Purpose: To investigate expression, regulation, potential role and targets of miR-195 and miR-497 in breast cancer.Experimental Design: The expression patterns of miR-195 and miR-497 were initially examined in breast cancer tissues and cell lines by Northern blotting and quantitative real-time PCR. Combined bisulfite restriction analysis and bisulfite sequencing were carried out to study the DNA methylation status of miR-195 and miR-497 genes. Breast cancer cells stably expressing miR-195 and miR-497 were established to study their role and targets. Finally, normal, fibroadenoma and breast cancer tissues were employed to analyze the correlation between miR-195/497 levels and malignant stages of breast tumor tissues.Results: MiR-195 and miR-497 were significantly downregulated in breast cancer. The methylation state of CpG islands upstream of the miR-195/497 gene was found to be responsible for the downregulation of both miRNAs. Forced expression of miR-195 or miR-497 suppressed breast cancer cell proliferation and invasion. Raf-1 and Ccnd1 were identified as novel direct targets of miR-195 and miR-497. miR-195/497 expression levels in clinical specimens were found to be correlated inversely with malignancy of breast cancer.Conclusions: Our data imply that both miR-195 and miR-497 play important inhibitory roles in breast cancer malignancy and may be the potential therapeutic and diagnostic targets.

Abstract. The European Centre for Medium-Range Weather Forecasts' (ECMWF's) next-generation reanalysis ERA5 provides many improvements, but it also confronts the community with a “big data” challenge. Data storage requirements for ERA5 increase by a factor of ∼80 compared with the ERA-Interim reanalysis, introduced a decade ago. Considering the significant increase in resources required for working with the new ERA5 data set, it is important to assess its impact on Lagrangian transport simulations. To quantify the differences between transport simulations using ERA5 and ERA-Interim data, we analyzed comprehensive global sets of 10-day forward trajectories for the free troposphere and the stratosphere for the year 2017. The new ERA5 data have a considerable impact on the simulations. Spatial transport deviations between ERA5 and ERA-Interim trajectories are up to an order of magnitude larger than those caused by parameterized diffusion and subgrid-scale wind fluctuations after 1 day and still up to a factor of 2–3 larger after 10 days. Depending on the height range, the spatial differences between the trajectories map into deviations as large as 3 K in temperature, 30 % in specific humidity, 1.8 % in potential temperature, and 50 % in potential vorticity after 1 day. Part of the differences between ERA5 and ERA-Interim is attributed to the better spatial and temporal resolution of the ERA5 reanalysis, which allows for a better representation of convective updrafts, gravity waves, tropical cyclones, and other meso- to synoptic-scale features of the atmosphere. Another important finding is that ERA5 trajectories exhibit significantly improved conservation of potential temperature in the stratosphere, pointing to an improved consistency of ECMWF's forecast model and observations that leads to smaller data assimilation increments. We conducted a number of downsampling experiments with the ERA5 data, in which we reduced the numbers of meteorological time steps, vertical levels, and horizontal grid points. Significant differences remain present in the transport simulations, if we downsample the ERA5 data to a resolution similar to ERA-Interim. This points to substantial changes of the forecast model, observations, and assimilation system of ERA5 in addition to improved resolution. A comparison of two Lagrangian trajectory models allowed us to assess the readiness of the codes and workflows to handle the comprehensive ERA5 data and to demonstrate the consistency of the simulation results. Our results will help to guide future Lagrangian transport studies attempting to navigate the increased computational complexity and leverage the considerable benefits and improvements of ECMWF's new ERA5 data set.

Abstract. We have performed backward trajectory calculations and simulations with the three-dimensional Chemical Lagrangian Model of the Stratosphere (CLaMS) for two succeeding monsoon seasons using artificial tracers of air mass origin. With these tracers we trace back the origin of young air masses (age <6 months) at the top of the Asian monsoon anticyclone and of air masses within the tropical pipe (6 months < age <18 months) during summer 2008. The occurrence of young air masses (<6 months) at the top of the Asian monsoon anticyclone up to ∼460 K is in agreement with satellite measurements of chlorodifluoromethane (HCFC-22) by the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) instrument. HCFC-22 can be considered as a regional tracer for continental eastern Asia and the Middle East as it is mainly emitted in this region. Our findings show that the transport of air masses from boundary layer sources in the region of the Asian monsoon into the tropical pipe occurs in three distinct steps. First, very fast uplift in “a convective range” transports air masses up to 360 K potential temperature within a few days. Second, air masses are uplifted from about 360 K up to 460 K within “an upward spiralling range” within a few months. The large-scale upward spiral extends from northern Africa to the western Pacific. The air masses are transported upwards by diabatic heating with a rate of up to 1–1.5 K per day, implying strong vertical transport above the Asian monsoon anticyclone. Third, transport of air masses occurs within the tropical pipe up to 550 K associated with the large-scale Brewer–Dobson circulation within ∼1 year. In the upward spiralling range, air masses are uplifted by diabatic heating across the (lapse rate) tropopause, which does not act as a transport barrier, in contrast to the extratropical tropopause. Further, in the upward spiralling range air masses from inside the Asian monsoon anticyclone are mixed with air masses convectively uplifted outside the core of the Asian monsoon anticyclone in the tropical adjacent regions. Moreover, the vertical transport of air masses from the Asian monsoon anticyclone into the tropical pipe is weak in terms of transported air masses compared to the transport from the monsoon anticyclone into the northern extratropical lower stratosphere. Air masses from the Asian monsoon anticyclone (India/China) contribute a minor fraction to the composition of air within the tropical pipe at 550 K (6 %), and the major fractions are from Southeast Asia (16 %) and the tropical Pacific (15 %).

Observational data concerning children’s compliance were collected from samples of 2-year-olds in PR China and Canada. Information on child-rearing attitudes was obtained from mothers. It was found that Chinese toddlers had higher scores on voluntary committed compliance than their Canadian counterparts. In contrast, Canadian toddlers had higher scores on externally imposed or situational compliance and overt protest than Chinese toddlers. Girls displayed more committed compliance than boys in both samples. Maternal warmth and induction were positively associated with committed compliance in Chinese toddlers, and maternal induction was positively associated with situational compliance in Canadian toddlers. Maternal punishment orientation was negatively associated with committed compliance and positively associated with situational control in Chinese toddlers, but not in Canadian toddlers. The results might indicate specific cultural “meanings” of different forms of child compliance.

Conventional chemotherapy of pancreatic cancer (PaCa) suffers the problems of low drug permeability and inherent or acquired drug resistance. Development of new strategies for enhanced therapy still remains a great challenge. Herein, we report a new ultrasound-targeted microbubble destruction (UTMD)-promoted delivery system based on dendrimer-entrapped gold nanoparticles (Au DENPs) for co-delivery of gemcitabine (Gem) and miR-21 inhibitor (miR-21i).Methods: In this study, Gem-Au DENPs/miR-21i was designed and synthesized. The designed polyplexes were characterized via transmission electron microscopy (TEM), Gel retardation assay and dynamic light scattering (DLS). Then, the optimum exposure parameters were examined by an ultrasound exposure platform. The cellular uptake, cytotoxicity and anticancer effects in vitro were analyzed by confocal laser microscopy, spectra microplate reader, flow cytometry and a chemiluminescence imaging system. Lastly, the anticancer effects in vivo were evaluated by contrast-enhanced ultrasound (CEUS), hematoxylin and eosin (H&E) staining, TUNEL staining and comparison of tumor volume.Results: The results showed that the Gem-Au DENPs/miR-21i can be uptake by cancer cells and the cellular uptake was further facilitated by UTMD with an ultrasound power of 0.4 W/cm2 to enhance the cell permeability. Further, the co-delivery of Gem and miR-21i with or without UTMD treatment displayed 82-fold and 13-fold lower IC50 values than the free Gem, respectively. The UTMD-promoted co-delivery of Gem and miR-21i was further validated by in vivo treatment and showed a significant tumor volume reduction and an increase in blood perfusion of xenografted pancreatic tumors.Conclusion: The co-delivery of Gem and miR-21i using Au DENPs can be significantly promoted by UTMD technology, hence providing a promising strategy for effective pancreatic cancer treatments.

To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-α-tocopherol polyethylene glycol succinate (TPGS) based PTX prodrug (TPGS-S-S-PTX), was synthesized here to fulfill the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of ∼140 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC50 of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration-time curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors.

This study explored the longitudinal relations among peer victimization, depression, and academic achievement in Chinese primary school students. Participants were N = 945 fourth-grade students (485 boys, 460 girls; M = 10.16 years, SD = 2 months) attending elementary schools in Shanghai, People's Republic of China. Three waves of data on peer victimization, depression, and academic achievement were collected from peer nominations, self-reports, and school records, respectively. The results indicated that peer victimization had both direct and indirect effects on later depression and academic achievement. Depression also had both direct and indirect negative effects on later academic achievement, but demonstrated only an indirect effect on later peer victimization. Finally, academic achievement had both direct and indirect negative effects on later peer victimization and depression. The findings show that there are cross-cultural similarities and differences in the various transactions that exist among peer victimization, depression, and academic achievement. Statement of contribution What is already known on this subject? Peer victimization directly and indirectly relates to depression and academic achievement. Depression directly and indirectly relates to academic achievement. Academic achievement directly and indirectly relates to depression. What the present study adds? A developmental cascade approach was used to assess the interrelations among peer victimization, depression, and academic achievement. Academic achievement mediates the relation between peer victimization and depression. Depression is related to peer victimization through academic achievement. Academic achievement directly and indirectly relates to peer victimization. Academic achievement is related to depression through peer victimization.

Bladder cancer is one of the concerning malignancies worldwide, which is lacking effective targeted therapy. Gene therapy is a potential approach for bladder cancer treatment. While, a safe and effective targeted gene delivery system is urgently needed for prompting the bladder cancer treatment in vivo . In this study, we confirmed that the bladder cancer had CD44 overexpression and small interfering RNAs (siRNA) with high interfere to Bcl2 oncogene were designed and screened. Then hyaluronic acid dialdehyde (HAD) was prepared in an ethanol-water mixture and covalently conjugated to the chitosan nanoparticles (CS-HAD NPs) to achieve CD44 targeted siRNA delivery. The in vitro and in vivo evaluations indicated that the siRNA-loaded CS-HAD NPs (siRNA@CS-HAD NPs) were approximately 100 nm in size, with improved stability, high siRNA encapsulation efficiency and low cytotoxicity. CS-HAD NPs could target to CD44 receptor and deliver the therapeutic siRNA into T24 bladder cancer cells through a ligand-receptor-mediated targeting mechanism and had a specific accumulation capacity in vivo to interfere the targeted oncogene Bcl2 in bladder cancer. Overall, a CD44 targeted gene delivery system based on natural macromolecules was developed for effective bladder cancer treatment, which could be more conducive to clinical application due to its simple preparation and high biological safety.