Search

Regeneration of myelin is mediated by oligodendrocyte progenitor cells (OPCs), an abundant stem cell population in the CNS and the principal source of new myelinating oligodendrocytes. Loss of myelin-producing oligodendrocytes in the central nervous system (CNS) underlies a number of neurological diseases, including multiple sclerosis (MS) and diverse genetic diseases1–3. Using high throughput chemical screening approaches, we and others have identified small molecules that stimulate oligodendrocyte formation from OPCs and functionally enhance remyelination in vivo4–10. Here we show a broad range of these pro-myelinating small molecules function not through their canonical targets but by directly inhibiting CYP51 (cytochrome P450, family 51), TM7SF2, or EBP (emopamil binding protein), a narrow range of enzymes within the cholesterol biosynthesis pathway. Subsequent accumulation of the 8,9-unsaturated sterol substrates of these enzymes is a key mechanistic node that promotes oligodendrocyte formation, as 8,9-unsaturated sterols are effective when supplied to OPCs in purified form while analogous sterols lacking this structural feature have no effect. Collectively, our results define a unifying sterol-based mechanism-of-action for most known small-molecule enhancers of oligodendrocyte formation and highlight specific targets to propel the development of optimal remyelinating therapeutics.

New vinyl oil monomers have been prepared by combining epoxidized unsaturated oils with vinyl carboxylic acids. This is accomplished by heating the reactants in the presence of free radical inhibitors and appropriate reaction catalysts. The reaction consists of cleavage of the oxirane ring followed by addition of the vinyl acid through its carboxylic group. By varying the reactants and the conditions of reaction, a large family of related, but different, vinyl oil monomers can be prepared. Vicinal methacryloxy-hydroxy soy oil monomers are clear, yellow, medium viscosity (2000–2500 cpoise), high molecular weight (1300–1500) liquids. Chemical analyses are presented for typical preparations. The monomers readily homopolymerize by a free radical mechanism to clear, solid, thermoset resins. They are compatible with a variety of commercial vinyl monomers and form copolymers which range from highly viscous liquids through soft gels, to tough rubbery products and hard resins. Data are presented on physical properties of copolymer castings of several specific vicinal methacryloxy-hydroxy soy oil monomers.

Details of apparatus construction and refinements are presented for a micro capillary rise method of determining absolute values of surface tension. Experimental values of surface tension for benzene, n-pentadecane, and methyl laurate are recorded and compared with previous literature values. Parachors are determined. The method requires a minute amount of sample and is simple, quick, precise, and accurate.

A variety of olefins were readily converted to acrylate monomers by combining them with t-butyl hypochlorite and acrylic or methacrylic acid at 25–65°C. The predominate product was the vicinal acyloxychloro derivative formed by addition at the olefinic double bond. By-products were the vicinal butoxychloro derivative and the still unsaturated chlorinated olefin. The main reaction was shown to occur by an ionic mechanism. 2-Chloro-1-methyl propyl methacrylate was isolated and identified as the main product of the reaction of 2-butene, methacrylic acid, and t-butyl hypochlorite. The crude olefin products readily homopolymerized and copolymerized with other vinyl monomers by incorporating free-radical initiators.

The experiments described here show that the deleterious effect of oxide cathodes on secondary-emitting surfaces of silver magnesium can be overcome by using tantalum instead of nickel as the base metal for the oxide coating.

Methyl esters of saturated naturally occurring fat acids from C6 through C18 were prepared and purified by fractional distillation. Refractive indices were used as a measure of their purity. A micro surface tension apparatus was constructed to comply with a modified capillary rise method devised by Ferguson. The surface tensions of water and of benzene were determined at several temperatures. The results obtained compared quite favorably with the values listed in the International Critical Tables. The surface tensions of the methyl esters were determined at 40°C., 60°C., and 80°C. with an accuracy of ±0.15 dynes/cm. Similar to other homologous series the surface tensions of the fat acid methyl esters decrease with increasing temperature, apparently in a linear manner. As the molecular weight of the methyl ester series increases, the surface tension also increases. Close correlation is shown for the methyl esters between the calculated parachors based upon Gibling’s system of values and the experimental parachors.

Acrosin and acrosomal hyaluronidase were inhibited by tetradecyl sodium sulphate (TDSS) in vitro at concentrations of less than 10(-4) M. TDSS prevented the removal in vitro of the cumulus oophorus by testicular hyaluronidase and the zona pellucida by acrosin. TDSS had a contraceptive effect in rabbits when administered intravaginally before coitus or released at levels of 1-3 micrograms/day from intrauterine silicone rubber devices.

A small sodium iodide scintillation detector was designed for insertion through a fiberoptic bronchoscope to detect and localize sites of deposition of cobalt-57 bleomycin in lung cancer. The detector was used in 40 diagnostic studies of 34 patients; 21 of the patients had tumors. We compared the sensitivity, specificity, accuracy, and predictive value of the detector to those of plain chest x-ray films and bronchoscopy in detecting tumors. Sensitivity and specificity for the detector were 68 percent and 80 percent, respectively; for bronchoscopy, 72 percent and 100 percent; and for roentgenograms, 80 percent and 53 percent. Sensitivity for the detector and bronchoscopy combined was 92 percent. The detector succeeded in locating nonvisible submucosal and extraluminal tumors, and may contribute to early diagnosis and more accurate staging of lung cancer.

A method for promoting dental health in which chewing gum is employed to alter the oral environment to provide natural resistance to dental caries. The method involves chewing a sugarless gum which contains a relatively insoluble, hydrophobic food-grade organic acid, preferably adipic acid. Chewing of the gum gradually releases the acid from the gum at a desirably linear rate over a period of approximately 20 to 30 minutes. Release of the acid from the gum into the mouth stimulates an increase in salivary flow rate greater than that experienced during chewing a non-acidulated chewing gum, resulting in increases in salivary electrolytes and basic proteins and in the concentration of natural salivary bicarbonate to a level in excess of that necessary to neutralize the acidulant being released from the gum. The excess of natural salivary bicarbonate raises the salivary pH and plaque pH and neutralizes microbially-formed lactic acid responsible for tooth demineralization and resultant dental caries.