Molecular architecture of Zinc chelating small molecules that inhibit spliceosome assembly at an early stage.

The removal of intervening sequences (introns) from a primary RNA transcript is catalyzed by the spliceosome, a large ribonucleoprotein complex. At the start of each splicing cycle, the spliceosome assembles anew in a sequentially ordered manner on the pre-mRNA intron to be removed. We describe here the identification of a series of naphthalen-2-yl hydroxamate compounds that inhibit pre-mRNA splicing in vitro with mid- to high-micromolar values of IC50. These hydroxamates stall spliceosome assembly at the A complex stage. A structure-activity analysis of lead compounds revealed three pharmacophores that are essential for splicing inhibition. Specifically, a hydroxamate as a zinc-binding group and a 6-methoxynaphthalene cap group are both critical, and a linker chain comprising eight to nine methylene groups is also important, for the specific binding to the docking site of a target protein molecule and precise positioning of the zinc binding group. As we found no correlation between the inhibition patterns of known histone deacetylases on the one hand and pre-mRNA splicing on the other, we conclude that these compounds may function through the inhibition of the activities of other, at present, unknown spliceosome-associated zinc metalloprotein(s)

K-means cluster analysis of the West African species of cereals based on nutritional value composition

The K-means algorithm was deployed to extract clusters within the prevalent cereal foods in West Africa. The West Africa Food Composition Table (WAFCT) presents all the 76 food sources in the cereals class as a single group without considering the similarity or dissimilarity in nutritional values. Using K-means clustering, the Euclidean distance between nutritional values of all cereal food items were measured to generate six sub- groups based on similarity. A one-way analysis to validate the results of the extracted clusters was carried out using the mean square values. For every nutrient, the “within groups” and “between groups” values of the mean squares were examined. This was done to ascertain how similar or dissimilar data points in the same or different clusters were to each other. It was discovered that the P values for all “between groups” and “within groups” mean squares for every nutrient was P < 0.01. Additionally, it was observed that in all cases, the mean square values of the “within groups” were significantly lower than those of the “between groups”. These outcomes are indications that clustering was properly done such that the variability in nutrient values for all food sources within the same clusters was significantly low, while those in different clusters were significantlyhigh. Thus, the ultimate objective of clustering, which is to maximize intra-cluster similarity and minimize inter-cluster similarity was effectively achieved. Cluster analysis in this study showed that all food items within a particular cluster are similar to each other and dissimilar to food items in a different cluster. These findings are valuable in dietaries, food labeling, raw materials selection, public health nutrition, and food science research, when answering questions on the choice of alternative food items. Where original choices are not available or unaffordable, the clusters can be explored to select other similar options within the same cluster as the original choice.&nbsp

PEG Branched Polymer for Functionalization of Nanomaterials with Ultralong Blood Circulation

Nanomaterials have been actively pursued for biological and medical applications in recent years. Here, we report the synthesis of several new poly(ethylene glycol) grafted branched-polymers for functionalization of various nanomaterials including carbon nanotubes, gold nanoparticles (NP) and gold nanorods (NRs), affording high aqueous solubility and stability for these materials. We synthesize different surfactant polymers based upon poly-(g-glutamic acid) (gPGA) and poly(maleic anhydride-alt-1-octadecene) (PMHC18). We use the abundant free carboxylic acid groups of gPGA for attaching lipophilic species such as pyrene or phospholipid, which bind to nanomaterials via robust physisorption. Additionally, the remaining carboxylic acids on gPGA or the amine-reactive anhydrides of PMHC18 are then PEGylated, providing extended hydrophilic groups, affording polymeric amphiphiles. We show that single-walled carbon nanotubes (SWNTs), Au NPs and NRs functionalized by the polymers exhibit high stability in aqueous solutions at different pHs, at elevated temperatures and in serum. Morever, the polymer-coated SWNTs exhibit remarkably long blood circulation (t1/2 22.1 h) upon intravenous injection into mice, far exceeding the previous record of 5.4 h. The ultra-long blood circulation time suggests greatly delayed clearance of nanomaterials by the reticuloendothelial system (RES) of mice, a highly desired property for in vivo applications of nanomaterials, including imaging and drug delivery

Cell Nucleus-Targeting Zwitterionic Carbon Dots

An innovative nucleus-targeting zwitterionic carbon dot (CD) vehicle has been developed for anticancer drug delivery and optical monitoring. The zwitterionic functional groups of the CDs introduced by a simple one-step synthesis using beta-alanine as a passivating and zwitterionic ligand allow cytoplasmic uptake and subsequent nuclear translocation of the CDs. Moreover, multicolor fluorescence improves the accuracy of the CDs as an optical code. The CD-based drug delivery system constructed by non-covalent grafting of doxorubicin, exhibits superior antitumor efficacy owing to enhanced nuclear delivery in vitro and tumor accumulation in vivo, resulting in highly effective tumor growth inhibition. Since the zwitterionic CDs are highly biocompatible and effectively translocated into the nucleus, it provides a compelling solution to a multifunctional nanoparticle for substantially enhanced nuclear uptake of drugs and optical monitoring of translocation.open

Nanotechnology in Head and Neck Cancer: The Race Is On

Rapid advances in the ability to produce nanoparticles of uniform size, shape, and composition have started a revolution in the sciences. Nano-sized structures herald innovative technology with a wide range of potential therapeutic and diagnostic applications. More than 1000 nanostructures have been reported, many with potential medical applications, such as metallic-, dielectric-, magnetic-, liposomal-, and carbon-based structures. Of these, noble metallic nanoparticles are generating significant interest because of their multifunctional capacity for novel methods of laboratory-based diagnostics, in vivo clinical diagnostic imaging, and therapeutic treatments. This review focuses on recent advances in the applications of nanotechnology in head and neck cancer, with special emphasis on the particularly promising plasmonic gold nanotechnology

Probing the Behaviors of Gold Nanorods in Metastatic Breast Cancer Cells Based on UV-vis-NIR Absorption Spectroscopy

In this work, behaviors of positively-charged AuNRs in a highly metastatic tumor cell line MDA-MB-231 are examined based on UV-vis-NIR absorption spectroscopy in combination with inductively coupled plasma mass spectrometry (ICP-MS), transmission electron microscopy (TEM) and dark-field microscopic observation. It is found that characteristic surface plasmon resonance (SPR) peaks of AuNRs can be detected using spectroscopic method within living cells that have taken up AuNRs. The peak area of transverse SPR band is shown to be proportionally related to the amount of AuNRs in the cells determined with ICP-MS, which suggests a facile and real time quantification method for AuNRs in living cells. The shape of longitudinal SPR band in UV-vis-NIR spectrum reflects the aggregation state of AuNRs in the cells during the incubation period, which is proved by TEM and microscopic observations. Experimental results reveal that AuNRs are internalized by the cells rapidly; the accumulation, distribution and aggregation of AuNRs in the cells compartments are time and dose dependent. The established spectroscopic analysis method can not only monitor the behaviors of AuNRs in living cells but may also be helpful in choosing the optimum laser stimulation wavelength for anti-tumor thermotherapy

Intracellular SERS nanoprobes for distinction of different neuronal cell types.

Distinction between closely related and morphologically similar cells is difficult by conventional methods especially without labeling. Using nuclear-targeted gold nanoparticles (AuNPs) as intracellular probes we demonstrate the ability to distinguish between progenitor and differentiated cell types in a human neuroblastoma cell line using surface-enhanced Raman spectroscopy (SERS). SERS spectra from the whole cell area as well as only the nucleus were analyzed using principal component analysis that allowed unambiguous distinction of the different cell types. SERS spectra from the nuclear region showed the developments during cellular differentiation by identifying an increase in DNA/RNA ratio and proteins transcribed. Our approach using nuclear-targeted AuNPs and SERS imaging provides label-free and noninvasive characterization that can play a vital role in identifying cell types in biomedical stem cell research

Legitimisation strategies and managerial capture: a critical discourse analysis of employment relations in Nigeria

YesIrrespective of the fundamental role of legitimacy in industrial relations as well as social and organisational life, little is known of the subtle meaning-making strategies through which organisational concepts, such as employment relations and engagement, are legitimised in modern world of work, particularly in developing countries such as Nigeria, which results in managerial capture. As a result, this paper explores the discursive legitimisation strategies used when making sense of employment relations in Nigeria’s conflictual, non-participatory employment relations terrain. Relying on Leeuwen’s (1995) legitimisation strategies, critical discourse analysis (CDA) and call by Bailey, Luck & Townsend (2009) and Legge (1995) to widen employment relations discourse, we explore interview, focus group and shadow report data, and distinguish and analyse five legitimisation strategies. The strategies include authorisation, moralisation, mythopoesis, rationalisation, and management. Therefore, we contend that while these specific legitimisation strategies appear in separate data source, their recurrent manifestation and application underscores legitimising discourse of managerial capture in Nigeria’s employment relations

Differences in the reported performances of foreign-controlled and domestically-controlled firms : some UK evidence

This study provides empirical evidence on the relative performances of Foreign Controlled Domestic Companies operating in the United Kingdom as compared to those of United Kingdom Controlled Domestic Dompanies. One hundred and fifty (150) Foreign Controlled Domestic Companies, selected from the Times 1000 (1995), were matched with 150 United Kingdom Domestic Companies on the bases of size and industry. The reported performance data of the two sub samples for five years were extracted from the FT Extel secured database. Statistical tests were then carried out, on five year average and annual bases, to establish whether there were differences in the performances of the two groups of firms. Results revealed statistically significant differences in the reported performances of Foreign Controlled Domestic Companies and United Kingdom Domestic Companies operating in the United Kingdom over the five year period. Foreign controlled firms significantly under performed United Kingdom Domestic Companies of comparable size and industry. The lower profitability figures reported by these firms were partly as a result of higher trading expenses. The study also found differences in the year to year magnitude of under performance by Foreign Controlled Domestic Companies. While findings in this study corroborate those of earlier United States based studies, the management and owners of Foreign Controlled Domestic Companies’ parents should be interested in the apparent underperformance of their United Kingdom based assets. It is possible, however, that the figures reported do not reflect real asset performance. In which case, the United Kingdom tax authorities may want to take a closer look at Foreign Controlled Domestic Ccompanies’ reported performances to establish whether they are the outcome of income shifting practices. Future studies could examine how the performances of the managers of these foreign located assets are evaluated and rewarded and explore other possible explanatory factors for their reported under performance