Human base excision repair enzymes apurinic/apyrimidinic endonuclease1 (APE1), DNA polymerase β and poly(ADP-ribose) polymerase 1: interplay between strand-displacement DNA synthesis and proofreading exonuclease activity

We examined interactions between base excision repair (BER) DNA intermediates and purified human BER enzymes, DNA polymerase β (pol β), apurinic/apyrimidinic endonuclease (APE1) and poly(ADP-ribose) polymerase-1 (PARP-1). Studies under steady-state conditions with purified BER enzymes and BER substrates have already demonstrated interplay between these BER enzymes that is sensitive to the respective concentrations of each enzyme. Therefore, in this study, using conditions of enzyme excess over substrate DNA, we further examine the question of interplay between BER enzymes on BER intermediates. The results reveal several important differences compared with data obtained using steady-state assays. Excess PARP-1 antagonizes the action of pol β, producing a complete block of long patch BER strand-displacement DNA synthesis. Surprisingly, an excess of APE1 stimulates strand-displacement DNA synthesis by pol β, but this effect is blocked by PARP-1. The APE1 exonuclease function appears to be modulated by the other BER proteins. Excess APE1 over pol β may allow APE1 to perform both exonuclease function and stimulation of strand-displacement DNA synthesis by pol β. This enables pol β to mediate long patch sub-pathway. These results indicate that differences in the stoichiometry of BER enzymes may regulate BER

Carbene Spin Multiplicity in Solution Probed Using Time-Resolved EPR Spectroscopy

Time-resolved (CW) EPR spectroscopy at X-band has been used to detect free radicals created by H-atom abstraction reactions of photochemically generated carbenes in n-hexadecane solutions at room temperature. Three different carbenes were studied, formed via loss of nitrogen after photo-excitation of a substituted biphenyl diazo precursor. The TREPR signals from two different alkyl radicals and the benzylic-type radical from the carbene are detected for two of the three diazo substrates. The radicals were unambiguously identified by spectral simulation using literature parameters (g-factors and hyperfine coupling constants). Previous transient optical absorption spectroscopy experiments have concluded that these two carbenes have triplet ground states, which is confirmed by the low field emissive, high field absorptive phase of the TREPR signals reported here. The spectra are strongly spin polarized by the Radical Pair Mechanism of CIDEP, and their overall intensities track with the measured quantum yields for carbene production. A third substrate, known to react via a concerted Wolff reaction or excited state rearrangement via a singlet state, showed no TREPR signal, as expected. Reactions run in acetonitrile, where the spin multiplicity is reversed to give a singlet ground state, did not lead to detectable TREPR signals for all three substrates. The observations are consistent with previously published laser flash photolysis results

СТАТИСТИЧЕСКИЙ АНАЛИЗ ДИНАМИКИ И ПРОГНОЗИРОВАНИЕ РОЖДАЕМОСТИ В ОРЕНБУРГСКОЙ ОБЛАСТИ

The revealed structure of the time series analyzed indicator is selected cyclical and trend components. The simulation of one-dimensional timeseries taking into account the selected cyclesand variability. Comparative analysis of trends and variability of total fertility rate for selectedcycles. The identified factors and their estimated impact on the dynamics of the total fertility rateat the beginning of the ascending phase of cycle(2004-2012). Developed factor forecast andforecast univariate time series.В статье изложена методика проведения анализадинамикиипрогнозированияобщего коэффициентарождаемости в Оренбургской области. Спомощьюсовременногостатистического инструментария выявлена структура временного ряда анализируемого показателя - выделена циклическая и трендовая составляющие, проведено моделирование одномерноговременногорядасучетомвыделенных циклов и колеблемости. Дан сравнительныйанализтенденциидинамикииколеблемостиобщегокоэффициентарождаемости по выделенным циклам. Выявлены факторы и оценено их влияние на динамику общего коэффициента рождаемости в начавшейся восходящей фазе цикла (2004-2012 годы).Разработан факторный прогноз и прогноз по одномерному временному ряду

The invertebrate fauna of anthropogenic soils in the High-Arctic settlement of Barentsburg, Svalbard

The terrestrial environment of the High Arctic consists of a mosaic of habitat types. In addition to the natural habitat diversity, various human-influenced types may occur. For the resident invertebrate fauna, these anthropogenic habitats may be either unusually favourable or detrimental. In the town of Barentsburg, Svalbard, soils were imported for the greenhouses from southern Russia. These soils were subsequently discarded outside the greenhouses and have become augmented with manure from the cowsheds. Both the greenhouse and the cowsheds are now derelict. This site represents an unusually nutrient-rich location with considerable development of organic soils, in stark contrast to the naturally forming organic soils in Svalbard, which are typically thin and nutrient poor. Few previous studies have examined the soil invertebrate communities of human-disturbed or -created habitats in the Arctic. In an often nutrient-poor terrestrial environment, it is unclear how the invertebrate fauna will react to such nutrient enhancement. In these soils, 46 species of invertebrates were determined. Eleven species have not been recorded from other habitats in Svalbard and are hence likely to have been introduced. The native species assemblage in the anthropogenic soils was not atypical for many natural sites in Svalbard. Despite the enriched organic soils and highly ameliorated winter temperature conditions, the soil invertebrate fauna biodiversity does not appear to be enhanced beyond the presence of certain probably introduced species

Radical Reactions with Double Memory of Chirality ( 2 MOC) for the Enantiospecific Synthesis of Adjacent Stereogenic Quaternary Centers in Solution: Cleavage and Bonding Faster than Radical Rotation

The solution photochemistry of bis(phenylpyrrolidinonyl)ketones (R,R)-1b and (S,S)-1b exhibited a remarkably high memory of chirality. Stereospecific decarbonylation to products (R,R)-3b and (S,S)-3b, respectively, occurred with an ee of ca. 80%. The reaction is thought to occur along the single state manifold by sequential Norrish type-I α-cleavage decarbonylation, and radical–radical combination in a time scale that is comparable to that required for the radical intermediate to expose its other enantiotopic face by rotation about an axis perpendicular to that of the p orbital (ca. 3–7 ps). The absolute configuration of a key intermediate and that of ketone (R,R)-1b were determined by single-crystal X-ray diffraction and the ee values of the photochemical products with the help of chiral shift reagent (+)-Eu(tfc)3 and chiral LC-MS/ MS. On the basis of the ee and de values at 25 °C, it could be determined that ca. 70% of the bond forming events occur with double memory of chirality, ca. 21% occur after rotation of one radical to form the meso product (R,S)-3b, and only 9% occur after double rotation to form the opposite enantiomer. This report represents the first example of a doubly enantiospecific Norrish type-I and decarbonylation reaction in solution and illustrates potentially efficient ways to obtain compounds with adjacent stereogenic quaternary centers

The effect of zinc complex of N-isopropenylimidazole on the morphological characteristics of gum tissues in experimental endodontic-periodontal lesions in rats Authors

Introduction: Combined inflammatory and destructive processes affecting the dental pulp and tissues of the periodontal complex are among the most problem diseases of the dental system. Current therapy with use of available pharmacological agents does not always allow achieving the expected positive result. In addition, often the lack of information about morphological processes in the tissues of the dental system, in particular the gums, with endodontic-periodontal lesion (EPL) limits the ability of dentists to carry out targeted pharmacotherapy with both traditional and, in particular, new medications. The aim of the study was to evaluate the morphological characteristics of gum tissues in a therapeutic context of N-isopropenylimidazole zinc complex derivative in experimental endodontic-periodontal lesion in rats. Materials and Methods: A simulation of EPL in rats was performed in two ways: simultaneous induction of acute periodontitis and parodontitis by pulp extraction and natural infection of the pulp cavity, as well as by ligation of the necks of lower incisors. The research protocols included 5 groups of animals: 1st – intact group (control-1); 2nd – animals with simulated EPL (control-2); 3rd – animals with simulated EPL and treated with Metrogyl Denta® gel (M-D); 4th – animals with simulated EPL and treated with N–isopropenylimidazole zinc complex derivative gel under the laboratory code Pilim-1; and 5th – animals with simulated EPL and treated with the combination of M-D + Pilim-1. The gum of the lower incisors was taken for morphological studies. Slides were stained with hematoxylin and eosin. Computer morphometry was performed using the ImageJ software. Results and Discussion: The substances M-D, Pilim-1 and, especially, the combination of M-D+Pilim-1 (against the background of chlorhexidine bigluconate used as oral rinse) for 14 days in rats with simulated EPL cause a significant improvement of the morphological structure of the gum with minimal residual dystrophy and sclerosis. The combination M-D + Pilim-1 led to a 1.3-time increase in epithelial thickness, and a 1.5-time decrease in acanthosis depth in comparison with M-D, while the number of capillaries and their diameter had no significant differences. Compared with Pilim-1, the epithelial thickness increased 1.5 times, and the acanthosis depth and the number of capillaries decreased 1.6 and 1.4 times, respectively, whereas the diameter of the capillaries did not change significantly. The pronounced protective effect of the combination M-D + Pilim-1 on the morphological structure of the gingival mucosa of rats with simulated EPL may be associated with antimicrobial, anti-inflammatory, regenerating, angioprotective and antioxidant properties of both M-D and Pilim-1 separately, and, possibly to a greater extent, of the combination M-D + Pilim-1. Conclusion: The substances M-D, Pilim-1 and, especially, the combination M-D + Pilim-1 (against the background of chlorhexidine bigluconate used as oral rinse) for 14 days in rats with simulated EPL have a protective effect on the epithelial structure and the connective tissue of the proper mucous plate, manifested in active normalization of pathological changes and significant restoration of their organotypic structure

КЛИНИЧЕСКИЕ И ПРОГНОСТИЧЕСКИЕ ОСОБЕННОСТИ ПАЦИЕНТОВ СТАРЧЕСКОГО ВОЗРАСТА С НЕСТАБИЛЬНОЙ СТЕНОКАРДИЕЙ ПРИ КОНСЕРВАТИВНОЙ ТАКТИКЕ ЛЕЧЕНИЯ В ЗАВИСИМОСТИ ОТ ФРАКЦИИ ВЫБРОСА ЛЕВОГО ЖЕЛУДОЧКА

Highlights High cardiovascular morbidity and mortality in the Russian Federation and in Kuzbass is mainly due to high number of elderly and senile patients; it simply reflects the current demographic situation in the country. Elderly and senile patients with acute coronary syndrome (ACS) account for 50% of hospitalized patients. In real clinical practice, a significant number of elderly patients with ACS receive conservative treatment, whereas the prognosis in this cohort is determined by the development of recurrent coronary events and the progression of heart failure. Due to small number of patients older than 75-80 years included in randomized clinical trials, there are certain gaps in the management of elderly patients with ACS and heart failure. Obviously, elderly patients require a special approach to patient management, taking into account the complexity of clinical and anamnestic factors affecting the prognosis. AbstractAim. To study clinical and prognostic features of elderly patients with unstable angina pectoris undergoing conservative treatment depending on left ventricular ejection fraction (LVEF).Methods. 130 elderly patients, with mean age of 82 (77; 89) years, hospitalized for unstable angina with a GRACE score of less than 140 to a vascular center in Kemerovo were included in the study. During hospitalization, standard laboratory and instrumental studies were performed, except coronary angiography. The quality of life was assessed using the EQ-5D 3L questionnaire. After 12 months, patient compliance with treatment recommendations, primary and secondary endpoints, and quality of life were analyzed.Results. All patients were diagnosed with heart failure, 50 (38.5%) patients presented with LV EF less than 40% (the group I), 80 (61.5%) patients presented with LV EF more than 40% (the group II). The groups were comparable in gender, age, presence of multifocal of atherosclerotic disease, prevalence of aortic stenosis, arrhythmias and comorbidities. Women predominated in both groups, and arterial hypertension was noted in all patients. In the group I, a history of myocardial infarction, coronary revascularization, and NYHA FC III were more common (p<0.05). The level of quality of life at discharge was low in both groups: 34.8 (29; 42) and 39.4 (34; 46) points, respectively (p>0.05). Almost all patients were on triple neurohumoral blockade (beta-blockers, renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists) for heart failure and dual antiplatelet therapy. One year later, 85.2% of patients in the group I and 90% of patients in the group II were taking all prescribed medication at low or medium therapeutic doses (without the need for drug titration). The overall mortality in the groups was 46% and 37.5%; cardiovascular deaths accounted for 32% and 30%, respectively (p>0.05). There were no differences in the frequency of endpoints (hospitalization, stroke, acute coronary syndrome, coronary revascularization) between the groups. The level of quality of life remained low in both groups.Conclusion. In patients over 75 years hospitalized for unstable angina, main clinical and anamnestic characteristics, annual prognosis and quality of life do not depend on LV EF, whereas the need for coronary revascularization during the 1 year remains high.Основные положенияРост сердечно-сосудистой заболеваемости и смертности в РФ, в том числе в Кузбассе, в основном вызван увеличением числа больных пожилого и старческого возраста, что отражает текущую демографическую ситуацию в стране. Пациенты пожилого и старческого возраста с острым коронарным синдромом (ОКС) составляют до 50% госпитализированных в стационар. В реальной клинической практике значительное количество больных старческого возраста с ОКС получают консервативное лечение, а прогноз в этой когорте обусловлен развитием повторных коронарных событий и прогрессированием сердечной недостаточности. В связи с небольшой долей лиц старше 75–80 лет, включенных в рандомизированные клинические исследования, в вопросах ведения пациентов старческого возраста с ОКС и сердечной недостаточностью остаются пробелы. Очевидно, что больные старческого возраста требуют особого подхода с учетом наличия комплекса клинических и анамнестических факторов, оказывающих влияние на прогноз. РезюмеЦель. Изучение клинических и прогностических особенностей когорты пациентов старческого возраста с нестабильной стенокардией при консервативной тактике стационарного лечения в зависимости от величины фракции выброса левого желудочка (ФВ ЛЖ).Материалы и методы. В исследование включены 130 больных старческого возраста, 82 (77; 89) лет, госпитализированных по поводу нестабильной стенокардии в первичный сосудистый центр г. Кемерово с баллом по шкале GRACE менее 140. В течение госпитализации больным проведены стандартные лабораторные и инструментальные исследования, за исключением коронароангиографии. Оценено качество жизни с помощью опросника EQ-5D 3L. Через 12 мес. проанализированы соблюдение рекомендаций по лечению, первичные и вторичные конечные точки, качество жизни.Результаты. У всех пациентов диагностирована сердечная недостаточность: у 50 (38,5%) – с ФВ ЛЖ менее 40% (группа I), у 80 (61,5%) – с ФВ ЛЖ более 40% (группа II). Сравниваемые группы не отличались по полу, возрасту, мультифокальности атеросклеротического поражения, частоте аортального стеноза, нарушениям ритма и сопутствующей патологии. В обеих группах преобладали женщины, у всех больных зарегистрирована артериальная гипертензия. В группе I в анамнезе чаще отмечены перенесенный инфаркт миокарда, реваскуляризация миокарда и III функциональный класс хронической сердечной недостаточности по классификации NYHA (р<0,05). Уровень качества жизни при выписке был низким в обеих группах: 34,8 (29; 42) и 39,4 (34; 46) балла соответственно (р>0,05). Практически все пациенты в соответствии с существовавшими на период проведения исследования рекомендациями получали тройную нейрогуморальную терапию сердечной недостаточности (блокаторы ренин-ангиотензин-альдостероновой системы, бета-блокаторы, антагонисты минералокортикоидных рецепторов) и двойную дезагрегантную терапию. Через год 85,2% больных группы I и 90% группы II принимали назначенные препараты в низких или среднетерапевтических дозах без титрации. Общая смертность в группах составила 46 и 37,5%; сердечно-сосудистая – 32 и 30% соответственно (р>0,05). Различий в частоте регистрации жестких конечных точек (госпитализация, инсульт, острый коронарный синдром, коронарная реваскуляризация) между группами не обнаружено. Уровень качества жизни оставался низким в обеих группах.Заключение. У пациентов старше 75 лет, госпитализированных по поводу нестабильной стенокардии, основные клинико-анамнестические характеристики, годовой прогноз и уровень качества жизни не зависят от величины ФВ ЛЖ, а потребность в реваскуляризации миокарда в течение года остается высокой.

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec