Recent developments in peptide-based nucleic acid delivery

Despite the fact that non-viral nucleic acid delivery systems are generally considered to be less efficient than viral vectors, they have gained much interest in recent years due to their superior safety profile compared to their viral counterpart. Among these synthetic vectors are cationic polymers, branched dendrimers, cationic liposomes and cellpenetrating peptides (CPPs). The latter represent an assortment of fairly unrelated sequences essentially characterised by a high content of basic amino acids and a length of 10-30 residues. CPPs are capable of mediating the cellular uptake of hydrophilic macromolecules like peptides and nucleic acids (e.g. siRNAs, aptamers and antisenseoligonucleotides), which are internalised by cells at a very low rate when applied alone. Up to now, numerous sequences have been reported to show cell-penetrating properties and many of them have been used to successfully transport a variety of different cargos into mammalian cells. In recent years, it has become apparent that endocytosis is a major route of internalisation even though the mechanisms underlying the cellular translocation of CPPs are poorly understood and still subject to controversial discussions. In this review, we will summarise the latest developments in peptide-based cellular delivery of nucleic acid cargos. We will discuss different mechanisms of entry, the intracellular fate of the cargo, correlation studies of uptake versus biological activity of the cargo as well as technical problems and pitfalls

HiPEP Ion Optics System Evaluation Using Gridlets

Experimental measurements are presented for sub-scale ion optics systems comprised of 7 and 19 aperture pairs with geometrical features that are similar to the HiPEP ion optics system. Effects of hole diameter and grid-to-grid spacing are presented as functions of applied voltage and beamlet current. Recommendations are made for the beamlet current range where the ion optics system can be safely operated without experiencing direct impingement of high energy ions on the accelerator grid surface. Measurements are also presented of the accelerator grid voltage where beam plasma electrons backstream through the ion optics system. Results of numerical simulations obtained with the ffx code are compared to both the impingement limit and backstreaming measurements. An emphasis is placed on identifying differences between measurements and simulation predictions to highlight areas where more research is needed. Relatively large effects are observed in simulations when the discharge chamber plasma properties and ion optics geometry are varied. Parameters investigated using simulations include the applied voltages, grid spacing, hole-to-hole spacing, doubles-to-singles ratio, plasma potential, and electron temperature; and estimates are provided for the sensitivity of impingement limits on these parameters

Complex surface singularities with integral homology sphere links

While the topological types of {normal} surface singularities with homology sphere link have been classified, forming a rich class, until recently little was known about the possible analytic structures. We proved in [Geom. Topol. 9(2005) 699-755] that many of them can be realized as complete intersection singularities of "splice type", generalizing Brieskorn type. We show that a normal singularity with homology sphere link is of splice type if and only if some naturally occurring knots in the singularity link are themselves links of hypersurface sections of the singular point. The Casson Invariant Conjecture (CIC) asserts that for a complete intersection surface singularity whose link is an integral homology sphere, the Casson invariant of that link is one-eighth the signature of the Milnor fiber. In this paper we prove CIC for a large class of splice type singularities. The CIC suggests (and is motivated by the idea) that the Milnor fiber of a complete intersection singularity with homology sphere link Sigma should be a 4-manifold canonically associated to Sigma. We propose, and verify in a non-trivial case, a stronger conjecture than the CIC for splice type complete intersections: a precise topological description of the Milnor fiber. We also point out recent counterexamples to some overly optimistic earlier conjectures in [Trends in Singularities, Birkhauser (2002) 181--190 and Math. Ann. 326(2003) 75--93].Comment: Published by Geometry and Topology at http://www.maths.warwick.ac.uk/gt/GTVol9/paper18.abs.htm

Conifold geometries, topological strings and multi-matrix models

We study open B-model representing D-branes on 2-cycles of local Calabi--Yau geometries. To this end we work out a reduction technique linking D-branes partition functions and multi-matrix models in the case of conifold geometries so that the matrix potential is related to the complex moduli of the conifold. We study the geometric engineering of the multi-matrix models and focus on two-matrix models with bilinear couplings. We show how to solve this models in an exact way, without resorting to the customary saddle point/large N approximation. The method consists of solving the quantum equations of motion and using the flow equations of the underlying integrable hierarchy to derive explicit expressions for correlators. Finally we show how to incorporate in this formalism the description of several group of D-branes wrapped around different cycles.Comment: 35 pages, 5.3 and 6 revise

Theory of band gap bowing of disordered substitutional II-VI and III-V semiconductor alloys

For a wide class of technologically relevant compound III-V and II-VI semiconductor materials AC and BC mixed crystals (alloys) of the type A(x)B(1-x)C can be realized. As the electronic properties like the bulk band gap vary continuously with x, any band gap in between that of the pure AC and BC systems can be obtained by choosing the appropriate concentration x, granted that the respective ratio is miscible and thermodynamically stable. In most cases the band gap does not vary linearly with x, but a pronounced bowing behavior as a function of the concentration is observed. In this paper we show that the electronic properties of such A(x)B(1-x)C semiconductors and, in particular, the band gap bowing can well be described and understood starting from empirical tight binding models for the pure AC and BC systems. The electronic properties of the A(x)B(1-x)C system can be described by choosing the tight-binding parameters of the AC or BC system with probabilities x and 1-x, respectively. We demonstrate this by exact diagonalization of finite but large supercells and by means of calculations within the established coherent potential approximation (CPA). We apply this treatment to the II-VI system Cd(x)Zn(1-x)Se, to the III-V system In(x)Ga(1-x)As and to the III-nitride system Ga(x)Al(1-x)N.Comment: 14 pages, 10 figure

RNAi revised - Target mRNA-dependent enhancement of gene silencing

The discovery of RNA interference (RNAi) gave rise to the development of new nucleic acid-based technologies as powerful investigational tools and potential therapeutics. Mechanistic key details of RNAi in humans need to be deciphered yet, before such approaches take root in biomedicine and molecular therapy. We developed and validated an in silico-based model of siRNA-mediated RNAi in human cells in order to link in vitro-derived pre-steady state kinetic data with a quantitative and time-resolved understanding of RNAi on the cellular level. The observation that product release by Argonaute 2 is accelerated in the presence of an excess of target RNA in vitro inspired us to suggest an associative mechanism for the RNA slicer reaction where incoming target mRNAs actively promote dissociation of cleaved mRNA fragments. This novel associative model is compatible with highmultiple turnover rates of RNAibased gene silencing in living cells and accounts for target mRNA concentration-dependent enhancement of the RNAi machinery

Th17 and Th17/Treg ratio at early HIV infection associate with protective HIV-specific CD8+ T-cell responses and disease progression

The aim of this study was to analyze Th17 and Treg subsets and their correlation with anti-HIV T-cell responses and clinical parameters during (acute/early) primary HIV infection (PHI) and up to one year post-infection (p.i). Samples from 14 healthy donors (HDs), 40 PHI patients, 17 Chronics, and 13 Elite controllers (ECs) were studied. The percentages of Th17 and Treg subsets were severely altered in Chronics, whereas all HIV-infected individuals (including ECs) showed Th17/Treg imbalance compared to HDs, in concordance with higher frequencies of activated CD8+ T-cells (HLA-DR+/CD38+). Better clinical status (higher CD4 counts, lower viral loads and activation) was associated with higher Th17 and lower Treg levels. We found positive correlations between Th17 at baseline and anti-HIV CD8+ T-cell functionality: viral inhibitory activity (VIA) and key polyfunctions (IFN-γ+/CD107A/B+) at both early and later times p.i, highlighting the prognostic value of Th17 cells to preserve an effective HIV T-cell immunity. Th17/Treg ratio and the IL-17 relative mean fluorescence intensity (rMFI of IL-17) were also positively correlated with VIA. Taken together, our results suggested a potential link between Th17 and Th17/Treg ratio with key HIV-specific CD8+ T-cell responses against the infection.Fil: Falivene, Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Ghiglione, Yanina Alexandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Laufer, Natalia Lorna. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Socías, María Eugenia. Fundación Huésped; ArgentinaFil: Holgado, María Pía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Ruiz, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Maeto, Cynthia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Figueroa, María Inés. Fundación Huésped; ArgentinaFil: Giavedoni, Luis D.. Texas Biomedical Research Institute; Estados UnidosFil: Cahn, Pedro. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina. Fundación Huésped; ArgentinaFil: Salomon, Horacio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Sued, Omar Gustavo. Fundación Huésped; ArgentinaFil: Turk, Gabriela Julia Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Gherardi, Maria Magdalena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentin

Exchange-correlation vector potentials and vorticity-dependent exchange-correlation energy densities in two-dimensional systems

We present a new approach how to calculate the scalar exchange-correlation potentials and the vector exchange-correlation potentials from current-carrying ground states of two-dimensional quantum dots. From these exchange-correlation potentials we derive exchange-correlation energy densities and examine their vorticity (or current) dependence. Compared with parameterizations of current-induced effects in literature we find an increased significance of corrections due to paramagnetic current densities.Comment: 5 figures, submitted to PR

Dietary Silicon Deficiency Does Not Exacerbate Diet-Induced Fatty Lesions in Female ApoE Knockout Mice.

BACKGROUND: Dietary silicon has been positively linked with vascular health and protection against atherosclerotic plaque formation, but the mechanism of action is unclear. OBJECTIVES: We investigated the effect of dietary silicon on 1) serum and aorta silicon concentrations, 2) the development of aortic lesions and serum lipid concentrations, and 3) the structural and biomechanic properties of the aorta. METHODS: Two studies, of the same design, were conducted to address the above objectives. Female mice, lacking the apolipoprotein E (apoE) gene, and therefore susceptible to atherosclerosis, were separated into 3 groups of 10-15 mice, each exposed to a high-fat diet (21% wt milk fat and 1.5% wt cholesterol) but with differing concentrations of dietary silicon, namely: silicon-deprived (-Si; <3-μg silicon/g feed), silicon-replete in feed (+Si-feed; 100-μg silicon/g feed), and silicon-replete in drinking water (+Si-water; 115-μg silicon/mL) for 15-19 wk. Silicon supplementation was in the form of sodium metasilicate (feed) or monomethylsilanetriol (drinking water). RESULTS: The serum silicon concentration in the -Si group was significantly lower than in the +Si-feed (by up to 78%; P < 0.003) and the +Si-water (by up to 84%; P < 0.006) groups. The aorta silicon concentration was also lower in the -Si group than in the +Si-feed group (by 65%; P = 0.025), but not compared with the +Si-water group. There were no differences in serum and aorta silicon concentrations between the silicon-replete groups. Body weights, tissue wet weights at necropsy, and structural, biomechanic, and morphologic properties of the aorta were not affected by dietary silicon; nor were the development of fatty lesions and serum lipid concentrations. CONCLUSIONS: These findings suggest that dietary silicon has no effect on atherosclerosis development and vascular health in the apoE mouse model of diet-induced atherosclerosis, contrary to the reported findings in the cholesterol-fed rabbit model