Direct Synthesis of Partially Modified 2′‐O‐Pivaloyloxymethyl RNAs by a Base‐Labile Protecting Group Strategy and their Potential for Prodrug‐Based Gene‐Silencing Applications

An original and straightforward synthesis of partially modified 2′‐O‐pivaloyloxymethyl‐substituted (PivOM‐substituted) oligoribonucleotides has been achieved. The aim of this 2′‐enzymolabile modification was to enhance nuclease stability of RNA and transmembrane transport. To make these modified RNAs easily available we developed a base‐labile protecting group strategy with standard protections for nucleobases (acyl) and phosphates (cyanoethyl), a Q‐linker and two different acetalester protection groups for 2′‐OH: propionyloxymethyl (PrOM) and PivOM. Interestingly, orthogonal deprotection conditions based on anhydrous butylamine in THF were found to remove propionyloxymethyl groups selectively, while preserving PivOM groups. Duplex stability, circular dichroism studies and nuclease resistance, as well as the ability to inhibit gene expression of modified 2′‐O‐PivOM RNA, were evaluated.     

Synthesis, solution structure and immune recognition of an epidermal growth factor-like domain from Plasmodium falciparum merozoite surface protein-1

The Plasmodium falciparum merozoite surface protein-1 19 kDa fragment (MSP-1(19)) comprises two closely packed EGF-like domains (EGF=epidermal growth factor), each stabilized by three disulfide bonds. The native conformation of this protein is important for eliciting P. falciparum growth inhibitory antibodies. Here we show that the N-terminal EGF domain alone can be chemically synthesized and efficiently refolded to a native-like state, as shown by its solution structure as determined by NMR spectroscopy. In order to study its immunogenicity, the domain was coupled through its N terminus to a phospholipid and incorporated into reconstituted influenza virus-like particles (virosomes). When used to immunize mice, the peptide-loaded virosomes elicited potent humoral immune responses that were shown by Western blots and immunofluorescence assays to cross-react with native MSP-1 on the surfaces of P. falciparum blood stage parasites. This opens the way for a medicinal chemistry-oriented approach to the study and optimization of the antigenicity of the protein as a potential malaria vaccine candidate, whilst exploiting the immunopotentiating properties of influenza virosomes as a delivery vehicle.     

Tribological properties of powder metallurgical tool steels used in powder compaction pressing dies

The tribological properties of two powder metallurgical (PM) tool steels, high and low nitrogen containing, are investigated by means of three different wear tests: ball‐on‐disc, rubber wheel and scratch test. The ball‐on‐disc tests showed two distinct friction curves corresponding to each material. In order to simulate the tribosystem existing in metal powder compaction dies, the rubber wheel and the scratch test were modified. The rubber wheel test was performed using ferrous powder instead of sand, and scratch testing was carried out by sliding a powder compact over the tool steels. The scratch tests indicated a higher steady‐state coefficient of friction for the low nitrogen containing PM steel as compared with the high nitrogen containing alloy. Additionally, the results from the rubber wheel tests were in agreement with industrial experiences, showing the low nitrogen containing tool steel to suffer from severe galling. Copyright © 2011 John Wiley & Sons, Ltd.     

Luminal bacteria and small-intestinal permeability

BACKGROUND: The influence of luminal bacteria on small-intestinal permeability has not been fully assessed. This study addressed this issue. METHODS: Thirty-four subjects (mean age 64 years; range 22-95 years) were investigated for possible small-intestinal bacterial overgrowth (SIBO) with culture of a small-intestinal aspirate. A lactulose/mannitol small-intestinal permeability test was performed, small-intestinal histology assessed and serum vitamin B12 concentrations measured in all subjects. Permeability was also assessed in a control group of 34 asymptomatic volunteers. RESULTS: Urinary lactulose/mannitol ratios were significantly increased in subjects with SIBO with colonic-type flora (P < 0.0005), even in the absence of villous atrophy. Urinary lactulose/mannitol ratios were increased in this group due to significantly increased urinary lactulose concentrations (P < 0.0005) rather than reduced urinary mannitol levels, after correcting for inter-subject variations in renal function. Counts of intraepithelial lymphocytes of CD8 phenotype were significantly increased in this group (P = 0.003). Although a significant correlation was found between intraepithelial lymphocyte counts and small-intestinal permeability overall (P < 0.002), these counts were not significantly different in subjects with SIBO with colonic-type flora whose permeability values were < or = > 0.028, the upper limit of normal in asymptomatic controls. Serum vitamin B12 concentrations did not differ significantly between groups (P > 0.5). Ageing did not independently influence small-intestinal permeability (P > 0.5). CONCLUSIONS: Small-intestinal permeability is increased in subjects with SIBO with colonic-type bacteria. This effect is independent of ageing and not mediated by vitamin B12 deficiency. Although counts of intraepithelial lymphocytes of CD8 phenotype are increased in this disorder, it is also unlikely that these cells play an important causative role in this process. Routine light microscopic assessment underestimates the prevalence of small-intestinal functional disturbance in this disorder.     

The pathogenesis of Graves'' disease

The renal countercurrent bundles of elasmobranch fish were studied by light and electron microscopy. The kidneys of the lesser spotted dogfish, Scyliorhinus caniculus Blainville, and the little skate, Raja erinacea Mitchill, were investigated. Three-dimensional reconstruction with computer assistance revealed the spatial association of the renal tubular segments and their relationships to each other, as well as to the microvasculature. Regular association between structures was assessed by quantification of contact points on histological sections. The bundles contain a hairpin loop of neck segment and the beginning of the proximal tubule, PIa. The limbs of this loop closely adhere to each other, and a second loop (the early distal tubule) coils around the first loop at the tip of the bundle. The collecting tubule runs between the two loops, and merges with the collecting duct inside the end portion of the bundle. A single lymph capillary-like vessel originates from a few blind-ended rami at the tip of the bundle and runs in close contact with the collecting tubule along the entire bundle. This central vessel merges via several side branches with the venous sinusoid capillaries of the peritubular blood circulation. Thereby the central vessel provides a channel for convective flow of NaCl-rich fluid unidirectionally to the venous portal system of the mesial tissue zone of the kidney. By the close spatial arrangement of the collecting tubule and the central vessel countercurrent exchange of urea from the collecting tubule urine to the fluid in the central vessel is feasible. Thus, the spatial organisation of renal tubular segments and the central vessel is considered to represent the morphological correlate to urea retention by the kidney of Elasmobranchii.     

Interleukin-6 and small intestinal luminal immunoglobulins

Our aim was to determine the relationships between interleukin-6 and immunoglobulin levels within small intestinal luminal secretions. Twenty adult subjects with small intestinal bacterial overgrowth (N = 13), irritable bowel syndrome (N = 4), and nonulcer dyspepsia (N = 3) underwent endoscopic aspiration of secretions from the small intestinal mucosal surface for assessment of IL-6, IgA1, IgA2, IgM, IgG1, IgG2, IgG3, and IgG4 concentrations. Serum immunoglobulin concentrations and small intestinal histology were also determined. IgA2 and IgG3 were the predominant IgA and IgG subclasses in luminal secretions in 19/20 (95%) and 20/20 (100%) subjects, respectively. IgA1 and IgG1 predominated in serum in all subjects. No subject had villous atrophy. Luminal IL-6 concentrations correlated significantly with luminal IgA2, IgM, and IgG3 concentrations but not with IgA1 or any other IgG subclass levels. Conversely, luminal IL-6 or immunoglobulin concentrations did not correlate significantly with levels of any immunoglobulin isotype in serum. These observations suggest that important relationships exist between local IL-6 and IgA2, IgM, and IgG3 responses in human small intestinal luminal secretions. Local investigation is mandatory when assessing intestinal immune activity.     

A note on the inner problem for head-sea diffraction by a slender body of rectangular cross-section

Summary When the problem of the diffraction of head seas by a slender body is solved by the method of matched asymptotic expansions it is known that the inner (cross-sectional) problem can be singular at a number of discrete frequencies, though the precise circumstances under which these singularities occur is not yet clear. Here, a body of rectangular cross-section is considered, a case for which an accurate solution can be readily calculated. For non-zero draught it is found that there are two frequencies of the incident wave field for which the problem is singular, unless the draught-to-beam ratio is sufficiently large, in which case there are none.     

Motives for strategic alliances in cultural and creative industries

Cultural and creative industries are gaining importance in Western economies. In these industries, as in several other business sectors, micro‐firms, i.e., firms that employ fewer than ten employees, are the predominant firm type. As these industries have become an integral part of most economies, the literature has started to explore the strategic behavior of cultural and creative micro‐firms. Although micro‐firms are characterized by certain specificities that can affect how likely they are to engage in external relationships, there is a dearth of knowledge concerning collaboration through strategic alliances in this specific context. Seeking to advance the understanding of partnerships between micro‐firms in cultural and creative industries, the purpose of this article is to reveal the specific motives for engaging in strategic alliances in this context. In doing so, we focus on six case studies of strategic alliances between micro‐firms in cultural and creative industries in France. Our results show that strategic alliances involving creative micro‐firms seek the reduction of overspecialization, target a high degree of quality of life and pleasure at work, and are envisaged only if there is trust and mutual support among the partners. Moreover, opportunism and necessity motivations guide the creative micro‐firms' decision to enter strategic alliances.     

CRYSTAL SIZE GROWTH IN THE LIQUID PHASE METHANOL SYNTHESIS CATALYST

ABSTRACT

The phenomenon of crystal growth in the methanol synthesis catalyst has been studied. Crystallite size distributions in the cuo/ZnO/Al₂O₃ methanol synthesis catalyst have been determined. The effects of temperature, reaction environment and time under reaction conditions have been studied. It is observed that water in the reaction mixture promotes crystal growth.     

A SINGLE-STAGE,LIQUID-PHASE DIMETHYL ETHER SYNTHESIS PROCESS FROM SYNGAS III. DUAL CATALYST CRYSTAL GROWTH,DEACTIVATION, AND ACTIVITY CONSERVATION STUDIES

ABSTRACT

In the liquid phase dimethyl ether (DME) synthesis process, both the methanol synthesis catalyst )composed of CuO, ZnO, and Al₂O₃) and the methanol dehydration catalyst (composed of gamma-alumina) are slurried in the inert oil phase. Various long-term activity checks were conducted on these dual catalysts to characterize the crystal growth and the thermal aging behavior. X-ray powder diffraction, X-ray fluorescence and elemental intensity compositions, and the crystallite size distributions of the aged catalysts were examined. Based on the current investigation, it was established that the crystal growth and the catalyst deactivation problems in the methanol synthesis catalyst are less severe when it is used along with the methanol dehydration catalyst.