target gene of miRNA-448. Expression of the target gene was detected by qRT-PCR and immunohistochemistry. Growth of miRNA-448- or target gene-expressing HCC xenograft tumors in nude mice was measured. RESULTS: miRNA-448 was expressed at a lower level in HCC tissues than ANTs, and correlated with a larger tumor size, incomplete tumor encapsulation, and advanced Barcelona Clinic Liver Cancer stage. miRNA-448 inhibited HCC cell growth. The downstream target of miRNA-448 was BCL-2, which was highly expressed in HCC tissues and its mRNA level was negatively correlated with miRNA-448 expression. In vivo, BCL-2 attenuated the tumor inhibiting effect of miRNA-448. CONCLUSION: miRNA-448 functions as a tumor suppressor by targeting BCL-2 in HCC.

Modulatory effect of International Standard Scalp Acupuncture on brain activation in the elderly as revealed by resting-state fMRI.

The specific mechanisms by which acupuncture affects the central nervous system are unclear. In the International Standard Scalp Acupuncture system, acupuncture needles are applied at the middle line of the vertex, anterior parietal-temporal oblique line, and the posterior parietal-temporal oblique line. We conducted a single-arm prospective clinical trial in which seven healthy elderly volunteers (three men and four women; 50-70 years old) received International Standard Scalp Acupuncture at MS5 (the mid-sagittal line between Baihui (DU20) and Qianding (DU21)), the left MS6 (line joining Sishencong (EX-HN1) and Xuanli (GB6)), and the left MS7 (line joining DU20 and Qubin (GB7)). After acupuncture, resting-state functional magnetic resonance imaging demonstrated changes in the fractional amplitude of low frequency fluctuations and regional homogeneity in various areas, showing remarkable enhancement of regional homogeneity in the bilateral anterior cingulate, left medial frontal gyrus, supramarginal gyrus, right middle frontal gyrus, and inferior frontal gyrus. Functional connectivity based on a seed region at the right middle frontal gyrus (42, 51, 9) decreased at the bilateral medial superior frontal gyrus. Our data preliminarily indicates that the international standard scalp acupuncture in healthy elderly participants specifcally enhances the correlation between the brain regions involved in cognition and implementation of the brain network regulation system and the surrounding adjacent brain regions. The study was approved by the Ethics Committee of the China-Japan Union Hospital at Jilin University, China, on July 18, 2016 (approval No. 2016ks043).