Search

Far-red pentamethine cyanine dyes as fluorescent probes for detection of serum albumins. The absorption spectra of the studied dyes (1μM) in acetonitrile, DMSO and MeOH

Les années séparant sa mise en retrait de la vie publique de son entrée en politique, en 1819, sont pour Benjamin Constant décisives, en ce qu’elles lui permettent de préciser les contours de sa pensée politique. Durant ces cinq années, il s’attelle à définir les principes cardinaux que sont l’autorité, la liberté et la légitimité, afin de voir en quoi ceux-ci peuvent se compléter mutuellement, offrant à long terme une stabilité politique bienvenue après vingt-cinq ans de troubles politiques., The years between Benjamin Constant’s withdrawing from public life and his entry into politics in 1819 are crucial to gain more insight into his political thought. In those years, Constant defines the key principles of his political thought – authority, civil liberties and legitimacy. In doing so, he intends to see how these principles can complement one another and therefore ensure political stability in France – which would be welcome after twenty-five years of political havoc.

Benzothiazole based cyanine dyes with bridged groups in pentamethine chain were studied as potential far-red fluorescent probes for protein detection. Spectral-luminescent properties were characterized for unbound dyes and in the presence of serum albumins (bovine (BSA), human (HSA), equine (ESA)), and globular proteins (β-lactoglobulin, ovalbumin). We have observed that the addition of albumins leads to a significant increase in dyes fluorescence intensity. However, the fluorescent response of dyes in the presence of other globular proteins was notably lower. The value of fluorescence quantum yield for dye bearing sulfonate group complexed with HSA amounted to 42% compared with 0.2% for the free dye. The detection limit of HSA by this dye was about greater than 0.004 mg ml−1 that indicates the high sensitivity of dye to low HSA concentrations. Modelling of structure of the dyes complexes with albumin molecules was performed by molecular docking. According to these data, dyes could bind to up to five sites on the HSA molecule; the most preferable are the hemin-binding site in subdomain IB and the dye-binding site in the pocket between subdomains IA, IIA and IIIA. This work confirms that pentamethine cyanine dyes could be proposed as powerful far-red fluorescent probes applicable for highly sensitive detection of albumins.

International audience; No abstract

Penelitian ini dilakukan dengan tujuan untuk mengetahui bagaimana pengaturan macam-macam perbarengan (samenloop, concursus) tindak pidana dalam KUHP dan bagaimana sistem tanggung jawab pidana dalam perbarengan tindak pidana menurut KUHP. Dengan menggunakan metode penelitian yuridis normative, disimpulkan: 1. Pengaturan macam-macam perbarengan (samenloop, concursus) tindak pidana dalam KUHP, yaitu mencakup: a. perbarengan peraturan, b. perbuatan berlanjut, dan c. perbarengan perbuatan; di mana perbarengan perbuatan ini dapat lebih dirinci lagi atas: 1) perbarengan perbuatan yang semuanya merupakan kejahatan yang diancam dengan pidana pokok yang sejenis (Pasal 65); 2) perbarengan perbuatan yang semuanya merupakan kejahatan yang diancam dengan pidana pokok yang tidak sejenis (Pasal 66 KUHP); 3) perbarengan perbuatan yang merupakan perbarengan pelanggaran dengan kejahatan (Pasal 70 ayat (1) KUHP); 4) perbarengan perbuatan yang merupakan perbarengan pelanggaran dengan pelanggaran (Pasal 70 ayat (1) KUHP). 2. Sistem tanggung jawab pidana dalam perbarengan tindak pidana menurut KUHP, mencakup 4 (empat macam) sistem, yaitu: a. sistem absorpsi murni untuk perbarengan perbuatan dan perbuatan berlanjut; b. sistem absorpsi yang dipertajam untuk perbarengan perbuatan atas kejahatan-kejahatan yang diancam dengan pidana pokok yang sejenis; c. sistem kumulasi terbatas untuk perbarengan perbuatan atas kejahatan-kejahatan yang diancam dengan pidana pokok yang tidak sejenis; d. sistem kumulasi murni untuk perbarengan pelanggaran dengan pelanggaran. Tetapi, keberadaan ketentuan-ketentuan tentang perbarengan tindak pidana dalam KUHP, bukannya memberatkan pidana, melainkan cenderung lebih merupakan dasar untuk meringankan pidana dari pelaku yang melakukan beberapa tindak pidana. Kata kunci: Tinjauan Yuridis, Tanggungjawab Pidana, Perbarengan.

Aim To investigate the proportional contributions of coronary heart disease (CHD) determinants to the observed CHD mortality rates in Ireland between 2000–2015. Methods The validated IMPACT model on CHD mortality, which has been developed with the purpose of merging epidemiological data that is available for each country, was utilized for the estimations. Data on population statistics, CHD patient numbers, treatment uptakes and population trends on key risk factors (eg. smoking, total cholesterol, hypertension, obesity, DM and physical inactivity) were sourced from national registries, hospital administration systems, national health surveys, large cohort studies, international registries and meta-analyses. CHD Deaths Prevented or Postponed (DPPs) were used as outcome measurement. Results CHD mortality in Ireland fell by 56% (4060 fewer deaths), faster in women than in men (63% vs 53%), in the period 2000–2015 in those aged 25–84 years. Improvements in CHD risk factors, ie decrease in smoking prevalence (5%), population systolic blood pressure (-25%) and mean cholesterol serum levels (-11%), contributed to 30% of the decline with 785 DPPs in men vs 425 in women. In women, both systolic blood pressure reductions and cholesterol reductions contributed equally (200 DPPs each), and decreased smoking prevalence contributed to 80 DPPs. Likewise, DPPs in men followed a similar trend (SBP - 825; total cholesterol- 250; and, smoking-110). Improvements in cardiological treatments, specially in secondary prevention and heart failure treatments, contributed to approximately 60% of the observed decline (1620 DPPs in men and 825 in women). Both males and females benefitted the most DPPs from improvements in secondary prevention (850 and 355 DPPs, respectively). These gains were offset by increases in physical inactivity (2%), diabetes prevalence (6%) and BMI (4%). Overall, improvements in CHD treatments were more beneficial to men whilst better risk factor contribution were higher in women. Advancements in CHD treatments were more beneficial than risk factors in all age groups. These proportions remained relatively consistent across a wide range of assumptions and estimates in a sensitivity analysis except for physical inactivity which has transcended the null line. Conclusion The CHD mortality decline has continued between 2000–2015 of which 90% can be explained by improvements in cardiological treatments and population risk factors with the IMPACT modelling study. However, worsening trends in diabetes prevalence, obesity and physical inactivity have reversed the gains. Investments in improving CHD death determinants and targeted policies are necessary to sustain a further decline in CHD mortality rates in Ireland.

Precision medicine has generated diagnoses for many patients with challenging undiagnosed disorders. Some individuals remain without a diagnosis despite comprehensive testing, and this impedes their treatment. This report addresses the role of personalized medicine in identifying effective therapy for an undiagnosed disease. A 22-year-old woman presented with chronic severe recurrent trismus, facial pain, progressive multicentric inflammatory and fibrotic masses, and high C-reactive protein. Sites of disease included the pterygomaxillary region, masseter muscles, mandible, lung, pericardium, intrabdominal cavity, and retroperitoneum. A diagnosis was not established after an extensive assessment, including multiple biopsies. The patient was subsequently evaluated under the Undiagnosed Diseases Program at the National Institutes of Health. Large scale genotyping, proteomic studies, and in vitro and gene expression analyses of fibroblasts obtained from a major disease locus were performed. Germline genetic testing did not identify strong candidate genes; proteomic studies of the patient's serum and bronchoalveolar lavage fluid and gene expression analyses of her cells were consistent with dysregulation of the tumor necrosis factor-alpha pathway. The patient's cultured fibroblasts were incubated with selected drugs, and cell proliferation was inhibited by hydroxychloroquine. Treatment of the patient with hydroxychloroquine conferred prolonged beneficial clinical effects, including stabilization of trismus and reduction of corticosteroid dose, C-reactive protein, and size of masses. This case represents an example of precision medicine applied to discover effective treatments for individuals with enigmatic undiagnosed disorders.

Survival and growth of trees in high-mountain regions is limited by harsh environmental conditions, and is therefore sensitive to climate change. The main aims of this study were to develop the regional boundary line for high-mountain spruce forests of the Low Tatra Mts., to reconstruct and compare the disturbance regime of investigated localities, and to present the impact of recent climate change on release potential of Norway spruce. The study area included three localities with forest stands dominated by Norway spruce that were selected to represent the altitudinal zone 1200–1500 m a.s.l., excluding the tree line and extreme sites. In order to determine the most important climate characteristics driving tree growth, site chronologies were computed from the sample cores of dominant and co-dominant trees, and correlations between chronologies and monthly climate variables from the previous May to the current September were computed for the period 1901–2008. Analysis of release potential and disturbance histories was performed using the boundary line method. Uniform macro-climate and site conditions in the selected region enabled to construct the regional boundary line for Norway spruce in the Low Tatra. The comparison between boundary lines developed for Norway spruce in the Low Tatra and the other regions showed considerable differences. Therefore, in the high-mountain conditions, the transfer of boundary lines from other regions cannot be recommended. In investigated localities, we identified different disturbance regimes that resulted in variable stand structures and modified the growth responsiveness of Norway spruce to climate. A higher sensitivity to previous October temperature was observed in the most disturbed locality, whereas the growth of Norway spruce on the site with the lowest disturbance rates showed the highest correlation with current June–July temperature. After 1990, we registered enhanced release potential of Norway spruce accompanied by the increase of disturbance rates. Increased release potential was detected even for the trees older than 150 years.

Aim. To identify novel FGFR1 inhibitors using virtual screening approach. Methods. We used methods of organic synthesis, molecular docking via the Autodock 4.2.6 program package and in vitro biochemical tests with γ-32P. Results. In vitro experiments showed that 9 of 23 tested compounds possess inhibitory activity against FGFR1 with IC50 values in the range from 0.9 to 5.6 μM. Conclusions. Nine FGFR1 inhibitors were developed. The mode of compounds binding with the ATP-acceptor site was determined using molecular docking methods and the dependence of the compounds’ activity on the substituents R1, R4 and R5 was evaluated Мета. Пошук нових інгібіторів протеїнкінази FGFR1. Методи. В роботі використовувались методи органічного синтезу, молекулярний докінг програмним пакетом Autodock 4.2.6 та біохімічне тестування in vitro із використанням γ-32P ATФ. Результати. Експерименти in vitro показали, що 9 з 23 сполук проявляють інгібувальну активність щодо FGFR1 зі значенням IC50 в межах від 0.9 до 5.6μМ. Висновки. Було розроблено дев'ять інгібіторів FGFR1. За допомогою методів молекулярного моделювання було визначено спосіб зв'язування із АТФ-акцепторним сайтом та вивченозалежність активності сполук від замісників R1, R4 та R5. Цель. Поиск новых химических соединений со способностью ингибировать протеинкиназу FGFR1. Методы. В работе использовались методы органического синтеза, молекулярного докинга программным пакетом Autodock 4.2.6 и биохимическое тестирование in vitro, используя γ-32P ATФ. Результаты. Биохимическое тестирование показало, что 9 из 23 исследуемых соединений ингибируют протеинкиназу FGFR1 в диапазоне значений IC50 от 0.9 до 5.6 μМ. Выводы. Было разработано девять ингибиторов FGFR1. С помощью молекулярного докинга было определено положение лигандов в АТФ-акцепторном сайте и изучено зависимость активности от структуры заместителей R1, R4 та R5.

En 1818, Bonald publie ses Observations sur l’ouvrage ayant pour titre : Considérations sur les principaux événements de la Révolution française par Mme la baronne de Staël : deux stratégies intellectuelles et deux visions de l’Histoire se font face. Mais sous l’opposition évidente se cache une structure en chiasme, qui tend à créer des effets de convergence puisque les deux auteurs, en prêtant la même acception à certains concepts, accordent une place primordiale à la question morale., In 1818, Bonald published his Observations sur l’ouvrage de Mme la baronne de Staël, ayant pour titre: Considérations sur les principaux événements de la Révolution française: it opposed two intellectual strategies and two visions of History. Yet under the appearance of an opposition, we actually find a structure of chiasmus, tending towards effects of convergence, since the two authors, while sharing the same understanding of certain concepts, both attribute an important place to the moral question.

The high-risk human papillomaviruses (HR-HPVs) are involved in the development of cervical cancer. Nevertheless, there are differences in the oncogenic potential among them. HPV-16 and HPV-18 are associated with approximately 70% of cancer worldwide, and both types are the most extensively studied HR-HPV. Great variations in the prevalence of HR-HPV have been described in different countries. The impact of these variations on the epidemiology of lesions and cervical cancer is currently unknown. A high prevalence of HPV-66 has been detected in Chile. Here, we have analyzed the genetic variability of the L1 gene from HPV-66-infected Chilean women. Higher order interactions between identified mutations were analyzed by co-variation and cluster analyses. Antigenic-index alterations following L1 mutations and B-cell epitopes were predicted by BcePred algorithm. HPV-66 L1 sequences clustered phylogenetically into two main clades. The genetic variability in the HPV-66 L1 gene involved thirty nucleotide changes. Four of these were for the first time identified in this study. Some of these variants are embedded in the B-cell epitope regions. Amino acid homology in the immunodominant epitopes of HPV-66 L1 protein (DE, FG and H1 loops) was 42.9-59.1% and 28.6-68.9% compared with HPV-16 and HPV-18, respectively. The results of this research suggest that the neutralizing epitopes of HPV-66 are antigenically different compared to HPV-16 and HPV-18. Our findings show the need to perform new structural and immunological studies on HPV-66 L1 protein to evaluate the cross-protection conferred by current HPV vaccines.