Structure-activity relationships on cynnamoyl derivatives as inhibitors of p300 Histone acetyltransferase

Human p300 is a polyhedric transcriptional coactivator, playing a crucial role by acetylating histones on specific lysine residues. A great deal of evidences shows that p300 is involved in several diseases as leukemia, tumors and viral infection. Its involvement in pleiotropic biological roles and connections to diseases provide the rationale as to how its modulation could represent an amenable drug target. Several p300 inhibitors (HATi) have been described so far, but all suffer from low potency, lack of specificity or low cell-permeability, highlighting the need to find more effective inhibitors. Our cinnamoyl derivative, RC 56, was identified as active and selective p300 inhibitor, proving to be a good hit candidate to investigate the structure-activity relationship towards p300. Herein we describe the design, synthesis and biological evaluation of new HATi structurally related to our hit, investigating, moreover, the interactions between p300 and the best-emerged hits by means of induced fit docking and molecular dynamics simulations, gaining insight on the peculiar chemical features that influenced their activity toward the targeted enzyme

Anatomy of mouse recombination hot spots

Genome-wide analyses have suggested thousands of meiotic recombination hot spots across mammalian genomes. However, very few hot spots have been directly analyzed at a sub-kb scale for crossover (CO) activity. Using recombinant inbred strains as a CO library, here we report the identification and detailed characterization of seven new meiotic hot spots on mouse chromosome 19, more than doubling the number of currently available mouse hot spots. Although a shared feature is the narrow 1.5–2.5-kb width of these recombinogenic sites, these analyses revealed that hot spots have diverse sequence attributes and distinct symmetric and asymmetric CO profiles. Interestingly, CO molecules with discontinuous conversion tracts are commonly observed, contrasting with those found in human. Furthermore, unlike human hot spots, those present in the mouse do not necessarily have a quasi-normal CO distribution but harbor CO repulsion zones within recombinogenic cores. We propose a model where local chromatin landscape directs these repulsion zones

Klimatyczne uwarunkowania obszaru Ukrainy dla najlepszej lokalizacji budynków energoaktywnych

The article analyzes the possibilities of using renewable energy sources (solar and wind power plants) in energy-active buildings throughout the whole territory of Ukraine. The conducted analysis identifies the most efficient areas of Ukraine for the placement of such buildings.Artykuł analizuje możliwości wykorzystania odnawialnych źródeł energii (elektrownie słoneczne i wiatrowe) w budynkach energoaktywnych na całym terytorium Ukrainy. Przeprowadzona analiza wskazuje najbardziej odpowiednie obszary Ukrainy do lokalizacji tego typu budynków

Узагальнення одного алгоритму побудови рекурентних сплайнів

We have analyzed two algorithms, close in composition, for constructing a smoothing spline, which imply a change only in the last link of the spline when new experimental data arrive. The main feature of the N. D. Dicoussar algorithm is the form of a polynomial representation in order to describe a link of the spline. It is shown that a given polynomial is one of the hierarchical form of the Hermitian polynomial.We have proposed a modification to the D. A. Silaev algorithm for constructing a smoothing spline with different orders of smoothness: from zero to the second, aimed at enhancing the stability of this algorithm. To this end, we substantiated recommendations related to the form of polynomials representation, which describe the links of splines of the specified form. For this purpose, we estimated conditionality of matrices used in the algorithm. For the spline of zero-order smoothness, the most advisable is to apply a polynomial in the N. D. Dicoussar form, and for splines with higher orders of smoothness of joining the links, it is appropriate to use different forms of the Hermitian polynomials.Based on computational examples, a possibility was demonstrated to generalize the D. A. Silaev algorithm to construct a spline with links of various lengths, which is determined by the rate of change in the examined parameter. That makes it possible to reduce the volume of information that contains a description of the spline itself, and to prevent such a widespread shortcoming of approximation when using polynomials as parasitic oscillations. It was shown as well that in the presence of significant measurement errors in experimental data there may occur a need to decrease the length of the spline's link (compared to that derived by the D. A. Silaev rule) in order to provide the spline with a property of robustnessПредложены модификации алгоритма Д. А. Силаева построения сглаживающего сплайна разных порядков гладкости: от нулевого до второго, которые направлены на повышение устойчивости этого алгоритма. Обоснованы рекомендации относительно формы представления полиномов, которые описывают звенья сплайнов указанного вида. На вычислительных примерах показана возможность обобщения алгоритма Д. А. Силаева на неравномерные сеткиЗапропоновано модифікації алгоритму Д. О. Силаєва побудови згладжуючого сплайна різних порядків гладкості: від нульового до другого, які спрямовані на підвищення стійкості цього алгоритму. Обґрунтовано рекомендації щодо форми подання поліномів, які описують ланки сплайнів указаного виду. На обчислювальних прикладах показано можливість узагальнення алгоритму Д. О. Силаєва на нерівномірні сітк