Systematic Artifacts in Support Vector Regression-Based Compound Potency Prediction Revealed by Statistical and Activity Landscape Analysis

Support vector machines are a popular machine learning method for many classification tasks in biology and chemistry. In addition, the support vector regression (SVR) variant is widely used for numerical property predictions. In chemoinformatics and pharmaceutical research, SVR has become the probably most popular approach for modeling of non-linear structure-activity relationships (SARs) and predicting compound potency values. Herein, we have systematically generated and analyzed SVR prediction models for a variety of compound data sets with different SAR characteristics. Although these SVR models were accurate on the basis of global prediction statistics and not prone to overfitting, they were found to consistently mispredict highly potent compounds. Hence, in regions of local SAR discontinuity, SVR prediction models displayed clear limitations. Compared to observed activity landscapes of compound data sets, landscapes generated on the basis of SVR potency predictions were partly flattened and activity cliff information was lost. Taken together, these findings have implications for practical SVR applications. In particular, prospective SVR-based potency predictions should be considered with caution because artificially low predictions are very likely for highly potent candidate compounds, the most important prediction targets.     

Carriage of Neisseria meningitidis and Neisseria lactamica in northern Greece

In response to an increase in the number of cases of invasive meningococcal disease (IMD) in northern regions of Greece, a survey was carried out to determine if there was an increase in carriage of Neisseria meningitidis, particularly in areas where there have been increases in immigrant populations from neighbouring countries. The second objective was to determine if there was an increase in the serogroup C:2a:P1.5,2 a phenotype associated with recent outbreaks or changes in antibiotic sensitivities. As carriage of Neisseria lactamica is associated with development of natural immunity to IMD, the third objective was to determine the carriage rate of N. lactamica in this population. Among 3167 individuals tested, meningococci were isolated from 334 (10.5%). Compared with our previous studies, the proportion of meningococcal carriers was significantly increased among children in secondary education (11.3%) (chi2=9.67, P<0.005) and military recruits (37.4%) (chi2=21.11, P<0.000). Only 5/334 (1.5%) isolates expressed the phenotype associated with the increase in IMD in Greece. N. lactamica was isolated from 146/3167 (4.6%) participants. It was isolated from 71/987 (7.2%) children attending primary or nursery schools; however, the highest proportion of carriers (11.3%) was found in the boarding school for young Albanian men. In the 21-59-year age range, the majority of N. lactamica isolates (22/25, 88%) were from women, probably due to closer or more prolonged contact with children in the primary school age range. Smoking was significantly associated with isolation of meningococci from men but not from women. Penicillin-insensitive strains (25/334, 7.5%) were identified in all four regions examined; the majority (14/25, 56%) were obtained from military personnel. We conclude that there was a higher proportion of carriers in the population of northern Greece; however, the increase in carriage rate was not associated with the influx of immigrants from neighbouring countries, and there was not a higher incidence of the C:2a:P1.5,2 strain responsible for increased disease activity in Greece in either the immigrant or local populations.     

Affinity, capacity and oxygen sensitivity of two different mechanisms for bicarbonate utilization in Ulva lactuca L. (Chlorophyta)

Ulva lactuca, collected on the west coast of Sweden at the end of May, was able to utilize the HCO₃ ^? pool of seawater only through extracellular dehydration via carbonic anhydrase, followed by uptake of the CO₂ formed. A decrease in the CO₂ supply via this mechanism resulted in the gradual development of an additional method of HCO₃ ^? utilization, namely a direct uptake of HCO₃ ^? . Photosynthesis could then be supported by either a ‘HCO₃ ^? dehydration mechanism’ or a ‘HCO₃ ^? uptake mechanism’. Through selective inhibition of either of these mechanisms, the physiological properties of the other could be assessed. These properties suggest that the HCO₃ ^? uptake mechanism of U. lactuca is important under conditions when low concentrations of inorganic C, high pH and high external O₂ concentrations would limit photosynthesis supported by the HCO₃ ^? dehydration mechanism. Such conditions may occur during intense irradiation of the alga in rockpools or in shallow bays with low rates of water exchange. The results are discussed in relation to a possible coupling between mechanisms for inorganic C acquisition and cell structure (or even morphology) of green macroalgae. They also illustrate some necessary precautions when using Michaelis–Menten kinetics for estimations of V_max and K_1/2 values.     

Gestation length in rhesus macaques (Macaca mulatta)

We describe some of the sources of variation in gestation length among rhesus macaques. the data were obtained from the timed-mating breeding program at the California Regional Primate Research Center (CRPRC). Information about approximately 700 pregnancies that resulted in spontaneous vaginal deliveries of liveborn young is presented. The average length of these pregnancies was 166.5 days. In this population, older females with higher parities had significantly longer pregnancies and significantly heavier infants than other females did. Other factors, including infant sex, month of conception, maternal reproductive history, and paternal identity, had no consistent effect upon gestation length.     

Ultrastructural identification of cells storing pancreatic-type glucagon in dog stomach

Summary The oxyntic mucosa of the dog stomach is rich in cells storing pancreatic-type glucagon. The cells were identified by immunocytochemistry and found to be indistinguishable from pancreatic A cells in the electron microscope. Ultrastructural identification of the immunoreactive cells was accomplished by the use of consecutive semithin-ultrathin sections, a technique that permitted the use of optimally fixed material.     

Protein nitration

Various proteins/enzymes obtained commercially were tested for the presence of endogenously nitrated tyrosine by Western blot analysis omitting reducing agent in the step of SDS-PAGE. Histones II-S and VIII-S, IgG, cAMP-dependent protein kinase (PKA), phosphorylase b, and phosphorylase kinase exhibited strong immunoreactive bands. Histone VI-S, glycogen synthase, lactate dehydrogenase, actin, thyroglobulin, and macroglobulin exhibited moderate immunoreactivity. Histone III-S, casein, acetyl cholinesterase, DNase I, and lipase had only traceable immunoreactivity. Whereas histone VII-S, pyruvate kinase, trypsin, pepsin, chymotrypsin, protease IV, and protease XIII, and glutathione S-transferase lacked immunoreactivity. A variation of immunoreactivity between hypertensive and normaltensive rat hearts was found in the histone-agarose fractions of crude extracts. Additionally, nitrotyrosine immunoreactivity was observed in non-mammalian organisms including Eschericia coli, Saccharomyces cerevisiae and Triticum vulgaris. Upon the treatment of 15 M peroxynitrite (PN), strong oxidant derived from nitric oxide (NO), the apparent K_m of PKA for cAMP increased from approximately 10^-8 to 10^-6 M. The results imply that the varied nitration of tyrosine residues in proteins/enzymes may occur as a post-translational modification in vivo, and such discriminative nitration may be vital in PN/NO-regulated signal transduction cascade.