Reliable structural information for rational design of benzoxazole type potential cholesteryl ester transfer protein (CETP) inhibitors through multiple validated modeling techniques

Abstract

The drug design and discovery of lipid modulators is very demanding as no new molecule has entered into the market in the last 35 years. Cholesteryl ester transfer protein (CETP) is a promising target as lipid modulators. Inhibition of the CETP enzyme reduces the risk of cardiovascular events. The first CETP inhibitor torcetrapib and related drug candidates failed in the clinical trial due to the off-target effects leading to high toxicity. Thus, newer CETP inhibitors have now paramount importance to accelerate the drug discovery efforts in the field of cardiovascular disease (CVD). In the present study, 140 benzoxazole compounds were studied by using different chemometric techniques, for example, pharmacophore mapping, molecular docking, three-dimensional quantitative structure–activity relationship comparative molecular field analysis (3D-QSAR CoMFA), topomer CoMFA and Bayesian classification, in order to generate complete and reliable information regarding the structural requirements for the CETP inhibition. The best pharmacophore hypothesis was statistically significant (regression coefficient of 0.957 and a lower root mean square of 0.890). Molecular docking study revealed that cyano-substituted compounds form hydrogen bond with targeted macromolecule. The 3D-QSAR CoMFA model also produced a leave-one-out (LOO) cross-validated Q² of 0.527, an R² of 0.853 and an R²_Pred of 0.603. Similarly, two topomer CoMFA models were also statistically significant and reliable in terms of their Q², R² and R²_Pred values. The Bayesian classification study also provided the excellent ROC values of 0.919 and 0.939 for training and test sets, respectively. Overall, this study may help in the rational design of newer benzoxazole type compounds with higher CETP inhibition.

Communicated by Ramaswamy H. Sarma     

Automatic fetal biometry prediction using a novel deep convolutional network architecture

PurposeFetal biometric measurements face a number of challenges, including the presence of speckle, limited soft-tissue contrast and difficulties in the presence of low amniotic fluid. This work proposes a convolutional neural network for automatic segmentation and measurement of fetal biometric parameters, including biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL) from ultrasound images that relies on the attention gates incorporated into the multi-feature pyramid Unet (MFP-Unet) network.MethodsThe proposed approach, referred to as Attention MFP-Unet, learns to extract/detect salient regions automatically to be treated as the object of interest via the attention gates. After determining the type of anatomical structure in the image using a convolutional neural network, Niblack's thresholding technique was applied as pre-processing algorithm for head and abdomen identification, whereas a novel algorithm was used for femur extraction. A publicly-available dataset (HC18 grand-challenge) and clinical data of 1334 subjects were utilized for training and evaluation of the Attention MFP-Unet algorithm.ResultsDice similarity coefficient (DSC), hausdorff distance (HD), percentage of good contours, the conformity coefficient, and average perpendicular distance (APD) were employed for quantitative evaluation of fetal anatomy segmentation. In addition, correlation analysis, good contours, and conformity were employed to evaluate the accuracy of the biometry predictions. Attention MFP-Unet achieved 0.98, 1.14 mm, 100%, 0.95, and 0.2 mm for DSC, HD, good contours, conformity, and APD, respectively.ConclusionsQuantitative evaluation demonstrated the superior performance of the Attention MFP-Unet compared to state-of-the-art approaches commonly employed for automatic measurement of fetal biometric parameters.     

Daily Rhythms Related to Distinct Social Tasks inside an Eusocial Bee Colony

A bee colony is often compared to a multicellular organism, mainly because of its spatial organization. We propose that a temporal organization of equal importance is also present. To support this view, we studied the reproductive processes of two closely related species of stingless bees. Stingless bees enable observations of daily rhythms that are performed by distinct social classes. The emergent process, POP, is cyclic and consists of the building and provisioning of brood cells by the worker bees and egg‐laying by the queen. Colonies were kept in the laboratory under constant conditions with the exit tube opening to the environment; thus, foragers had direct access to environmental cycles. At a later stage of the experiment, the exit tube was closed by a sieve; in this case, bees had their own stock of food, but the environmental LD cycle could still be detected when they were inside the exit tube. Daily POP rhythms were present and showed distinct temporal patterns in each species. A third condition was imposed on one of the species only: the exit tube was closed by a sieve and maintained inside a box that was provided with constant illumination. In this colony, the POP rhythm was perturbed by the destruction of the brood cells. Restoration of POP consisted of a rapid reconstruction of cells followed by a late oviposition in the same day. As different rhythmic patterns were detected, but showed regular timings with respect to one another, an interpretation based upon the concept of an internal temporal order is suggested.     

杉木不同生长类型对养分供应的持续效应

应用“正态分布标准差分类法”把杉木(Cunninghamia lanceolata)试验林分树高生长划分为5个生长类型，按不同生长类型进行施肥试验。结果表明，不同生长类型杉木施肥后2年生长期的树高年生长量表现为，生长类型好的群体对施肥有更好的持续促进高生长效应；生长类型差的群体，在施肥量相对少时高生长持续效应不明显，当施肥量较大时能有较好的树高年生长量持续生长效应。不同生长类型杉木胸径年生长量对施肥量的响应表现为，相同条件下，好的生长类型比差的生长类型有更好的胸径年生长量效果，施肥量相对不足时，差的生长类型群体胸径年生长持续效应逐渐衰退，好的生长类型对施肥有更好的持续促进生长效果，施肥量大对胸径年生长有更好的持续促进作用，与树高生长表现基本一致。研究表明，遗传品质好的杉木群体对立地适应能力越强，有更好的耐瘠薄能力和更好的年生长量。施肥措施对不同遗传品质生长类型杉木树高与胸径年生长量都有较好的促进效应，能有效恢复与提高杉木低产林分生长，为杉木低产与小老林林分改良提供理论指导。     

Fluorescence anisotropy from diphenylhexatriene in rat liver plasma membranes

Rat livers were fractionated to obtain intracellular membrane preparations and a highly purified preparation of bile canaliculi. The fraction containing bile canaliculi was homogenized and subfractionated to give fractions representing fragments of contiguous membrane and of canalicular microvilli. The relative purity and extent of contamination of each preparation was determined. When the fluorescent probe 1,6-diphenyl-1,3,5-hexatriene was incorporated into aliquots of each fraction at the same probe: lipid ratio and the steady-state anisotropy of its fluorescence measured, it was found that the plasma membrane preparations were much more ordered than the intracellular membrane preparations. Of the plasma membrane preparations, that containing the canalicular microvilli was the most ordered, even allowing for any contribution of contaminants. Thus the microvillus membrane of the bile canaliculus appears to be the most ordered domain of the plasma membrane of the hepatocyte. The high order in this domain may be a factor in reducing the susceptibility to bile salt damage during bile secretion, since it is this region which is exposed to high concentrations of bile salts in vivo.     

Hostplants and classification: a review of nymphalid butterflies

In reviewing the hostplant associations of nymphalid butterflies, particular emphasis is placed on the intractable problem of nymphalid classification. Although offering few certain conclusions, if used in conjunction with more formal morphological characters, the data presented should contribute toward a resolution of the inter-relationships of the many widely recognized groupings within the Nymphalidae, several of which seem to be broadly characterized by typical host families. As a direct result of this analysis, the presumed association between larval hostplants and unpalatability is re-appraised.     

Evidence of a genetically distinct population of Vrljika softmouth trout Salmo obtusirostris Heckel evolved by vicariance

Mitochondrial DNA haplotypes (control region, partial cytochrome b and ATPase6 genes) indicate a sister relationship between Vrljika and Neretva softmouth (Adriatic) trout Salmo obtusirostris . This relationship was supported by a tree of individuals based on microsatellite results [allele sharing distances ( D _AS)], which revealed three distinctive clusters, corresponding to Jadro softmouth, Neretva brown trout Salmo trutta and Neretva softmouth trout. Within the latter taxon, Vrljika trout are clearly separated from other trout. The genetic results contradict the synonymy of Jadro with Vrljika softmouth trout, as recently proposed in the Red Book of Freshwater Fish in Croatia. Vrljika softmouth trout appear to have originated from a vicariance that split a common ancestor into large (Neretva) and small (Vrljika) fragmented populations 135 000–270 000 years ago. Vrljika softmouth trout can be distinguished by an array of derived phenotypic and molecular character states. For conservation, this population should be recognized formally at the same taxonomic level as the other geographically separated populations of softmouth trout.     

A computational algorithm for classifying step and spin turns using pelvic center of mass trajectory and foot position

Transient changes in direction during ambulation are typically performed using a step (outside) or spin (inside) turning strategy, often identified through subjective and time-consuming visual rating. Here, we present a computational, marker-based classification method utilizing pelvic center of mass (pCOM) trajectory and time-distance parameters to quantitatively identify turning strategy. Relative to visual evaluation by three independent raters, sensitivity, specificity, and overall accuracy of the pCOM-based classification method were evaluated for 90-degree turns performed by 3 separate populations (5 uninjured controls, 5 persons with transtibial amputation, and 5 persons with transfemoral amputation); each completed turns using two distinct cueing paradigms (i.e., laser-guided “freeform” and verbally-guided “forced” turns). Secondarily, we compared the pCOM-based turn classification method to adapted versions of two existing computational turn classifiers which utilize trunk and shank angular velocities (AV). Among 366 (of 486 total) turns with unanimous intra- and inter-rater agreement, the pCOM-based classification algorithm was 94.5% accurate, with 96.6% sensitivity (accuracy of spin turn classification), and 93.5% specificity (accuracy of step turn classification). The pCOM-based algorithm (vs. both AV-based methods) was more accurate (94.5% vs. 81.1–80.6%; P < 0.001) overall, as well as specifically in freeform (92.9 vs. 80.4–76.8%; P < 0.003) and forced (96.0 vs. 83.8–81.8%; P < 0.001) cueing, and among individuals with (92.4 vs. 80.2–78.8%; P < 0.001) and without (99.1 vs. 86.2–80.8%; P < 0.001) amputation. The pCOM-based algorithm provides an efficient and objective method to accurately classify 90-degree turning strategies using optical motion capture in a laboratory setting, and may be extended to various cueing paradigms and/or populations with altered gait.