Different examples of the application of quantum mechanical (QM) methods combined with experimental approaches, such as NMR spectroscopy and electronic circular dichroism (ECD), are reported to ...highlight their successful application in the determination of the stereochemical arrangement of organic compounds. A first part is dedicated to various examples and methodological studies based on the comparison of experimental NMR parameters (13C and 1H NMR chemical shifts, homonuclear and heteronuclear J coupling constants) and their related values calculated at the QM theory level, with particular applications in the assignment of the relative configuration of organic compounds. A final section is focused on the determination of the absolute configuration by the comparison of experimental and predicted NMR parameters and ECD spectra.
Different applications of the QM/NMR combined approach are described regarding the elucidation of the relative and absolute configurations of organic compounds. The advantage in comparing experimental NMR parameters (13C and 1H NMR chemical shifts, homonuclear and heteronuclear J coupling constants) and ECD spectra and their related counterparts calculated at the QM theory level is also discussed.
Quantum mechanical/nuclear magnetic resonance (NMR) approaches are widely used for the configuration assignment of organic compounds generally comparing one cluster of experimentally determined data ...(e.g., 13C NMR chemical shifts) with those predicted for all possible theoretical stereoisomers. More than one set of experimental data, each related to a specific stereoisomer, may occur in some cases, and the accurate stereoassignments can be obtained by combining the experimental and computed data. We introduce here a straightforward methodology based on the simultaneous analysis, combination, and comparison of all sets of experimental/calculated 13C chemical shifts for aiding the correct configuration assignment of groups of stereoisomers. The comparison of the differences between the calculated/experimental chemical shifts instead of the shifts themselves led to the advantage of avoiding errors arising from calibration procedures, reducing systematic errors, and highlighting the most diagnostic differences between calculated and experimental data. This methodology was applied on a tetrad of synthesized cladosporin stereoisomers (cladologs) and further corroborated on a tetrad of pochonicine stereoisomers, obtaining the correct correspondences between experimental and calculated sets of data. The new MAEΔΔδ parameter, useful for indicating the best fit between sets of experimental and calculated data, is here introduced for facilitating the stereochemical assignment of groups of stereoisomers.
The estimation of the binding of a set of molecules against BRD9 protein was carried out through an in silico molecular dynamics-driven exhaustive analysis to guide the identification of potential ...novel ligands. Starting from eight crystal structures of this protein co-complexed with known binders and one
form, we conducted an exhaustive molecular docking/molecular dynamics (MD) investigation. To balance accuracy and an affordable calculation time, the systems were simulated for 100 ns in explicit solvent. Moreover, one complex was simulated for 1 µs to assess the influence of simulation time on the results. A set of MD-derived parameters was computed and compared with molecular docking-derived and experimental data. MM-GBSA and the per-residue interaction energy emerged as the main indicators for the good interaction between the specific binder and the protein counterpart. To assess the performance of the proposed analysis workflow, we tested six molecules featuring different binding affinities for BRD9, obtaining promising outcomes. Further insights were reported to highlight the influence of the starting structure on the molecular dynamics simulations evolution. The data confirmed that a ranking of BRD9 binders using key parameters arising from molecular dynamics is advisable to discard poor ligands before moving on with the synthesis and the biological tests.
GP-BAR1, a member G protein coupled receptor superfamily, is a cell surface bile acid-activated receptor highly expressed in the ileum and colon. In monocytes, ligation of GP-BAR1 by secondary bile ...acids results in a cAMP-dependent attenuation of cytokine generation.
To investigate the role GP-BAR1 in regulating intestinal homeostasis and inflammation-driven immune dysfunction in rodent models of colitis.
Colitis was induced in wild type and GP-BAR1(-/-) mice by DSS and TNBS administration. Potential GP-BAR1 agonists were identified by in silico screening and computational docking studies.
GP-BAR1(-/-) mice develop an abnormal morphology of colonic mucous cells and an altered molecular architecture of epithelial tight junctions with increased expression and abnormal subcellular distribution of zonulin 1 resulting in increased intestinal permeability and susceptibility to develop severe colitis in response to DSS at early stage of life. By in silico screening and docking studies we identified ciprofloxacin as a GP-BAR1 ligand. In monocytes, ciprofloxacin increases cAMP concentrations and attenuates TNFα release induced by TLR4 ligation in a GP-BAR1 dependent manner. Treating mice rendered colitic by TNBS with ciprofloxacin and oleanolic acid, a well characterized GP-BAR1 ligand, abrogates signs and symptoms of colitis. Colonic expression of GP-BAR1 mRNA increases in rodent models of colitis and tissues from Crohn's disease patients. Flow cytometry analysis demonstrates that ≈90% of CD14+ cells isolated from the lamina propria of TNBS-treated mice stained positively for GP-BAR1.
GP-BAR1 regulates intestinal barrier structure. Its expression increases in rodent models of colitis and Crohn's disease. Ciprofloxacin is a GP-BAR1 ligand.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate an MRI radiomics-powered machine learning (ML) model's performance for the identification of deep myometrial invasion (DMI) in endometrial cancer (EC) patients and explore its clinical ...applicability.
Preoperative MRI scans of EC patients were retrospectively selected. Three radiologists performed whole-lesion segmentation on T2-weighted images for feature extraction. Feature robustness was tested before randomly splitting the population in training and test sets (80/20% proportion). A multistep feature selection was applied to the first, excluding noninformative, low variance features and redundant, highly-intercorrelated ones. A Random Forest wrapper was used to identify the most informative among the remaining. An ensemble of J48 decision trees was tuned and finalized in the training set using 10-fold cross-validation, and then assessed on the test set. A radiologist evaluated all MRI scans without and with the aid of ML to detect the presence of DMI. McNemars's test was employed to compare the two readings.
Of the 54 patients included, 17 had DMI. In all, 1132 features were extracted. After feature selection, the Random Forest wrapper identified the three most informative which were used for ML training. The classifier reached an accuracy of 86% and 91% and areas under the Receiver Operating Characteristic curve of 0.92 and 0.94 in the cross-validation and final testing, respectively. The radiologist performance increased from 82% to 100% when using ML (p = 0.48).
We proved the feasibility of a radiomics-powered ML model for DMI detection on MR T2-w images that might help radiologists to increase their performance.
The scientific community has been re-evaluating the clinical relevance of hysteroscopy in the diagnosis and treatment of uterine factors and its role in the infertility work-up, thanks to its ...potential capability to improve reproductive outcomes and reduce time to pregnancy.
The objective of this systematic review and meta-analysis was to assess the efficacy of diagnostic and operative hysteroscopy in improving the live birth rate (LBR) of infertile women, with and without intrauterine abnormalities, at any stage of the infertility work-up.
PubMed, Embase, the Cochrane Library and the Clinical Trials Registry using Medical Subject Headings and free text terms were searched up to June 2014, without language or year restrictions. Randomized controlled trials (RCTs) enrolling infertile women with no suspected intrauterine cavity abnormalities and comparing hysteroscopy versus no hysteroscopy at any stage of the diagnostic work-up, but prior to the first attempt of standard IVF or ICSI or after (one or more) failed attempts of IVF/ICSI were included. RCTs enrolling infertile women with intrauterine abnormalities and comparing operative versus diagnostic hysteroscopy were also included. Risk of bias was assessed using the criteria recommended by the Cochrane Collaboration and the overall quality of evidence was assessed using the GRADE approach. Results were pooled by meta-analysis using the random effect model.
The primary outcome evaluated was the LBR, while secondary outcomes were pregnancy rate, miscarriage rate and procedure-related complications. Five hundred and eighty-eight records were retrieved after removing duplicates. Nine studies were included, with 2976 participants. Four studies included infertile women with one or more failed IVF/ICSI cycles. Two studies included infertile women who were candidates for their first IVF/ICSI. One study included candidates both for first IVF/ICSI and with one or more failed IVF/ICSI cycles. Two studies included infertile women affected by uterine fibroids and endometrial polyps, who had not received IVF/ICSI nor were candidates. Seven studies were included in the meta-analysis. Comparing hysteroscopy with no hysteroscopy prior to any (first or subsequent) IVF/ICSI attempt in infertile women without intrauterine abnormalities, there was very low-quality evidence that hysteroscopy increased LBR (relative risk (RR) 1.48, 95% confidence interval (CI) 1.20-1.81; three studies with 1088 participants) and moderate quality evidence that it increased pregnancy rate (RR 1.45, 95% CI 1.26-1.67; seven studies, 2545 participants). Results on pregnancy rate were confirmed in the subgroup analysis of five studies including only women with one or more implantation failures (RR 1.41, 95% CI 1.14-1.75) and three studies where hysteroscopy was performed before the first IVF/ICSI attempt (RR 1.55, 95% CI 1.26-1.91). Comparing operative hysteroscopy for intrauterine abnormalities in infertile women with already diagnosed polyps or fibroids, there was low-quality evidence that operative hysteroscopy increases pregnancy rate (RR 2.13, 95% CI 1.56-2.92). None of the studies comparing operative versus diagnostic hysteroscopy assessed LBR.
Robust and high-quality RCTs are still needed before hysteroscopy can be regarded as a first-line procedure in all infertile women, especially during the basal clinical assessment of the couple, when assisted reproductive treatment is not indicated yet.
hard shells, green leafy involucres, leaves, and male flowers have shown to be a source of diarylheptanoids, a class of natural products with promising biological activities. Cyclic diarylheptanoids, ...named giffonins, were isolated from the Italian cultivar "Tonda di Giffoni." Even if many efforts have been made to establish the chemistry of these compounds, little is known about their biological properties. Herein, the inhibitory effects of diarylheptanoids isolated from
byproducts against α-glucosidase enzyme were evaluated. Molecular docking experiments disclosed the establishment of several key interactions between all the screened diarylheptanoids and the protein counterpart, whose model was built through homology modeling procedure, thus rationalizing the detected inhibitory activities. Specifically, the most active compounds giffonin J (
), K (
), and P (
) were able to make both H-bonds and π-π stacking contacts with different residues belonging to the binding site responsible for the catalytic activity of the investigated enzyme. To highlight the occurrence of the bioactive diarylheptanoids in the extracts of
byproducts obtained by eco-friendly extractions, their LC-MS profiles were analyzed. LC-MS analysis showed how giffonin J (
), K (
), and P (
) occurred in the ethanol extract of the leaves, while in the extracts of shells and green leafy involucres only giffonin P (
) was evident. Moreover, the quantitative analysis of giffonin J (
), K (
), and P (
) in
byproducts was carried out by an analytical approach based on LC-ESI/QTrap/MS, using the Multiple Reaction Monitoring (MRM) experiment. These results prompt to evaluate
byproducts, especially the leaves, as a prospective source of bioactive diarylheptanoids for the development of functional ingredients for the treatment of diabetes.
Introduction: Endometriosis is a gynecological disease with a severe impact on quality of life. The aim of this study is to assess mental health status in a group of women with endometriosis, ...investigating their clinical history, pain symptoms and systemic comorbidities.
Methods: An observational cross-sectional study was performed on a group of Italian Caucasian women with endometriosis (n = 134). All patients filled the 'Patient Health Questionnaire' (PHQ), a self-administered screening tool for mental health disorders. The characteristics of endometriosis, pain symptoms and their severity, the presence and types of comorbid systemic disorders were added into the same survey.
Results: According to PHQ algorithms, 59% of patients were affected by at least one psychiatric disorder, with a significant correlation with pain symptoms (p = 0.0026). Patients with severe pain showed a higher incidence of multiple psychiatric disorders (p = 0.026) and somatoform disorder than those with mild pain (p = 0.0009). There was no correlation between the presence of psychiatric disorders and age, BMI, parity, infertility, need for surgery, number of intervention, localization of endometriotic lesions and systemic comorbidities.
Discussion: Women with endometriosis showed a high frequency of PHQ results positive for psychiatric disorders, with a significant association with pain severity.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The recent release of the main protein structures belonging to SARS CoV-2, responsible for the coronavirus disease-19 (COVID-19), strongly pushed for identifying valuable drug treatments. With this ...aim, we show a repurposing study on FDA-approved drugs applying a new computational protocol and introducing a novel parameter called IVS
ratio
. Starting with a virtual screening against three SARS CoV-2 targets (main protease, papain-like protease, spike protein), the top-ranked molecules were reassessed combining the Inverse Virtual Screening novel approach and MM-GBSA calculations. Applying this protocol, a list of drugs was identified against the three investigated targets. Also, the top-ranked selected compounds on each target (rutin
vs.
main protease, velpatasvir
vs.
papain-like protease, lomitapide
vs.
spike protein) were further tested with molecular dynamics simulations to confirm the promising binding modes, obtaining encouraging results such as high stability of the complex during the simulation and a good protein-ligand interaction network involving some important residues of each target. Moreover, the recent outcomes highlighting the inhibitory activity of quercetin, a natural compound strictly related to rutin, on the SARS-CoV-2 main protease, strengthened the applicability of the proposed workflow.
New computational protocol applied to a repurposing campaign against SARS-CoV-2.
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