Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing understanding of how to apply cellular assays to identify oligonucleotides with improved pharmacological properties in vivo. Locked nucleic acid (LNA), which exhibits high binding affinity and potency, is widely used for this purpose. Our understanding of RNA biology has also expanded tremendously, resulting in new approaches to engage RNA as a therapeutic target. Recent observations indicate that each oligonucleotide is a unique entity, and small structural differences between oligonucleotides can often lead to substantial differences in their pharmacological properties. Here, we outline new principles for drug discovery exploiting oligonucleotide diversity to identify rare molecules with unique pharmacological properties.

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Salt grass is an important pioneer plant in early stages of succession. The sharp‐pointed rhizomes with numerous epidermal silica cells, and the aerenchymatous network of the rhizome, leaf sheath, and roots facilitate development of the plant in heavy clays, shales, and inundated soils. In salt marshes of southern Utah, salt grass contributes to a hummock‐building process that favors localized removal of salts by capillary action and evaporation. This process provides a narrow strip of soil that is favorable for the rooting of extended rhizomes. In laboratory experiments, maximum growth for Distichlis spicata, a perennial salt marsh grass, was obtained at 15,000 ppm soluble salts in nutrient solution cultures. Comparable concentrations of salts occurred in soils of the habitat from which plants were taken. Nearly equal concentrations of sodium and potassium were found in the plant tissue where the growth of the plants was optimal; such a ratio was maintained in the plants during most of the growing season. In the field the greatest amount of growth of salt grass takes place when temperatures are cool and soil moisture is quite high during the early spring. During mid‐summer as air temperatures rise, crude protein in the plant decreases. During periods of high salt and water stress, morphological and anatomical adaptations of the stomata, salt glands, and trichomes of salt grass are important for survival. Stomata on exposed ridges of vascular bundles, where desiccation is greatest, usually are covered by four epidermal cells. In contrast, stomata found in the grooves between vascular bundles tend to be uncovered. The salt gland is composed of a large basal cell and a cap cell and actively excretes (in a diurnal rhythm) excess sodium, potassium, and chloride ions. A mechanism for salt excretion from this gland is postulated. The silica‐containing trichomes on the leaves may play a role in cooling the leaf under conditions of high solar radiation and also serve to protect the plant against attack by herbivores.

Fluoride detection through hydrogen bonding or deprotonation is most commonly achieved using amide, urea or pyrrole derivatives. The sensor molecules are often complex constructs and several synthetic steps are required for their preparation. Here we report the discovery that simple arylaldoximes have remarkable properties as fluoride anion sensors, providing distinct colorimetric or fluorescent readouts, depending on the structure of the arylaldoxime. The oximes showed exceptional selectivity towards fluoride over other typical anions, and low detection limits for fluoride in both DMSO and DMSO-water mixtures were obtained.

Salt grass is an important pioneer plant in early stages of succession. The sharp-pointed rhizomes with numerous epidermal silica cells, and the aerenchymatous network of the rhizome, leaf sheath, and roots facilitate development of the plant in heavy clays, shales, and inundated soils. In salt marshes of southern Utah, salt grass contributes to a hummock-building process that favors localized removal of salts by capillary action and evaporation. This process provides a narrow strip of soil that is favorable for the rooting of extended rhizomes. In laboratory experiments, maximum growth for Disticlilis spicata, a perennial salt marsh grass, was obtained at 15,000 ppm soluble salts in nutrient solution cultures. Comparable concentrations of salts occurred in soils of the habitat from which plants were taken. Nearly equal concentrations of sodium and potassium were found in the plant tissue where the growth of the plants was optimal; such a ratio was maintained in the plants during most of the growing season. In the field the greatest amount of growth of salt grass takes place when temperatures are cool and soil moisture is quite high during the early spring. During mid-summer as air temperatures rise, crude protein in the plant decreases. During periods of high salt and water stress, morphological and anatomical adaptations of the stomata, salt glands, and trichomes of salt grass are important for survival. Stomata on exposed ridges of vascular bundles, where desiccation is greatest, usually are covered by four epidermal cells. In contrast, stomata found in the grooves between vascular bundles tend to be uncovered. The salt gland is composed of a large basal cell and a cap cell and actively excretes (in a diurnal rhythm) excess sodium, potassium, and chloride ions. A mechanism for salt excretion from this gland is postulated. The silica-containing trichomes on the leaves may playa role in cooling the leaf under conditions of high solar radiation and also serve to protect the plant against attack by herbivores. 635

Disulfide dithymidines linked 3'-5' or 3'-6' were synthesized and incorporated into oligonucleotides through a combined phosphotriester and phosphoramidite solid-phase oligonucleotide synthesis approach. The disulfide links are cleaved and formed reversibly in the presence of thiols and oligonucleotides. This link was shown to be sequence-adaptive in response to given templates in the presence of mercaptoethanol. The artificial 3'-5' and 3'-6' disulfide link was tolerated by polymerases in the polymerase chain reaction (PCR). By using sequencing analysis, we show that single mutations frequently occurred randomly in the amplification products of the PCR.

Light and electron microscopy was used to determine the distribution of chloride ions in cells and tissues of Salicornia pacifica Standl, var. utahensis (Tidestrom) Munz. Chlorenchyma cells with chloroplasts around the periphery and sclereid-like cells with distinct wall thickenings which extended from the anastomosing vascular system to near the epidermis were present in the cortex. The vascular bundles or stelar strands were surrounded by several layers of large parenchyma cells. Tissues were treated with silver acetate for silver chloride precipitation. Silver chloride precipitation sites were present in all cell types. Precipitation sites were readily evident in the vacuoles but not in other organelles.

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