Antisense and antigene inhibition of gene expression by cell-permeable oligonucleotide-oligospermine conjugates

Oligonucleotides and their derivatives are a proven chemical strategy for modulating gene expression. However, their negative charge remains a challenge for delivery and target recognition inside cells. Here we show that oligonucleotide-oligospermine conjugates (Zip nucleic acids or ZNAs) can help overcome these shortcomings by serving as effective antisense and antigene agents. Conjugates containing DNA and locked nucleic acid (LNA) oligonucleotides are active, and oligospermine conjugation facilitates carrier-free cell uptake at nanomolar concentrations. Conjugates targeting the CAG triplet repeat within huntingtin (HTT) mRNA selectively inhibit expression of the mutant huntingtin protein. Conjugates targeting the promoter of the progesterone receptor (PR) function as antigene agents to block PR expression. These observations support further investigation of ZNA conjugates as gene silencing agents.     

On-chip pre-concentration and complexation of [¹⁸F]fluoride ions via regenerable anion exchange particles for radiochemical synthesis of Positron Emission Tomography tracers

Microfluidic approaches have demonstrated a relevant impact on radiochemical reactions involving Positron Emission Tomography (PET) nuclides, due to shorter reaction times and smaller precursor quantities. However, little attention has been given to the integration of the initial pre-concentration and drying of radioactive [(18)F]fluoride ions, required for the labeling of radiotracer compounds. In this work we report the design, fabrication and implementation of a glass microfluidic device filled with recyclable anion exchange particles for the repeated recovery of [(18)F] and [(19)F]fluoride ions. The device was first tested with non radioactive [(19)F]fluoride ions and it was shown to repeatedly trap and elute >95% fluoride over 40 successive experimental runs with no decrease in efficiency. The same device was then tested for the trapping and release of [(18)F]fluoride ions over 20 experiments with no measurable decrease in performance. Finally, the [(18)F]fluoride ions were eluted as a K(18)F/K2.2.2 complex, dried by repeated dissolution in acetonitrile and evaporation of residual water, and reacted with ethyl ditosylate (EtDT) leading to the desired product ([(18)F]fluoroethyltosylate) with 96 ± 3% yield (RCY). The overall time needed for conditioning, trapping, elution and regeneration was less than 6 min. This approach will be of great benefit towards an integrated platform able to perform faster and safer radiochemical synthesis on the micro-scale.     

The orientation-preserving diffeomorphism group of {\mathbb{S}^{2}} deforms to SO(3) smoothly

Smale proved that the orientation-preserving diffeomorphism group of \mathbbS²{\mathbb{S}^{2}} has a continuous strong deformation retraction to SO(3). In this paper, we construct such a strong deformation retraction which is diffeologically smooth.     

Left Ventricular Geometry,Tissue Composition,and Residual Stress in High Fat Diet Dahl-Salt Sensitive Rats

Background

Hypertension drives myocardial remodeling, leading to changes in structure, composition and mechanical behavior, including residual stress, which are linked to heart disease progression in a gender-specific manner. Emerging therapies are also targeting constituent-specific pathological features. All previous studies, however, have characterized remodeling in the intact tissue, rather than isolated tissue constituents, and did not include sex as a biological variable.

Objective

In this study we first identified the contribution of collagen fiber network and myocytes to the myocardial residual stress/strain in Dahl-Salt sensitive rats fed with high fat diet. Then, we quantified the effect of hypertension on the remodeling of the left ventricle (LV), as well as the existence of sex-specific remodeling features.

Methods

We performed mechanical tests (opening angle, ring-test) and histological analysis on isolated constituents and intact tissue of the LV. Based on the measurements from the tests, we performed a stress analysis to evaluate the residual stress distribution. Statistical analysis was performed to identify the effects of constituent isolation, elevated blood pressure, and sex of the animal on the experimental measurements and modeling results.

Results

Hypertension leads to reduced residual stress/strain in the intact tissue, isolated collagen fibers, and isolated myocytes in male and female rats. Collagen remains the largest contributor to myocardial residual stress in both normotensive and hypertensive animals. We identified sex-differences in both hypertensive and normotensive animals.

Conclusions

We observed both constituent- and sex-specific remodeling features in the LV of an animal model of hypertension.

     

Formation of segregated and integrated groups

A model of group formation is presented such that the number of groups is fixed, and a person can only join a group if the group’s members approve the person’s joining. Agents have either local status preferences (each agent wants to be the highest status agent in his group) or global status preferences (each agent wants to join the highest status group that she can join). For both preference types, conditions are provided which guarantee the existence of a segregated stable partition such that similar people are grouped together, and conditions are provided which guarantee the existence of an integrated stable partition such that dissimilar people are grouped together. Additionally, in a dynamic framework we show that if a new empty group is added to a segregated stable partition, then integration may occur.     

Dephasing calculations of de Haas-van Alphen scattering

A review and assessment of existing dephasing calculations is given.     

New cesium titanate layer structures

A phase study of the Cs₂OTiO₂ system in the composition range 75–100 mole% TiO₂ and the temperature range 850–1200°C revealed the existence of two new cesium titanates, with compositions Cs₂Ti₅O₁₁ and Cs₂Ti₆O₁₃. The former compound undergoes a reversible hydration reaction below 200°C to form Cs₂Ti₅O₁₁ · (1 + x)H₂O, 0.5 < x < 1. The structures of the three phases have been determined. They are based on corrugated layers of edge-shared octahedra, with cesium ions (and H₂O) packing between the layers. In Cs₂Ti₆O₁₃, the layers are continuous in two dimensions, whereas in Cs₂Ti₅O₁₁ and Cs₂Ti₅O₁₁ · (1 + x)H₂O, the layers are periodically stepped to give 5-octahedra wide, corner-linked ribbons.     

The effect of ionicity and hybridization on the calculation of spectroscopic coupling parameters and dipole moments

Calculations have been carried out in order to calculate thes-character and ionicity of the carbon-halogen bonds in eight halomethanes from experimental values of (1)¹³C-H couplings, (2) nuclear quadrupole couplings, and (3) dipole moments. Two sets of results were obtained based on the use, first, of (1) and (2) and, second, on the use of (1) and (3). The two sets of results show a reasonable degree of consistency, under the assumptions and methods involved, and tend to support the need for considering both hybridization and charge transfer in accounting for substituent effects on the properties studied.

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Zusammenfassung Es wurden Rechnungen zur Bestimmung dess- und des Ionencharakters von Kohlenstoff-Halogen-Bindungen in acht Halogenmethanen aus den experimentellen Daten von (1)¹³C-H-Koppelungen, (2) Kernquadrupolkoppelungen und (3) Dipolmomenten durchgeführt. Zwei Sätze von Ergebnissen wurden erhalten, die auf der Benutzung von (1) und (2) bzw. (1) und (3) basieren. Die Ergebnisse der beiden Rechnungen sind im Rahmen der Annahmen und Methoden konsistent und ergeben die Notwendigkeit, sowohl Hybridisierung als auch Ladungsübergang bei der Betrachtung von Substitutionseffekten auf die zu untersuchenden Eigenschaften zu berücksichtigen.

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Résumé On a calculé le caractères et l'ionicité des liaisons carbone-halogène dans huit halogénométhanes à partir des valeurs expérimentales (1) des couplages¹³C-H, (2) des constantes de couplage quadrupolaire nudéaire (3), des moments dipolaires. Deux ensembles de résultats ont été obtenus à partir de (1) et (2) et de (1) et (3). Ces deux ensembles de résultats montrent un degré raisonnable de consistance, étant données les hypothèses et les méthodes utilisées, et sont en faveur d'une intervention simultanée de l'hybridation et du transfert de charge pour rendre compte des effets de substituants sur les propriétés étudiées.

     

A combined LEED/RHEED Auger study of oxygen adsorption on the W(112) surface

LEED, RHEED and Auger spectroscopy have been used to study the adsorption of oxygen on to a clean and carbon contaminated (112) face of tungsten. At room temperature all the features reported previously were observed together with a p(1 × 4) surface structure which appeared at an exposure of about 1. 4L just before the formation of the p(1 × 2). Previously a p(1 × 4) structure has been reported only after heating to 2000K. RHEED showed this p(1 × 4) structure clearly; using LEED, the structure was difficult to distinguish. This appears to confirm suspicions that in some situations involving gas adsorption, RHEED has a greater sensitivity than LEED. Possibly most of these situations involve, as does the present p(1 × 4) structure, monolayer islands where the differing coherence widths of the RHEED and LEED beams account for the differing sensitivities. Carbon on the (112) surface also appears to exist as thin islands, either of the previously reported c(6 × 4) structure, or in smaller amounts, on a surface showing (1 × 1) symmetry. Removal of all carbon by heat treatment alone was found to be impossible in a reasonable time and heating in oxygen was necessary. Oxygen adsorption on a carbon contaminated surface did not give rise to any new structures but rather a reduction in the visibility/formation of the clean surface/oxygen structures.