Ensemble modeling with machine learning and deep learning to provide interpretable generalized rules for classifying CNS drugs with high prediction power.

The trade-off between a machine learning (ML) and deep learning (DL) model's predictability and its interpretability has been a rising concern in central nervous system-related quantitative structure-activity relationship (CNS-QSAR) analysis. Many state-of-the-art predictive modeling failed to provide structural insights due to their black box-like nature. Lack of interpretability and further to provide easy simple rules would be challenging for CNS-QSAR models. To address these issues, we develop a protocol to combine the power of ML and DL to generate a set of simple rules that are easy to interpret with high prediction power. A data set of 940 market drugs (315 CNS-active, 625 CNS-inactive) with support vector machine and graph convolutional network algorithms were used. Individual ML/DL modeling methods were also constructed for comparison. The performance of these models was evaluated using an additional external dataset of 117 market drugs (42 CNS-active, 75 CNS-inactive). Fingerprint-split validation was adopted to ensure model stringency and generalizability. The resulting novel hybrid ensemble model outperformed other constituent traditional QSAR models with an accuracy of 0.96 and an F1 score of 0.95. With the power of the interpretability provided with this protocol, our model laid down a set of simple physicochemical rules to determine whether a compound can be a CNS drug using six sub-structural features. These rules displayed higher classification ability than classical guidelines, with higher specificity and more mechanistic insights than just for blood-brain barrier permeability. This hybrid protocol can potentially be used for other drug property predictions.

Formation of tetrahydrofurans via a 5-endo-tet cyclization of aziridines--synthesis of (-)-pachastrissamine.

The formation of tetrahydrofurans from 2-hydroxyalkyl-oxirane or aziridine is reported. The 5-endo-tet cyclization/ring opening of aziridine proceeded smoothly to give tetrahydrofurans (THFs) under mild conditions. In contrast, the corresponding process of oxirane was unsuccessful and a sequence of SN2 substitution/cyclization was required to form THFs. The application of the process to prepare ent-(-)-pachastrissamine is described.

Beneficial effects of yam on carbon tetrachloride-induced hepatic fibrosis in rats.

BACKGROUND: In a previous study, lyophilised yam reduced brain amyloid beta-protein (Abeta) accumulation and improved the antioxidative defence system in senescence-accelerated (SAMP8) mice. Therefore, the aim of this study was to investigate the hepatic protection of yam in the carbon tetrachloride-induced hepatic fibrosis of rats. Hepatic fibrosis was induced in rats via intraperitoneal injections of CCl(4) at a dose of 1 mL kg(-1) body weight (BW) twice weekly for 8 weeks. Three groups of rats were gavaged daily with yams at doses of 0.5, 1 and 2 g kg(-1) BW for 8 weeks, respectively. RESULTS: Yam treatments significantly decreased the ratio of liver/body weight, levels of gamma-glutaminotranspeptidase (GGT), low-density lipoprotein, and triglyceride in serum when compared with those administered CCl(4) alone. Treatment with yams significantly elevated antioxidant activities of glutathione peroxidase (GSH-Px) and superoxidase dismutase (SOD) in livers. Microscopically, yam-treated groups presented with low histoscores of CCl(4)-induced liver injury and fibrosis. Additionally, yam treatment reduced the area of GGT-positive foci and the index of proliferating cell nuclear antigen (PCNA) in liver. CONCLUSION: Daily administration of yam attenuates CCl(4)-induced hepatic fibrosis in rats in a dose-dependent manner; this attenuation may be related to the antioxidant properties of yams.

Dynamics of the lung microbiome in intensive care patients with chronic obstructive pulmonary disease and community-acquired pneumonia.

Little is known about the composition and clinical implications of lung microbiome in patients with chronic obstructive pulmonary disease (COPD) and community-acquired pneumonia requiring invasive mechanical ventilation and intensive care unit admission. Therefore, this study aimed to explore the longitudinal changes in microbial airway composition and its variations between COPD patients with different weaning outcomes. Fifty-one endotracheal aspirate samples from 21 participants and 5 saline samples were collected as the patient and control group, respectively. Sequence analysis revealed significant increases and upward trends in the relative abundance of the Acinetobacter genus and Acinetobacter baumannii complex species in paired comparisons of sampling points and over time, respectively, in patients with failed weaning (p for trend = 0.012 and 0.012, respectively) but not in those with successful weaning (p for trend = 0.335 and 0.426, respectively). Furthermore, significant changes in the composition of the bacterial community were observed in paired comparisons of sampling points in patients with failed weaning compared with those with successful weaning. The alpha diversity did not differ between the patients with different weaning outcomes. These results further the understanding of longitudinal airway microbiome structure analysis and its clinical implications when managing critically ill patients with and without COPD.

Anomalous wind triggered the largest phytoplankton bloom in the oligotrophic North Pacific Subtropical Gyre.

In summer 2010, a massive bloom appeared in the middle (16-25°N, 160-200°E) of the North Pacific Subtropical Gyre (NPSG) creating a spectacular oasis in the middle of the largest oceanic desert on Earth. Peaked in June 2010 covering over two million km2 in space, this phytoplankton bloom is the largest ever recorded by ocean color satellites in the NPSG over the period from 1997 to 2013. The initiation and mechanisms sustaining the massive bloom were due to atmospheric and oceanic anomalies. Over the north (25-30°N) of the bloom, strong anticyclonic winds warmed sea surface temperature (SST) via Ekman convergence. Subsequently, anomalous westward ocean currents were generated by SST meridional gradients between 19°N and 25°N, producing strong velocity shear that caused large number of mesoscale (100-km in order) cyclonic eddies in the bloom region. The ratio of cyclonic to anticyclonic eddies of 2.7 in summer 2010 is the highest over the 16-year study period. As a result of the large eddy-number differences, eddy-eddy interactions were strong and induced submesoscale (smaller than 100 km) vertical pumping as observed in the in-situ ocean profiles. The signature of vertical pumping was also presented in the in-situ measurements of chlorophyll and nutrients, which show higher concentrations in 2010 than other years.

Exercise type relates to inhibitory and error processing functions in older adults.

This study investigated the association between exercise type and inhibition of prepotent responses and error detection. Totally, 75 adults (M = 68.88 years) were classified into one of three exercise groups: those who were regular participants in open- or closed-skill forms of exercise, and those who exercised only irregularly. The participants completed a Stroop and task-switching tasks with event-related brain potentials (ERPs) recorded. The results revealed that regular exercisers displayed faster reaction times (RTs) in the Stroop task compared with irregular exercisers. The open-skill exercisers exhibited smaller N200 and larger P300a amplitudes in the Stroop task compared with irregular exercisers. Furthermore, the open-skill exercisers showed a tendency of shorter error-related negativity latencies at the task-witching test. The findings suggest that older adults may gain extra cognitive benefits in areas such as inhibition functioning and error processing from participating in open-skill forms of physical exercises.

A high-density genetic recombination map of sequence-tagged sites for sorghum, as a framework for comparative structural and evolutionary genomics of tropical grains and grasses.

We report a genetic recombination map for Sorghum of 2512 loci spaced at average 0.4 cM ( approximately 300 kb) intervals based on 2050 RFLP probes, including 865 heterologous probes that foster comparative genomics of Saccharum (sugarcane), Zea (maize), Oryza (rice), Pennisetum (millet, buffelgrass), the Triticeae (wheat, barley, oat, rye), and Arabidopsis. Mapped loci identify 61.5% of the recombination events in this progeny set and reveal strong positive crossover interference acting across intervals of

Chinese yam (Dioscorea alata cv. Tainung No. 2) feeding exhibited antioxidative effects in hyperhomocysteinemia rats.

Antioxidative effects of Dioscorea alata (D. alata) were investigated in hyperhomocysteinemia (HHcy) induced by methionine (Met) oral feeding (1 (g/kg of BW)/day). HHcy rats were fed a standard laboratory chow supplemented without or with freeze-dried D. alata powder at 1, 2.5, and 5 (g/kg of BW)/day, assigned as Met, Met + D1, Met + D2, and Met + D3 groups, respectively. Twelve weeks after D. alata feeding, plasma homocysteine levels (16.3-24.2 microM) were significantly decreased compared to that of the Met group (34.1 +/- 9.9 microM) (p < 0.01), and similar to the basal level (15.0 +/- 1.9 microM). Thrombin-induced platelet aggregation (PA) of the Met + D2 and Met + D3 groups was significantly lower than that of the Met group. Plasma malondialdehyde levels, an indicator of lipid peroxidation, and hepatic reactive oxygen species, an indicator of oxidative stress, of HHcy with D. alata feeding were significantly lower than that without D. alata feeding. The hepatic catalase in the Met + D2 and Met + D3 groups was significantly elevated compared to that in the Met group. D. alata feeding did not significantly change hepatic superoxide dismutase, glutathione peroxidase, and glutathione reductase, which were adaptively enhanced by Met feeding. The decreased glutathione/glutathione disulfide ratio in the Met group was increased after D. alata feeding. These results indicated that HHcy induced by Met could be reversed by D. alata feeding. D. alata feeding exhibited its antioxidative effects in HHcy including alleviating PA, lipid peroxidation, and oxidative stress, but did not induce activity of antioxidant enzymes which had already adaptively increased by HHcy.

Valproic acid enhances Oct4 promoter activity through PI3K/Akt/mTOR pathway activated nuclear receptors.

Valproic acid (VPA) has been shown to increase the reprogramming efficiency of induced pluripotent stem cells (iPSC) from somatic cells, but the mechanism by which VPA enhances iPSC induction has not been defined. Here we demonstrated that VPA directly activated Oct4 promoter activity through activation of the PI3K/Akt/mTOR signaling pathway that targeted the proximal hormone response element (HRE, -41∼-22) in this promoter. The activating effect of VPA is highly specific as similar compounds or constitutional isomers failed to instigate Oct4 promoter activity. We further demonstrated that the upstream 2 half-sites in this HRE were essential to the activating effect of VPA and they were targeted by a subset of nuclear receptors, such as COUP-TFII and TR2. These findings show the first time that NRs are implicated in the VPA stimulated expression of stem cell-specific factors and should invite more investigation on the cooperation between VPA and NRs on iPSC induction.

The hepatoprotective effect of Bupleurum kaoi, an endemic plant to Taiwan, against dimethylnitrosamine-induced hepatic fibrosis in rats.

In the present study, three materials extracted or isolated from the roots of B. kaoi, an endemic plant to Taiwan, were used to be examined the hepatoprotective effect against dimethylnitrosamine (DMN)-induced hepatic fibrosis in rats, they were water extract (BKW), polysaccharide-enriched fractions (BKP) and saponin-enriched fractions (BKS). After treated with DMN for 4 weeks, the levels of aminotrasferases (GOT, GPT) were significantly elevated in serum, and the levels of total protein (TP) and albumin were significantly decreased in serum and liver homogenates. Furthermore, the collagen contents were significantly elevated in liver homogenates and corresponded to the hepatofibrotic pathological examination. As the results showed, treated with groups of BKW, BKP, BKS markedly reduced GOT, GPT levels in rats serum. In addition, treated with groups of BKW, BKP, BKS markedly raised TP levels in rats serum and liver homogenates. Furthermore, treated with groups of BKW, BKP markedly raised albumin levels in rats serum and liver homogenates. Treated with groups of BKW, BKP, BKS markedly raised interferon-gamma (IFN-gamma) levels in rats serum, where only BKS and silymarin markedly raised interkeukin-10 (IL-10) levels in rats serum compared to that of DMN treated rats. None of test materials of B. kaoi except silymarin reduced the malondialdehyde (MDA) levels, but BKW, BKP markedly raised hepatic glutathione (GSH) levels to reveal the activity of anti-lipid peroxidation. Otherwise, treated with groups of BKW, BKP, BKS significantly reduced collagen contents in rats liver homogenates. In conclusion, B. kaoi demonstrated the anti-inflammatory and anti-fibrotic activities followed by anti-oxidant activity of enhanced GSH production, enhanced the liver cell regeneration and concerned with regulations of INF-gamma and IL-10. The ability of hepatoprotective and anti-fibrotic activities of B. kaoi are higher than B. chinense, a Bupleuri Radix imported from China to Taiwan.

Hairy root cultures of Gynostemma pentaphyllum (Thunb.) Makino: a promising approach for the production of gypenosides as an alternative of ginseng saponins.

Hairy root cultures of Gynostemma pentaphyllum were established by infecting leaf discs with Agrobacterium rhizogenes. The dry biomass of hairy roots grown in MS medium for 49 days was 7.3 g l(-1) with a gypenoside content of 38 mg g(-1) dry wt.

Protective effect of water yam (Dioscorea alata L.) extract on the copper-driven fenton reaction and X-ray induced DNA damage in vitro.

The rhizome extract of Dioscorea has been shown to possess radical scavenging activity. In this study, the protective effect of water yam (Dioscorea alata L.) rhizome extract on calf thymus DNA and plasmid DNA strand breakage by the copper-driven Fenton reaction and X-irradiation was examined. The protective activity in vitro of four lyophilized extracts obtained from yam rhizomes: (1) aqueous extract (YAE); (2) 30% ethanolic extract (YEE); (3) aqueous extract boiled for 30 min (BYAE); and (4) 30% ethanolic extract boiled for 30 min (BYEE) were evaluated by ethidium bromide binding assay and DNA nicking assay. The YAE, YEE, and BYEE effectively inhibited the copper-driven Fenton reaction-induced damage of calf thymus DNA, while inhibition was less pronounced in the case of X-ray induced strand breakage of plasmid DNA. While BYAE potently inhibited X-ray induced strand breaks in plasmid pGL3 DNA, it failed to inhibit, and even greatly enhanced copper-H(2)O(2) induced damage of calf thymus DNA. The present results demonstrate strong copper chelating and weak hydroxyl radical scavenging activities in yam rhizome extracts, and these activities may vary depending on the procedures used in preparing the extract.