A comparative study on the application of hierarchical-agglomerative clustering approaches to organize outputs of reiterated docking runs

Reiterated runs of standard docking protocols usually provide a collection of possible binding modes rather than pinpoint a single solution. Usually, this ensemble is then ranked by means of an energy-based scoring function. However, since many degrees of approximation have to be introduced in the computation of the binding free energy, scoring functions cannot always rank the experimental pose among the top scorers. Cluster analysis might help to overcome this limit, provided that data clusterability has been earlier assessed. In this paper, first, we present a modified version of a test earlier developed by Hopkins to assess whether or not docking outputs show the natural tendency to be grouped in clusters. Then, we report the results of a comparative study on the application of different hierarchical-agglomerative cluster rules to partition docking outputs. The rule that was able to best manage the observed data was finally applied to the whole ensemble of poses collected from several docking tools. The combination of the average linkage rule with the cutting function developed by Sutcliffe and co-workers turned out to be an approach that meets all of the criteria required for a robust clustering protocol. Furthermore, a consensus clustering allowed us to identify the pose closest to the experimental one within a statistically significant cluster, whose number was always of few units.     

Diffusion-weighted MRI in the characterization of cystic pancreatic lesions: usefulness of ADC values

Purpose

To evaluate the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI) in the differentiation of cystic pancreatic lesions.

Materials and Methods

Institutional review board approval was obtained, and written informed consent was taken from all enrolled subjects. Fifty-four patients with cystic pancreatic lesions of at least 1 cm in diameter (range:10–96 mm) at ultrasonography and/or computed tomography and 10 normal subjects underwent MRI at 1.5 T. These subjects included thirty-four patients with intraductal papillary mucinous tumors (IPMTs), 10 with pseudocysts, 5 with serous cystoadenoma and 5 with mucinous cystoadenoma. The MR protocol included axial T1w and T2w sequences and coronal MR cholangiopancreatography images. DW-MRI was performed using a breath-hold single-shot echo-planar sequence with a b gradient factor value of 500 s/mm² in the three orthogonal axes. Apparent diffusion coefficient (ADC) was calculated for cerebrospinal fluid, normal pancreatic parenchyma, and for each focal pancreatic lesion. Imaging results were correlated with endoscopic retrograde cholangiopancreatography, endoscopic ultrasound-guided fine needle aspiration, surgery and/or imaging follow-up.

Results

Mean ADC value was 4.1×10⁻³ mm²/s for cerebrospinal fluid, 1.73×10⁻³ mm²/s for normal pancreatic parenchyma, 4.09×10⁻³ mm²/s for IPMT, 3.89×10⁻³ mm²/s for mucinous cystoadenoma, 3.65×10⁻³ mm²/s for serous cystoadenoma and 2.83×10⁻³ mm²/s for pseudocyst. Mean ADC values of each of the different types of pancreatic lesions were statistically different (P<.05).

Conclusion

DW-MRI may be helpful in the differential diagnosis of cystic pancreatic lesions.     

Luminescence properties of Ba2NaNb5O15 crystals activated with Sm, Eu, Tb or Dy ions

Single crystals of Ba₂NaNb₅O₁₅ (BNN) singly doped with Sm³⁺, Eu³⁺, Tb³⁺ or Dy³⁺ have been grown by means of the flux growth method. Their visible emission and excitation spectra and the decay profiles of the luminescence have been measured at room temperature. All spectral features are significantly inhomogeneously broadened in consequence of the structural disorder of the host and of the doping mechanisms. The analysis of the observed spectra allows formulating an hypothesis about the site occupancy of the active ions in the BNN lattice.     

Unravelling the Phytochemical Composition and the Pharmacological Properties of an Optimized Extract from the Fruit from Prunus mahaleb L.: From Traditional Liqueur Market to the Pharmacy Shelf

Prunus mahaleb L. fruit has long been used in the production of traditional liqueurs. The fruit also displayed scavenging and reducing activity, in vitro. The present study focused on unravelling peripheral and central protective effects, antimicrobial but also anti-COVID-19 properties exerted by the water extract of P. mahaleb. Anti-inflammatory effects were studied in isolated mouse colons exposed to lipopolysaccharide. Neuroprotection, measured as a blunting effect on hydrogen-peroxide-induced dopamine turnover, was investigated in hypothalamic HypoE22 cells. Antimicrobial effects were tested against different Gram+ and Gram- bacterial strains. Whereas anti-COVID-19 activity was studied in lung adenocarcinoma H1299 cells, where the gene expression of ACE2 and TMPRSS2 was measured after extract treatment. The bacteriostatic effects induced on Gram+ and Gram- strains, together with the inhibition of COX-2, TNFα, HIF1α, and VEGFA in the colon, suggest the potential of P. mahaleb water extract in contrasting the clinical symptoms related to ulcerative colitis. The inhibition of the hydrogen peroxide-induced DOPAC/DA ratio indicates promising neuroprotective effects. Finally, the downregulation of the gene expression of ACE2 and TMPRSS2 in H1299 cells, suggests the potential to inhibit SARS-CoV-2 virus entry in the human host. Overall, the results support the valorization of the local cultivation of P. mahaleb.     

Palladium complexes of 8-(di-tert-butylphosphinooxy) quinoline

The preparation of the new ligand 8-(di-tert-butylphosphinooxy)quinoline (1) and the palladium derivatives [PdCl₂(1)] (2), [Pd(η³-all)(1)]⁺ [all = C₃H₅ (3a), 1-PhC₃H₄ (3b) and 1,3-Ph₂C₃H₃ (3c)] and [Pd(η²-ol)(1)] [ol = dimethyl fumarate (4a) and fumaronitrile (4b)] is reported. The cationic species 3a-3c have been isolated as salts. The complex 3a(BF₄) is obtained either from the reaction of 1 with [Pd(μ-Cl)(η³-C₃H₅)]₂ or from the reaction of ClP(CMe₃)₂ with [Pd(η³-C₃H₅)(8-oxyquinoline)], followed in both cases by chloride abstraction with NaBF₄. In the complexes, the ligand 1 is P,N chelated to the central metal, as shown by the X-ray structural analysis of 3a(BF₄). At 25 °C in solution, 3a(BF₄) and 3b(BF₄) undergo a fast η³−η¹−η³ dynamic process which brings about a syn-anti exchange only for the allylic protons cis to phosphorus, while for 4a and 4b a slow rotation of the olefin around its bond axis to palladium takes place. The complexes 2 and 3a(BF₄) are efficient catalyst precursors in the coupling of the phenylboronic acid with aryl bromides and chlorides.     

Exact state-to-state quantum dynamics of the F + HD --> HF(v' = 2) + D reaction on model potential energy surfaces

In this paper, we present the results of a theoretical investigation on the dynamics of the title reaction at collision energies below 1.2 kcal/mol using rigorous quantum reactive scattering calculations. Vibrationally resolved integral and differential cross sections, as well as product rotational distributions, have been calculated using two electronically adiabatic potential energy surfaces, developed by us on the basis of semiempirical modifications of the entrance channel. In particular, we focus our attention on the role of the exothermicity and of the exit channel region of the interaction on the experimental observables. From the comparison between the theoretical results, insight about the main mechanisms governing the reaction is extracted, especially regarding the bimodal structure of the HF(v = 2) nascent rotational state distributions. A good overall agreement with molecular beam scattering experiments has been obtained.     

Preclinical pharmacokinetics comparison between resveratrol 2-hydroxypropyl-β-cyclodextrin complex and resveratrol suspension after oral administration

Trans-Resveratrol (RV) is a natural polyphenol characterized by interesting pleiotropic potentials and health benefits, but its administration is hampered by a unsatisfactory pharmacokinetics. Various approaches have been identified to circumvent it: among them, 2-hydroxypropyl-β-cyclodextrins (HPβCD) are valuable strategy. Here, we compare the employment of HPβCD based formulation with a resveratrol nanosupension (obtained by diluting a RV ethanol solution with PBS, added of 0.05 % hydroxyethylcellulose) to improve RV bioavailability after oral administration to mice. The inclusion of RV in HPβCD was confirmed by differential scanning calorimetry, Fourier transformed infrared spectroscopy, and phase solubility study. The two formulations were orally administered to BALB-c mice. RV concentrations in plasma and tissues were detected at different time (0–120 min) by HPLC method. HPβCD complexation mediate a approximately fourfold increment in plasma RV C_max and  approximately twofold augment of RV AUC_0-120 in comparison with RV nanosuspension. Similar increased concentrations were observed in heart, liver, kidney and gut. In particular, HPβCD mediated a 5.5-folds increase of resveratrol concentration in the intestine, in comparison to the nanosuspension. In conclusion, based on our results, HPβCD complexation is a promising approach to increase the oral bioavailability of RV. Moreover, the achievement of high concentrations in gut suggested a potential employment of oral RV-HPβCD as anti-inflammatory/chemopreventive agent in this tissue.     

Diplophonia reappraised

The acoustic structure of diplophonia was investigated spectrographically and in terms of perturbation measures, while the perception of diplophonia among other voice qualities was confirmed auditorily by trained listeners. Recordings of pathological voices were presented to listeners for systematic evaluation, and narrowband spectrography was used to quantify the subharmonics within each sample. Subharmonics strongly correlated with the perception of diplophonia, but occurrence was mostly intermittent, and structure was highly variable between samples. Uniquely among voice qualities identified perceptually, diplophonia was found to correlate positively with the number of subharmonics (irrespective of percentage of occurrence) and with perturbation parameters measured separately. Exceptions to these group results indicated that diplophonia was perceived sometimes in the absence of subharmonic structure, and subharmonic structure was observed without a commensurate perception of diplophonia. In light of these data, a less deterministic relation between diplophonia and subharmonic structure is proposed.