"Brat naszego Boga". Międzynarodowe Sympozjum Naukowe na zakończenie Roku Adama Chmielowskiego – Świętego Brata Alberta (Klasztor Ojców Bernardynów w Lublinie, 16.12.2017)

"Brat naszego Boga". Międzynarodowe Sympozjum Naukowe na zakończenie Roku Adama Chmielowskiego – Świętego Brata Alberta (Klasztor Ojców Bernardynów w Lublinie, 16.12.2017

Performance of machine-learning scoring functions in structure-based virtual screening

Classical scoring functions have reached a plateau in their performance in virtual screening and binding affinity prediction. Recently, machine-learning scoring functions trained on protein-ligand complexes have shown great promise in small tailored studies. They have also raised controversy, specifically concerning model overfitting and applicability to novel targets. Here we provide a new ready-to-use scoring function (RF-Score-VS) trained on 15 426 active and 893 897 inactive molecules docked to a set of 102 targets. We use the full DUD-E data sets along with three docking tools, five classical and three machine-learning scoring functions for model building and performance assessment. Our results show RF-Score-VS can substantially improve virtual screening performance: RF-Score-VS top 1% provides 55.6% hit rate, whereas that of Vina only 16.2% (for smaller percent the difference is even more encouraging: RF-Score-VS top 0.1% achieves 88.6% hit rate for 27.5% using Vina). In addition, RF-Score-VS provides much better prediction of measured binding affinity than Vina (Pearson correlation of 0.56 and -0.18, respectively). Lastly, we test RF-Score-VS on an independent test set from the DEKOIS benchmark and observed comparable results. We provide full data sets to facilitate further research in this area (http://github.com/oddt/rfscorevs) as well as ready-to-use RF-Score-VS (http://github.com/oddt/rfscorevs_binary)

Tools4miRs – one place to gather all the tools for miRNA analysis

MiRNAs are short, non-coding molecules that negatively regulate gene expression and thereby play several important roles in living organisms. Dozens of computational methods for miRNA-related research have been developed, which greatly differ in various aspects. The substantial availability of difficult-to-compare approaches makes it challenging for the user to select a proper tool and prompts the need for a solution that will collect and categorize all the methods. Here, we present tools4miRs, the first platform that gathers currently more than 160 methods for broadly defined miRNA analysis. The collected tools are classified into several general and more detailed categories in which the users can additionally filter the available methods according to their specific research needs, capabilities and preferences. Tools4miRs is also a web-based target prediction meta-server that incorporates user-designated target prediction methods into the analysis of user-provided data

Development of carbohydrate disturbances after pregnancy complicated by gestational diabetes mellitus

Cukrzyca ciążowa (GDM, gestational diabetes mellitus) to zaburzenie tolerancji glukozy, które po raz pierwszy wystąpiło lub zostało rozpoznane w czasie ciąży. W populacji europejskiej częstość GDM określa się jako 2–6% wszystkich ciąż. W badaniach przeprowadzonych w różnych regionach Polski częstość GDM wynosiła 3,4%. U kobiet, u których w czasie ciąży ujawniła się GDM, ryzyko rozwoju cukrzycy, zwłaszcza cukrzycy typu 2, jest znacząco wyższe. Częstość rozwoju różnego stopnia zaburzeń tolerancji glukozy 12 lat po porodzie w regionie Gdańska wynosiła 53,1%. Określono czynniki ryzyka rozwoju cukrzycy typu 2 po ciąży powikłanej GDM.Gestational diabetes mellitus (GDM) is any degree of glucose intolerance with onset or first recognition during pregnancy. In European population the prevalence of GDM may range from 2% to 6% of all pregnancies. The mean prevalence of GDM in difference difference regions in Poland has been estimated on 3.4%. Women with GDM are at in significant increased risk for the development of diabetes, usually type 2, after pregnancy. The prevalence of different types of carbohydrate disturbances in district Gdansk during 12 years after pregnancy complicated by GDM was 53.1%. The risk factors of diabetes type 2 after pregnancy have been indicated

The impact of noradrenergic neurotoxin DSP-4 and noradrenaline transporter knockout (NET-KO) on the activity of liver cytochrome P450 3A (CYP3A) in male and female mice

Background Our earlier studies have shown that the brain noradrenergic system regulates cytochrome P450 (CYP) in rat liver via neuroendocrine mechanism. In the present work, a comparative study on the effect of intraperitoneal administration of the noradrenergic neurotoxin DSP-4 and the knockout of noradrenaline transporter (NET-KO) on the CYP3A in the liver of male and female mice was performed. Methods The experiments were conducted on C57BL/6J WT and $NET^{–/–}$ male/female mice. DSP-4 was injected intraperitoneally as a single dose (50 mg/kg ip.) to WT mice. The activity of CYP3A was measured as the rate of 6β-hydroxylation of testosterone in liver microsomes. The CYP3A protein level was estimated by Western blotting. Results DSP-4 evoked a selective decrease in the noradrenaline level in the brain of male and female mice. At the same time, DSP-4 reduced the CYP3A activity in males, but not in females. The level of CYP3A protein was not changed. The NET knockout did not affect the CYP3A activity/protein in both sexes. Conclusions The results with DSP-4 treated mice showed sex-dependent differences in the regulation of liver CYP3A by the brain noradrenergic system (with only males being responsive), and revealed that the NET knockout did not affect CYP3A in both sexes. Further studies into the hypothalamic–pituitary–gonadal hormones in DSP-4 treated mice may explain sex-specific differences in CYP3A regulation, whereas investigation of monoaminergic receptor sensitivity in the hypothalamic/pituitary areas of $NET^{–/–}$ mice will allow for understanding a lack of changes in the CYP3A activity in the NET-KO animals

Diurnal Blood Pressure Profile in Premenopausal Women with Disturbed Androgen Secretion

Wstęp Nieprawidłowe wydzielanie androgenów u kobiet z zaburzeniami owulacji w wieku przedmenopauzalnym jest znane już od bardzo wielu lat. W ostatnim okresie jednak coraz więcej uwagi poświęca się ocenie wpływu zwiększonego wydzielania męskich hormonów płciowych u kobiet na rozwój zaburzeń metabolicznych oraz chorób układu sercowo-naczyniowego.Nadal jednak w pełni nie oceniono ryzyka rozwoju powikłań sercowo-naczyniowych u kobiet z hiperandrogenizmem w okresie przedmenopauzalnym.Celem niniejszej pracy jest ocena dobowego profilu ciśnienia tętniczego krwi skurczowego (SBP),rozkurczowego (DBP)oraz częstotliwości serca (HR)u kobiet z zaburzonym wydzielaniem androgenów w wieku przedmenopauzalnym. Materiał i metody Badanie przeprowadzono w grupie 33 pacjentek leczonych z powodu zespołu policystycznych jajników z towarzyszącym zwiększonym stężeniem androgenów w surowicy krwi i metabolitów końcowych androgenów.Grupę kontrolną stanowiły 22 kobiety w wieku przedmenopauzalnym. W obu grupach wykonano 24-godzinną rejestrację SBP i DBP oraz HR. Wyniki Średnie dobowe SBP w grupie pacjentek z hiperandrogenizmem było znamiennie wyższe niż w grupie kontrolnej (123 ±11 mm Hg vs.115 ±8 mm Hg, pBackground Disturbed androgen secretion in premenopausal women with ovulation disturbances is well known for a very long time.Recently numerous studies on plasma male sex hormones in women in relation to coronary heart disease and hypertension have been performed.But still we have little knowledge about risk for coronary heart disease and atherosclerosis in hyperandrogenic women in premenopausal age.The aim of our study was to analyze 24 hour systolic (SBP),diastolic (DBP),day and night blood pressure and heart rate (HR)in premenopausal women with diagnosed disturbed androgen secretion.The study was performed in 33 premenopausal women treated because of polycystic ovary syndrome. Material and methods Control group consisted of 22 women with no fertility problems which were admitted to outpatient clinic for prophylactic examination.Mean 24 hour, day and night blood pressure performed by means of SpaceLabs 90207 monitor were statistically analyzed. Results Mean 24 hour SBP in hyperandrogenic women was significantly higher in comparison to control group (123 ±11 mm Hg vs.115 ±8 mm Hg).Mean day and night SBP were also significantly higher in women with hyper- androgenism (day 126 ±12 mm Hg vs.120 ±9 mm Hg, night 118 ±11 mm Hg vs.109 ±9 mm Hg).There was no significant differences in 24 hour,day and night DBP, and in 24 hour and day HR.Night heart rate was signifi- cantly higher in hyperandrogenic women than in control group (75 ±9 bpm vs.70 ±5 bpm).Double product (HR Ą SBP)was significantly higher in women with hy- perandrogenism (9731 ±1197 mm Hg/min vs.7686 ± ±3115 mm Hg/min,

The Association between Ambulatory Blood Pressure and Fasting Insulin and Glucose Plasma Levels in Normotensive Premenopausal Women

Podwyższone stężenia glukozy i insuliny w osoczu krwi są związane ze zwiększonym ryzykiem wystąpienia nadciśnienia tętniczego i choroby wieńcowej. Niewiele jest doniesień na temat związku insulinemii i glikemii na czczo z ciśnieniem tętniczym krwi u kobiet z prawidłowymi wartościami ciśnienia tętniczego w wieku przedmenopauzalnym. Celem pracy była ocena wpływu stężenia insuliny i glukozy na czczo na profil dobowy ciśnienia tętniczego u kobiet z prawidłowym ciśnieniem w wieku przedmenopauzalnym. Materiał i metody Badanie wykonano w grupie 88 kobiet (średni wiek 46 &plusmn; 4 lata) bez nadciśnienia tętniczego w wywiadzie, wśród których były 22 kobiety zdrowe, 33 pacjentki z zespołem policystycznych jajników, a 33 wykazywały zaburzenia sekrecji estrogenów. U wszystkich badanych wykonano 24-godzinne monitorowanie ciśnienia tętniczego skurczowego i rozkurczowego (SBP i DBP). Wyniki Wykazano istotną korelację między stężeniem insuliny na czczo a średnim dobowym skurczowym i rozkurczowym ciśnieniem tętniczym. Współczynniki korelacji wynosiły odpowiednio r = 0,41, p < 0,001 i r = 0,33, p < 0,002. Glikemia na czczo znamiennie korelowała ze średnim ciśnieniem skurczowym (r = 0,28, p < 0,01). Nie było istotnego związku glikemii z ciśnieniem rozkurczowym. Stężenie insuliny na czczo było statystycznie znamiennie związane zarówno z ciśnieniem skurczowym w ciągu dnia i w nocy (współczynniki korelacji wynosiły odpowiednio r = 0,36, p < 0,001 i r = 0,42, p < 0,001), jak i ze średnim ciśnieniem rozkurczowym w ciągu dnia i w nocy (odpowiednio: r = 0,28, p < 0,01 i r = 0,32, p < 0,002). W badanej grupie zaobserwowano ponadto istotną korelację między nocną częstotliwością akcji serca a glikemią i insulinemią na czczo (odpowiednio: r = 0,29, p < 0,005 i r = 0,37, p < 0,001). Wniosek Stężenie insuliny w osoczu na czczo jest związane ze średnim dobowym, a także dziennym i nocnym ciśnieniem tętniczym krwi skurczowym i rozkurczowym u kobiet z prawidłowym ciśnieniem w wieku przedmenopauzalnym. Wzrost stężenia insuliny na czczo u kobiet z prawidłowymi wartościami ciśnienia w wieku przedmenopauzalnym może być czynnikiem ryzyka wystąpienia nadciśnienia tętniczego.Background Elevated plasma glucose and insulin levels are associated with increased risk of hypertension and coronary heart disease. However there are very few reports on the relation between fasting insulin and glucose and blood pressure profile in normotensive premenopausal women. The aim of our study was to assess the influence of fasting plasma glucose and insulin level on 24-h systolic (SBP) and diastolic (DBP) blood pressure in normotensive premenopausal women. Material and methods The study was performed in 88 premenopausal women, mean age 46 &plusmn; 4 years (22 women with normal hormone profile, 33 women with hiperandrogenism and 33 women with disturbed estrogen secretion). Mean 24 hour, day and night blood pressure and heart rate recorded by Spacelabs 90207 were analysed. Results There was a significant correlation between fasting serum insulin level and 24-h SBP (r = 0,41, p < 0,001) and 24-h DBP (r = 0,33, p < 0,002). Fasting plasma glucose significantly correlated with 24-h SBP (r = 0,28, p < 0,01) but not with 24-h DBP. Similarly fasting insulin correlated significantly with day and night SBP (r = 0,36, p < 0,001 and r = 0,42, p < 0,001 respectively). Fasting insulin correlated significantly with day and night DBP (r = 0,28, p < 0,01 and r = 0,32, p < 0,002 respectively). In the study group we observed significant correlation between mean night heart rate and fasting plasma glucose and insulin (r = 0,29, p < 0,005 and r = 0,37, p < 0,001 respectively). Conclusions Our study revealed that fasting insulin level is significantly related to 24-h, day and night systolic and diastolic blood pressure in normotensive premenopausal women

Unveiling the Molecular Mechanism of SARS-CoV-2 Main Protease Inhibition from 137 Crystal Structures Using Algebraic Topology and Deep Learning

Currently, there is neither effective antiviral drugs nor vaccine for coronavirus disease 2019 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to its high conservativeness and low similarity with human genes, SARS-CoV-2 main protease (Mpro) is one of the most favorable drug targets. However, the current understanding of the molecular mechanism of Mpro inhibition is limited by the lack of reliable binding affinity ranking and prediction of existing structures of Mpro-inhibitor complexes. This work integrates mathematics (i.e., algebraic topology) and deep learning (MathDL) to provide a reliable ranking of the binding affinities of 137 SARS-CoV-2 Mpro inhibitor structures. We reveal that Gly143 residue in Mpro is the most attractive site to form hydrogen bonds, followed by Glu166, Cys145, and His163. We also identify 71 targeted covalent bonding inhibitors. MathDL was validated on the PDBbind v2016 core set benchmark and a carefully curated SARS-CoV-2 inhibitor dataset to ensure the reliability of the present binding affinity prediction. The present binding affinity ranking, interaction analysis, and fragment decomposition offer a foundation for future drug discovery efforts