Potent and novel 11β-HSD1 inhibitors identified from shape and docking based virtual screening

Several potent and novel 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors were discovered from in silico screening the commercially available Maybridge database. Among them, seven hit compounds showed good affinity, with IC(50) values lower than 100 nM and the best one 3.7 nM. To select the lead for further optimization, computational ADME/T prediction, the CYP3A4 inhibition and 11β-HSD1 over 11β-HSD2 selectivity test were also performed. Taking all of the above factors into consideration, two promising compounds were selected as lead structures for further development. The employed hierarchical virtual screening protocol not only demonstrates its efficiency, but also provides novel and selective compounds for developing 11β-HSD1 inhibitors to protect against metabolic syndrome.     

Laser tweezers as a biophotonic tool to investigate the efficacy of living sickle red blood cells in response to optical deformation

A laser tweezer technique based on single and/or dual-laser beams is proposed as a biophotonic tool to trap single cells and investigate their biophysical and biomechanical characteristics. Optical deformability and changes in size and cellular morphology of living and nonliving cells can be measured using the proposed technique. Representative results of red blood cell (RBC) optical deformability of 20 homozygous patients with sickle cell disease, including follow-up patients after treating with hydroxyurea (HU) for at least 3 months and 20 healthy control groups, are presented and compared. Shape recovery of deformed RBCs and relaxation time are recorded for each RBC. Results showed that healthy blood and patients treated with HU demonstrate significantly higher optical deformability and degree of optical elongation with morphological change of RBCs than untreated patients. Moreover, the healthy control group and patients treated with HU exhibited faster relaxation time for RBCs than untreated patients. A trapping power that reaches 180 mW caused no observable photo-damage at a wavelength 1064 nm.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12551-021-00790-0.     

Helical growth and the curved shape of Vibrio cholerae

The curved, comma, or bent shape of Vibrio cholerae is attributed to, and explained by, the normal helical growth of the cell. The comma-like shape of V. cholerae is not due to an asymmetrical positioning of peptidoglycan such that some chains of peptidoglycan are placed so they are more spread out on one side of the cell and squeezed together on the other side.     

Ecological and functional correlates of molar shape variation in European populations of Arvicola (Arvicolinae, Rodentia)

Lower first molar shape in Arvicola spp. at European level has been studied by means of Geometric Morphometrics. We took into account bioclimatic variables, size, lifestyle and phylogenetic relationships. We used Partial Least Squares and Phylogenetic Independent Contrasts in order to assess which factor affects the most molar shape morphology.Once the phylogenetic history was taken into account, climate resulted the most influencing factor in explaining molar morphology, followed by size. Molar shape is not related to lifestyle. Molar shape and size, even if different among species, are not phylogenetically structured. On the opposite, lifestyle depends on the phylogeny, and size and lifestyle are significantly related even considering phylogenetic relationships. Fossorial forms are significantly smaller than semi-aquatic ones, suggesting that they are less subjected to predator pressure of semi-aquatic species and that the two lifestyles are characterized by different allometric patterns.     

La and Gd induce shape change of giant unilamellar vesicles of phosphatidylcholine

Lanthanides such as La³⁺ and Gd³⁺ are well known to have large effects on the function of membrane proteins such as mechanosensitive ionic channels and voltage-gated sodium channels, and also on the structure of phospholipid membranes. In this report, we have investigated effects of La³⁺ and Gd³⁺ on the shape of giant unilamellar vesicle (GUV) of dioleoylphosphatidylcholine (DOPC-GUV) and GUV of DOPC/cholesterol by the phase-contrast microscopy. The addition of 10-100 μM La³⁺ (or Gd³⁺) through a 10-μm diameter micropipette near the DOPC-GUV (or DOPC/cholesterol-GUV) triggered several kinds of shape changes. We have found that a very low concentration (10 μM) of La³⁺ (or Gd³⁺) induced a shape change of GUV such as the discocyte via stomatocyte to inside budded shape transformation, the two-spheres connected by a neck to prolate transformation, and the pearl on a string to cylinder (or tube) transformation. To understand the effect of these lanthanides on the shape of the GUV, we have also investigated phase transitions of 30 μM dipalmitoylphosphatidylcholine-multilamellar vesicle (DPPC-MLV) by the ultra-sensitive differential scanning calorimetry (DSC). The chain-melting phase transition temperature and the L_β′ to P_β′ phase transition temperature of DPPC-MLV increased with an increase in La³⁺ concentration. This result indicates that the lateral compression pressure of the membrane increases with an increase in La³⁺ concentration. Thereby, the interaction of La³⁺ (or Gd³⁺) on the external monolayer membrane of the GUV induces a decrease in its area (A^ex), whereas the area of the internal monolayer membrane (Aⁱⁿ) keeps constant. Therefore, the shape changes of the GUV induced by these lanthanides can be explained reasonably by the decrease in the area difference between two monolayers (ΔA=A^ex−Aⁱⁿ).     

Label free imaging of cell‐substrate contacts by holographic total internal reflection microscopy

The study of cell adhesion contacts is pivotal to understand cell mechanics and interaction at substrates or chemical and physical stimuli. We designed and built a HoloTIR microscope for label‐free quantitative phase imaging of total internal reflection. Here we show for the first time that HoloTIR is a good choice for label‐free study of focal contacts and of cell/substrate interaction as its sensitivity is enhanced in comparison with standard TIR microscopy. Finally, the simplicity of implementation and relative low cost, due to the requirement of less optical components, make HoloTIR a reasonable alternative, or even an addition, to TIRF microscopy for mapping cell/substratum topography. As a proof of concept, we studied the formation of focal contacts of fibroblasts on three substrates with different levels of affinity for cell adhesion.

     

Bayesian Modeling of the Level and Duration of Fertility in the Menstrual Cycle

Time to pregnancy studies that identify ovulation days and collect daily intercourse data can be used to estimate the day-specific probabilities of conception given intercourse on a single day relative to ovulation. In this article, a Bayesian semiparametric model is described for flexibly characterizing covariate effects and heterogeneity among couples in daily fecundability. The proposed model is characterized by the timing of the most fertile day of the cycle relative to ovulation, by the probability of conception due to intercourse on the most fertile day, and by the ratios of the daily conception probabilities for other days of the cycle relative to this peak probability. The ratios are assumed to be increasing in time to the peak and decreasing thereafter. Generalized linear mixed models are used to incorporate covariate and couple-specific effects on the peak probability and on the day-specific ratios. A Markov chain Monte Carlo algorithm is described for posterior estimation, and the methods are illustrated through application to caffeine data from a North Carolina pregnancy study.     

Highly resistant regression and object matching

In many disciplines, it is of great importance to match objects. Procrustes analysis is a popular method for comparing labeled point configurations based on a least squares criterion. We consider alternative procedures that are highly resistant to outlier points, and we describe an application in electrophoretic gel matching. We consider procedures based on S estimators, least median of squares, and least quartile difference estimators. Practical implementation issues are discussed, including random subset selection and intelligent subset selection (where subsets with small size or near collinear subsets are ignored). The relative performances of the resistant and Procrustes methods are examined in a simulation study.