CM-CASL: Comparison-based Performance Modeling of Software Systems via Collaborative Active and Semisupervised Learning

Configuration tuning for large software systems is generally challenging due to the complex configuration space and expensive performance evaluation. Most existing approaches follow a two-phase process, first learning a regression-based performance prediction model on available samples and then searching for the configurations with satisfactory performance using the learned model. Such regression-based models often suffer from the scarcity of samples due to the enormous time and resources required to run a large software system with a specific configuration. Moreover, previous studies have shown that even a highly accurate regression-based model may fail to discern the relative merit between two configurations, whereas performance comparison is actually one fundamental strategy for configuration tuning. To address these issues, this paper proposes CM-CASL, a Comparison-based performance Modeling approach for software systems via Collaborative Active and Semisupervised Learning. CM-CASL learns a classification model that compares the performance of two given configurations, and enhances the samples through a collaborative labeling process by both human experts and classifiers using an integration of active and semisupervised learning. Experimental results demonstrate that CM-CASL outperforms two state-of-the-art performance modeling approaches in terms of both classification accuracy and rank accuracy, and thus provides a better performance model for the subsequent work of configuration tuning

Key residues in the nicotinic acetylcholine receptor β2 subunit contribute to α-conotoxin LvIA binding

alpha-Conotoxin LvIA (alpha-CTx LvIA) is a small peptide from the venom of the carnivorous marine gastropod Conus lividus and is the most selective inhibitor of alpha 3 beta 2 nicotinic acetylcholine receptors (nAChRs) known to date. It can distinguish the alpha 3 beta 2 nAChR subtype from the alpha 6 beta 2* (*indicates the other subunit) and alpha 3 beta 4 nAChR subtypes. In this study, we performed mutational studies to assess the influence of residues of the beta 2 subunit versus those of the beta 4 subunit on the binding of alpha-CTx LvIA. Although two beta 2 mutations, alpha 3 beta 2[F119Q] and alpha 3 beta 2[T59K], strongly enhanced the affinity of LvIA, the beta 2 mutation alpha 3 beta 2[V111I] substantially reduced the binding of LvIA. Increased activity of LvIA was also observed when the beta 2-T59L mutant was combined with the alpha 3 subunit. There were no significant difference in inhibition of alpha 3 beta 2[T59I], alpha 3 beta 2[Q34A], and alpha 3 beta 2[K79A] nAChRs when compared with wild-type alpha 3 beta 2 nAChR. alpha-CTx LvIA displayed slower off-rate kinetics at alpha 3 beta 2[F119Q] and alpha 3 beta 2[T59K] than at the wild-type receptor, with the latter mutant having the most pronounced effect. Taken together, these data provide evidence that the beta 2 subunit contributes to alpha-CTx LvIA binding and selectivity. The results demonstrate that Val(111) is critical and facilitates LvIA binding; this position has not previously been identified as important to binding of other 4/7 framework alpha-conotoxins. Thr(59) and Phe(119) of the beta 2 subunit appear to interfere with LvIA binding, and their replacement by the corresponding residues of the beta 4 subunit leads to increased affinity

Characterization of a novel alpha-conotoxin TxID from Conus textile that potently blocks rat alpha3/beta4 nicotinic acetylcholine receptors

The alpha 3 beta 4 nAChRs are implicated in pain sensation in the PNS and addiction to nicotine in the CNS. We identified an alpha-4/6-conotoxin (CTx) TxID from Conus textile. The new toxin consists of 15 amino acid residues with two disulfide bonds. TxID was synthesized using solid phase methods, and the synthetic peptide was functionally tested on nAChRs heterologously expressed in Xenopus laevis oocytes. TxID blocked rat alpha 3 beta 4 nAChRs with a 12.5 nM IC50, which places it among the most potent alpha 3 beta 4 nAChR antagonists. TxID also blocked the closely related alpha 6/alpha 3 beta 4 with a 94 nM IC50 but showed little activity on other nAChR subtypes. NMR analysis showed that two major structural isomers exist in solution, one of which adopts a regular alpha-CTx fold but with different surface charge distribution to other 4/6 family members. alpha-CTx TxID is a novel tool with which to probe the structure and function of alpha 3 beta 4 nAChRs

αO-Conotoxin GeXIVA Inhibits the Growth of Breast Cancer Cells via Interaction with α9 Nicotine Acetylcholine Receptors

The α9-containing nicotinic acetylcholine receptor (nAChR) is increasingly emerging as a new tumor target owing to its high expression specificity in breast cancer. αO-Conotoxin GeXIVA is a potent antagonist of α9α10 nAChR. Nevertheless, the anti-tumor effect of GeXIVA on breast cancer cells remains unclear. Cell Counting Kit-8 assay was used to study the cell viability of breast cancer MDA-MD-157 cells and human normal breast epithelial cells, which were exposed to different doses of GeXIVA. Flow cytometry was adopted to detect the cell cycle arrest and apoptosis of GeXIVA in breast cancer cells. Migration ability was analyzed by wound healing assay. Western blot (WB), quantitative real-time PCR (QRT-PCR) and flow cytometry were used to determine expression of α9-nAChR. Stable MDA-MB-157 breast cancer cell line, with the α9-nAChR subunit knocked out (KO), was established using the CRISPR/Cas9 technique. GeXIVA was able to significantly inhibit the proliferation and promote apoptosis of breast cancer MDA-MB-157 cells. Furthermore, the proliferation of breast cancer MDA-MB-157 cells was inhibited by GeXIVA, which caused cell cycle arrest through downregulating α9-nAChR. GeXIVA could suppress MDA-MB-157 cell migration as well. This demonstrates that GeXIVA induced a downregulation of α9-nAChR expression, and the growth of MDA-MB-157 α9-nAChR KO cell line was inhibited as well, due to α9-nAChR deletion. GeXIVA inhibits the growth of breast cancer cell MDA-MB-157 cells in vitro and may occur in a mechanism abolishing α9-nAChR

DSPE-PEG Modification of α-Conotoxin TxID

In order to improve stability of a peptide marine drug lead, α-conotoxin TxID, we synthesized and modified TxID at the N-terminal with DSPE-PEG-NHS by a nucleophilic substitution reaction to prepare the DSPE-PEG-TxID for the first time. The reaction conditions, including solvent, ratio, pH, and reaction time, were optimized systematically and the optimal one was reacted in dimethyl formamide at pH 8.2 with triethylamine at room temperature for 120 h. The in vitro stabilities in serum, simulated gastric juice, and intestinal fluid were tested, and improved dramatically compared with TxID. The PEG-modified peptide was functionally tested on α3β4 nicotinic acetylcholine receptor (nAChR) heterologously expressed in Xenopus laevis oocytes. The DSPE-PEG-TxID showed an obvious inhibition effect on α3β4 nAChR. All in all, the PEG modification of TxID was improved in stability, resistance to enzymatic degradation, and may prolong the half-life in vivo, which may pave the way for the future application in smoking cessation and drug rehabilitation, as well as small cell lung cancer

Novel αO-conotoxin GeXIVA[1,2] Nonaddictive Analgesic with Pharmacokinetic Modelling-Based Mechanistic Assessment

αO-conotoxin GeXIVA[1,2] was isolated in our laboratory from Conus generalis, a snail native to the South China Sea, and is a novel, nonaddictive, intramuscularly administered analgesic targeting the α9α10 nicotinic acetylcholine receptor (nAChR) with an IC50 of 4.61 nM. However, its pharmacokinetics and related mechanisms underlying the analgesic effect remain unknown. Herein, pharmacokinetics and multiscale pharmacokinetic modelling in animals were subjected systematically to mechanistic assessment for αO-conotoxin GeXIVA[1,2]. The intramuscular bioavailability in rats and dogs was 11.47% and 13.37%, respectively. The plasma exposure of GeXIVA[1,2] increased proportionally with the experimental dose. The plasma protein binding of GeXIVA[1,2] differed between the tested animal species. The one-compartment model with the first-order absorption population pharmacokinetics model predicted doses for humans with bodyweight as the covariant. The pharmacokinetics-pharmacodynamics relationships were characterized using an inhibitory loss indirect response model with an effect compartment. Model simulations have provided potential mechanistic insights into the analgesic effects of GeXIVA[1,2] by inhibiting certain endogenous substances, which may be a key biomarker. This report is the first concerning the pharmacokinetics of GeXIVA[1,2] and its potential analgesic mechanisms based on a top-down modelling approach

α-Conotoxin [S9A]TxID Potently Discriminates between α3β4 and α6/α3β4 Nicotinic Acetylcholine Receptors

α3β4 nAChRs have been implicated in various pathophysiological conditions. However, the expression profile of α3β4 nAChRs and α6/α3β4 nAChRs overlap in a variety of tissues. To distinguish between these two subtypes, we redesigned peptide 1 (α-conotoxin TxID), which inhibits α3β4 and α6/α3β4 nAChR subtypes. We systematically mutated 1 to evaluate analogue selectivity for α3β4 vs α6/α3β4 nAChRs expressed in Xenopus laevis oocytes. One analogue, peptide 7 ([S9A]TxID), had 46-fold greater potency for α3β4 versus α6/α3β4 nAChRs. Peptide 7 had ICs > 10 μM for other nAChR subtypes. Molecular dynamics simulations suggested that Ser-9 of TxID was involved in a weak hydrogen bond with β4 Lys-81 in the α6β4 binding site but not in the α3β4 binding site. When Ser-9 was substituted by an Ala, this hydrogen bond interaction was disrupted. These results provide further molecular insights into the selectivity of 7 and provide a guide for designing ligands that block α3β4 nAChRs