Replication Protein A (RPA) is a ssDNA binding protein that is essential for DNA replication and repair. The initiation of the DNA damage response by RPA is mediated by protein-protein interactions involving the N-terminal domain of the 70 kDa subunit with partner proteins. Inhibition of these interactions increases sensitivity towards DNA damage and replication stress and may therefore be a potential strategy for cancer drug discovery. Towards this end, we have discovered two lead series of compounds, derived from hits obtained from a fragment-based screen, that bind to RPA70N with low micromolar affinity and inhibit the binding of an ATRIP-derived peptide to RPA. These compounds may offer a promising starting point for the discovery of clinically useful RPA inhibitors.
Ovarian weight has been shown to increase markedly in the newborn ewe lamb, and factors which might contribute to this growth were examined. Follicle development was studied in the ovaries of 28 lambs aged 0, 2, 4, 6, 8 and 10 weeks. Plasma samples, pituitaries and one ovary were assayed for gonadotrophin or steroid hormone content.No significant differences between age groups were found in pituitary LH concentration or mean plasma LH. Pituitary FSH concentration increased with age, except for a small decrease at 8 weeks, but no significant changes were seen in plasma FSH. Ovarian progesterone and oestradiol concentrations did not appear to be associated with follicular development.Growing follicles were most numerous at 2 weeks whilst total vesicular follicles reached a peak at 4 weeks. Most vesicular follicles were less than 1 ·4 mm in diameter. Advanced atresia in vesicular follicles became apparent by 4 weeks although early signs were present in younger lambs. Fluctuations in gonadotrophin levels do not appear to be responsible for variations in number and size of vesicular and growing follicles in the lamb ovary. Other possible explanations are discussed.
The fine structure of follicles was studied in ovaries from lambs up to 32 days old. Some animals received pregnant mare serum gonadotrophin prior to sampling. Follicles examined were in the primordial to early antral stages. The oocyte is described and changes associated with its development and the formation of the zona pellucida are recorded. Characteristics in which the lamb oocyte differed from those of other mammals included a greater prominence of smooth endoplasmic reticulum, the presence of microtubules, fine filaments in the peripheral parts and a large number of almost empty vacuoles. The latter were more numerous in oocytes which appeared to be degenerating, including some of those in primordial follicles. Granulosa cells had characteristics usually associated with protein secretion while some theca cells had large amounts of endoplasmic reticulum bearing few ribosomes. In early atresia changes were evident successively in the oocyte, granulosa and theca.There was a weak positive reaction for 3p-hydroxy-AS-steroid dehydrogenase in the theca of some vesicular follicles from both control lambs and lambs treated with pregnant mare serum gonadotrophin. Follicles showing signs of atresia were negative for this enzyme.
Ovaries were obtained from 78 new-born lambs (12 singletons, 25 twins, 28 triplets, 10 quadruplets and 3 quintuplets) from flocks selected for (T902, T903 and Booroola) or against (0) multiple births. Sections of the ovaries were examined with a projection microscope and the numbers of all types of follicles were estimated. There were no differences between genetic lines in the number of primordial follicles, after adjustment for litter size and sire; however, there were significantly more of these follicles in single-born lambs than in lambs born in litters of two or more within genetic lines. The number of vesicular follicles was lower in Booroola than in 0 lambs.
like, are all influenced by chemical forces. Indeed, before substances can unite chemically, their particles must be brought first into proper subdivision and proximity, by solution, fusion, ionization, or even by mere pressure as has been demonstrated by W. Spring, who caused fine dry powders to combine by high pressure. Tf the degree of subdivision is not profound enough to permit of the combination oi' isolated atoms or ions with each other, chemical combination in the strict sense may not occur, but there may be produced "adsorption compounds" resulting from the union of atomic or ionic mobs in indefinite or non-stoichiometric proportions, under the influence of more or less modified chemical forces. On the other hand, if the degree of subdivision proceeds far enough, real chemical reactions may occur and be rendered irreversible by the diffusion or adsorption of one or more of the products into a surrounding colloidal sol or gel. LVhen we consider the great variety of bio-colloids and their susceptibility to changes of structure and diffusive or adsorptive capacity, we can easily understand the almost infinite number of reactions that may go on within their recesses, as they swing the balance of the law of mass action over particles reduced to a reactive degree of subdivision. And we must nol. be surprised to see technical processes develop upon the basis of these principles. LSR' YOSK, s Y-____-[COSTRIBUTIONS PROM THE CHEMICAL LABORATORY OF CORNELL UNIVERSITY. I THE NITRATION PRODUCTS OF TETRACHLOROFLUORAN AND SOME OF THEIR DERIVATIVES.
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