pK a is an important property in the lead optimization process since the charge state of a molecule in physiologic pH plays a critical role in its biological activity, solubility, membrane permeability, metabolism, and toxicity. Accurate and fast estimation of small molecule pK a is vital during the drug discovery process. We present MolGpKa, a web server for pK a prediction using a graph-convolutional neural network model. The model works by learning pK a related chemical patterns automatically and building reliable predictors with learned features. ACD/pK a data for 1.6 million compounds from the ChEMBL database was used for model training. We found that the performance of the model is better than machine learning models built with human-engineered fingerprints. Detailed analysis shows that the substitution effect on pK a is well learned by the model. MolGpKa is a handy tool for the rapid estimation of pK a during the ligand design process. The MolGpKa server is freely available to researchers and can be accessed at https://xundrug.cn/molgpka.

Observational studies and nonrandomized trials support an association between periodontal disease and atherosclerotic vascular disease. Both diseases occur frequently in Aboriginal Australians. We hypothesized that nonsurgical periodontal therapy would improve measures of arterial function and structure that are subclinical indicators of atherosclerotic vascular disease. This parallel-group, randomized, open label clinical trial enrolled 273 Aboriginal Australians aged ≥18 years with periodontitis. Intervention participants received full-mouth periodontal scaling during a single visit, whereas controls received no treatment. Prespecified primary end points measured 12-month change in carotid intima-media thickness, an indicator of arterial structure, and 3- and 12-month change in pulse wave velocity, an indicator of arterial function. ANCOVA used complete case data to evaluate treatment group differences. End points could be calculated for 169 participants with follow-up data at 3 months and 168 participants at 12 months. Intima-media thickness decreased significantly after 12 months in the intervention group (mean reduction=−0.023 [95% confidence interval {CI}, −0.038 to −0.008] mm) but not in the control group (mean increase=0.002 [95% CI, −0.017 to 0.022] mm). The difference in intima-media thickness change between treatment groups was statistically significant (−0.026 [95% CI, −0.048 to −0.003] mm; P =0.03). In contrast, there were no significant differences between treatment groups in pulse wave velocity at 3 months (mean difference, 0.06 [95% CI, −0.17 to 0.29] m/s; P =0.594) or 12 months (mean difference, 0.21 [95% CI, −0.01 to 0.43] m/s; P =0.062). Periodontal therapy reduced subclinical arterial thickness but not function in Aboriginal Australians with periodontal disease, suggesting periodontal disease and atherosclerosis are significantly associated.

In contrast to adults, plasma ADMA is reduced in SM in children, but hypoargininemia is more severe. Arginine bioavailability (reflected by low arginine:ADMA ratios) is therefore comparably low in SM in children as in adults. Therapies to increase NO bioavailability in malaria may be useful as adjunctive treatment of severe malaria in children.