The ultimate goal of drug design is to find novel compounds with desirable pharmacological properties. Designing molecules retaining particular scaffolds as the core structures of the molecules is one of the efficient ways to obtain potential drug candidates with desirable properties. We proposed a scaffold-based molecular generative model for scaffold-based drug discovery, which performs molecule generation based on a wide spectrum of scaffold definitions, including BM-scaffolds, cyclic skeletons, as well as scaffolds with specifications on side-chain properties. The model can generalize the learned chemical rules of adding atoms and bonds to a given scaffold. Furthermore, the generated compounds were evaluated by molecular docking in DRD2 targets and the results demonstrated that this approach can be effectively applied to solve several drug arXiv:1908.07209v4 [q-bio.QM] 5 Sep 2019 design problems, including the generation of compounds containing a given scaffold and de novo drug design of potential drug candidates with specific docking scores.

Antibiotic resistance is one of the biggest threats to public health, and new antibacterial agents hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Utilizing dimerization strategy, we rationally designed and efficiently synthesized a new series of small molecule dimeric lysine alkylamides as mimics of AMPs. Evaluation of these mimics against a panel of Gram-positive and Gram-negative bacteria including MDR strains was performed, and a broad-spectrum and potent compound 3d was identified. This compound displayed high specificity toward bacteria over mammalian cell. Time-kill kinetics and mechanistic studies suggest that compound 3d quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. In addition, lead compound 3d could inhibit biofilm formation and did not develop drug resistance in S. aureus and E. coli over 14 passages. These results suggested that dimeric lysine nonylamide has immense potential as a new type of novel small molecular agent to combat antibiotic resistance.

BackgroundImprovements in vitrification and frozen embryo transfer (FET) technologies have rapidly increased, and some evidence suggests that FET may increase pregnancy rates and lead to more favourable perinatal outcomes. However, the outcome of interest should be offspring safety. Therefore, the primary objective of our study was to investigate whether FET was preferable to fresh embryo transfer (ET) in terms of full-term neonatal birthweight and congenital malformations.MethodsThis was a retrospective cohort study of patients with no pregnancy-related complications who underwent first fresh ETs (n = 2059) or FETs (n = 2053), resulting in full-term singletons births. Outcome measures were neonatal birthweight, low birthweight (LBW), small-for-gestational age (SGA), large-for-gestational age (LGA), macrosomia and congenital malformations. Additionally, we used logistic regression to adjust for baseline characteristics (age, BMI, No. of embryos transferred and embryo stage) between the two groups.ResultsThe mean neonatal birthweight was higher for singletons born after FET than for singletons born after fresh ET (3468.7 ± 475.3 vs. 3386.7 ± 448.1; p < 0.001). The frequencies of full-term singleton LBW and SGA after FET were significantly lower than those after fresh ET (1.7% vs. 3.0 and 4.4% vs. 6.7%, respectively), with adjusted rate ratios of 0.59 (95% CI, 0.37 to 0.98; p = 0.026) and 0.73 (95% CI, 0.55 to 0.99; p = 0.041), respectively. FET resulted in higher frequencies of macrosomia and LGA (15.1% vs 10.2 and 22.8% vs. 17.5%, respectively) than fresh ET, with adjusted rate ratios of 1.43 (95% CI, 1.16 to 1.75; p = 0.001) and 1.26 (95% CI, 1.07 to 1.49; p = 0.007), respectively. Furthermore, the incidence of congenital malformations was not different between the two groups (1.2% vs. 0.9%), with a rate ratio of 0.288.ConclusionsAfter the cycles with pregnancy-related complications were excluded and after adjustments for baseline characteristics, women undergoing FET were associated with a higher neonatal birthweight than women undergoing fresh ET cycles. Additionally, the FET protocol was associated with lower rates of LBW and SGA and higher rates of macrosomia and LGA than the fresh ET protocol. Meanwhile, no difference in the congenital malformation rate was evident between the two groups.

ObjectiveAccording to the international guidelines, fresh frozen plasma (FFP) is unanimously used to treat coagulation disorders. The quality of FFP is critical for the clinical transfusion. Till now, few studies have integratedly evaluated the differences of FFP from blood donors at between high altitude (HA) and low altitude (LA). Besides, there were no special quality standards for HA FFP in China.Materials and methodsUp to 41 HA (Lhasa, 3700 m) and 46 LA (Chengdu, 500 m) blood donors were included in our study to estimate the differences of FFP from HA and LA blood donors. The concentration of total plasma proteins, prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), fibrinogen (Fbg), factor (F) II, FV, FVII, FVIII, FIX, FX, FXI, FXII, D-dimer, protein C (PC), protein S (PS), antithrombin III (ATIII) and von Willebrand factor antigen (vWF:Ag) were determined, respectively.ResultsAs compared with FFP of LA blood donors, the total protein content of HA blood donors showed a significant decrease (65.2±8.9 vs.57.2±6.3 g/L; p<0.001); PT, aPTT, TT were significantly increased (p<0.001); the levels of FII, FV, FVII, FVIII, FIX, FX, FXI, FXII and vWF:Ag were notably decreased (all p<0.05), whereas Fbg and D-dimer were dramaticly increased (p = 0.038). Additionly, in HA blood donors, vWF: Ag and FVIII:C of O-group was significantly lower (p<0.05) than that of non-O-group. It should be noted that FVIII:C of HA blood donors (0.64±0.10 IU/mL) was lower than the current Chinese quality requirements for FFP (≥ 0.7 IU/ml). No significant differences were observed in PC, PS and ATIII.ConclusionIn general, our findings showed that the quality of FFP was significantly different between HA and LA blood donors, and the current Chinese quality requirements of FFP are not suitable for HA FFP. Therefore, setting up a special quality requirement for HA is quite necessary and meaningful.

We describe measurements of thermodynamic temperature in the range 5 K to 24.5561 K (the triple point of neon) using single-pressure refractive-index gas thermometry (SPRIGT) with 4He. In the wake of the May 2019 re-definition of the kelvin and its associated mise en pratique, the main purpose of the work is to provide values of T–T 90, the discrepancy between thermodynamic temperature and that of the International Temperature Scale of 1990 (ITS-90). The link to ITS-90 is made via calibrated rhodium-iron resistance thermometers. Innovations required to reach the level of accuracy required for meaningful measurements (uncertainty in T–T 90 less than the expected deviation) include the suppression of temperature oscillations in a cryogen-free cryostat, a pressure stabilization scheme based on a non-rotating piston balance, modelling of the hydrostatic head correction and refinements of the measurement of microwave resonances in a quasi-spherical copper resonator. The accuracy of measurements varies from 0.05 mK to 0.17 mK and is competitive with that of all previous ones in this temperature range using other techniques. The improvement stems partly from the new techniques used for the new definition of the kelvin as well as ab initio calculations of the thermophysical properties ofgaseous 4He. In addition to confirming the validity of SPRIGT as an accurate, easier-to-implement alternative to other low-temperature primary thermometry techniques (e.g. acoustic gas thermometry) yet with scope for improvement, the results should provide important input data for any future revision of ITS-90.

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A stable microbial consortium, separated from a refinery wastewater sample, was able to utilize carbazole as the sole source of carbon, nitrogen, and energy, and liberated ammonia from excess nitrogen. Two bacterial strains (NCY and NCW) were isolated from the microbial consortium using a nutrient agar plate. Based on the 16S rDNA sequence analysis, the two bacteria were identified as Chryseobacterium sp. NCY and Achromobacter sp. NCW, respectively. No intermediates of carbazole degradation were detected by high-performance liquid chromatography. The substrate specificity assay showed that the consortium could utilize compounds similar to carbazole, such as phenanthrene, naphthalene, and imidazole. Neither the pure strain NCY nor NCW could degrade carbazole after domestication for several times. It was suggested that the two bacteria formed a microbial consortium capable of metabolizing carbazole.

Target fishing often relies on the use of reverse docking to identify potential target proteins of ligands from protein database. The limitation of reverse docking is the accuracy of current scoring funtions used to distinguish true target from non-target proteins. Many contemporary scoring functions are designed for the virtual screening of small molecules without special optimization for reverse docking, which would be easily influenced by the properties of protein pockets, resulting in scoring bias to the proteins with certain properties. This bias would cause lots of false positives in reverse docking, interferring the identification of true targets. In this paper, we have conducted a large-scale reverse docking (5000 molecules to 100 proteins) to study the scoring bias in reverse docking by DOCK, Glide, and AutoDock Vina. And we found that there were actually some frequency hits, namely interference proteins in all three docking procedures. After analyzing the differences of pocket properties between these interference proteins and the others, we speculated that the interference proteins have larger contact area (related to the size and shape of protein pockets) with ligands (for all three docking programs) or higher hydrophobicity (for Glide), which could be the causes of scoring bias. Then we applied the score normalization method to eliminate this scoring bias, which was effective to make docking score more balanced between different proteins in the reverse docking of benchmark dataset. Later, the Astex Diver Set was utilized to validate the effect of score normalization on actual cases of reverse docking, showing that the accuracy of target prediction significantly increased by 21.5% in the reverse docking by Glide after score normalization, though there was no obvious change in the reverse docking by DOCK and AutoDock Vina. Our results demonstrate the effectiveness of score normalization to eliminate the scoring bias and improve the accuracy of target prediction in reverse docking. Moreover, the properties of protein pockets causing scoring bias to certain proteins we found here can provide the theory basis to further optimize the scoring functions of docking programs for future research.