Mesoporous Silica Nanoparticles as a Carrier Platform for Intracellular Delivery of Nucleic Acids.

Virus-mediated gene delivery has been, to date, the most successful and efficient method for gene therapy. However, this method has been challenged because of serious safety concerns. Over the past decade, mesoporous silica nanoparticles (MSNs) have attracted much attention for intracellular delivery of nucleic acids. Delivery of cellular plasmid DNA (pDNA) is designed to replace the function of a defective gene and restore its normal function in the cell. Delivery of small interfering RNAs (siRNAs) can selectively knockdown genes by targeting specific mRNAs. The biocompatibility and unique structures of MSNs make these nanoparticles ideal candidates to act as biomolecule carriers. This concise review highlights current progress in the field of nucleic acid delivery using MSNs, specifically for delivery of pDNA, siRNA, and combinatorial delivery of nucleic acids and drugs. The review describes important design parameters presently being applied to MSNs to administer drugs and therapeutic nucleic acids.

The response of tenocytes to commercial scaffolds used for rotator cuff repair.

Surgical repairs of rotator cuff tears have high re-tear rates and many scaffolds have been developed to augment the repair. Understanding the interaction between patients' cells and scaffolds is important for improving scaffold performance and tendon healing. In this in vitro study, we investigated the response of patient-derived tenocytes to eight different scaffolds. Tested scaffolds included X-Repair, Poly-Tape, LARS Ligament, BioFiber (synthetic scaffolds), BioFiber-CM (biosynthetic scaffold), GraftJacket, Permacol, and Conexa (biological scaffolds). Cell attachment, proliferation, gene expression, and morphology were assessed. After one day, more cells attached to synthetic scaffolds with dense, fine and aligned fibres (X-Repair and Poly-Tape). Despite low initial cell attachment, the human dermal scaffold (GraftJacket) promoted the greatest proliferation of cells over 13 days. Expression of collagen types I and III were upregulated in cells grown on non-cross-linked porcine dermis (Conexa). Interestingly, the ratio of collagen I to collagen III mRNA was lower on all dermal scaffolds compared to synthetic and biosynthetic scaffolds. These findings demonstrate significant differences in the response of patient-derived tendon cells to scaffolds that are routinely used for rotator cuff surgery. Synthetic scaffolds promoted increased cell adhesion and a tendon-like cellular phenotype, while biological scaffolds promoted cell proliferation and expression of collagen genes. However, no single scaffold was superior. Our results may help understand the way that patients' cells interact with scaffolds and guide the development of new scaffolds in the future.

Betti reaction enables efficient synthesis of 8-hydroxyquinoline inhibitors of 2-oxoglutarate oxygenases.

There is interest in developing potent, selective, and cell-permeable inhibitors of human ferrous iron and 2-oxoglutarate (2OG) oxygenases for use in functional and target validation studies. The 3-component Betti reaction enables efficient one-step C-7 functionalisation of modified 8-hydroxyquinolines (8HQs) to produce cell-active inhibitors of KDM4 histone demethylases and other 2OG oxygenases; the work exemplifies how a template-based metallo-enzyme inhibitor approach can be used to give biologically active compounds.

Hypertension management: a comparison of urban versus rural general practitioners in Western Australia.

1. We have conducted a survey of 75 rural and 75 urban randomly selected general practioners (GPs) in Western Australia to ascertain how closely current practice mirrors published Australian guidelines for the management of hypertension. 2. Fifty-one rural and 49 urban GPs completed the 19 item questionnaire. The two groups were well matched in terms of age and years in general practice. An assessment of the criteria utilized to diagnose hypertension revealed a tendency for much greater scatter in the cut points used to define systolic compared to diastolic hypertension, but no systematic difference between urban and rural GPs. 3. After an initial finding of mild hypertension the follow-up time to the next check-up was significantly longer for rural patients compared to urban patients (72 +/- 13 and 36 +/- 5 days respectively, P < 0.01). Urban GPs reviewed established hypertensive patients more commonly at 1-3 monthly intervals (89%) while rural GPs reviewed more commonly at 3-6 monthly intervals (86%). 4. In terms of target blood pressure (BP) for BP reduction, 67% rural compared to 83% urban GPs aimed for a systolic BP of < 140 mmHg (P = 0.06), while 95% of both groups aimed for diastolic BP < 90 mmHg. 5. The profile of first line antihypertensive agents most commonly used was also similar in both groups with 46% preferring angiotensin converting enzyme inhibitors, 18.5% diuretics, 18.5% beta blockers, 16% calcium entry blockers and 1% prazosin. 6. This study demonstrates a clear preference for the newer anti-hypertensive agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple isotope effect probes of glutamate decarboxylase.

The enzymatic decarboxylation of glutamic acid shows a carbon isotope effect k12/k13 = 1.018 at 37 degree C, pH 4.7. In D2O under otherwise identical conditions, k12/k13 = 1.009. Under the same conditions solvent isotope effects are Vmax H2O/Vmax D2O = 5.0 and (Vmax/Km)H2O/(Vmax/Km)D2O = 2.6. With the assumption that the carbon isotope effect on the decarboxylation step is in the usual range (1.05--1.07), it is possible to derive relative rates and solvent isotope effects for all steps in the enzyme mechanism. Substrate binding in approximately 2-fold weaker in H2O than in D2O, probably because of the desolvation which accompanies binding of the substrate to the enzyme. A proton inventory analysis of the reaction shows that the Schiff base interchange has a large solvent isotope effect composed of relatively small contributions from at least four separate sites. A conformation change probably accompanies this step. The decarboxylation step shows a solvent isotope effect of approximately 2. Schiff base interchange and decarboxylation are both partially rate determining. The pH dependence of the isotope effects indicates that the initial step in the reaction can occur by way of two different pathways.

Oxygen and hydrogen isotopic ratios in plant cellulose.

The variations of the D/H and (18)O/(16)O ratios of nonexchangeable hydrogen and oxygen in plant cellulose reveal systematic differences between terrestrial plant groups. The slope of deltaD versus delta(18)O of cellulose from a variety of aquatic plants is close to 8 (the meteoric water value), while the slope for a number of terrestrial species is greater than or equal to about 24. Two models involving incorporation of CO(2) and H(2)O into cellulose precursors are proposed to account for these differences. Effects of evaporative transpiration on the isotopic composition of water in leaves are measured and discussed in the context of these models.