Structure–activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells

The cytotoxicity of three alkaloids from the roots of Aconitum yesoense var. macroyesoense as well as 36 semi-synthetic C20-diterpenoid atisine-type alkaloid derivatives against A549 human lung carcinoma cells was examined. Ten acylated alkaloid derivatives, pseudokobusine 11-veratroate (9), 11-anisoate (12), 6,11-dianisoate (14), 11-p-nitrobenzoate (18), 11,15-di-p-nitrobenzoate (22), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate (27), and kobusine 11-p-trifluoromethylbenzoate (35), 11-m-trifluoromethylbenzoate (36) and 11,15-di-p-nitrobenzoate (39), exhibited cytotoxic activity, and 11,15-dianisoylpseudokobusine (16) was found to be the most potent cytotoxic agent. Their IC50 values against A549 cells ranged from 1.72 to 5.44 μM. In the occurrence of cytotoxic effects of atisine-type alkaloids, replacement by an acyl group at both C-11 and C-15 resulted in the enhancement of activity of the parent alkaloids compared to that from having hydroxy groups at this position, and the presence of a hydroxy group at the C-6 position was required for the cytotoxic effects. These acylated alkaloid derivatives inhibit cell growth through G1 arrest

Hydrogeochemical evolution of groundwater in a Quaternary sediment and Cretaceous sandstone unconfined aquifer in Northwestern China

A better understanding of the hydrogeochemical evolution of groundwater in vulnerable aquifers is important for the protection of water resources. To assess groundwater chemistry, groundwater sampling was performed from different representative aquifers in 2012–2013. A Piper trilinear diagram showed that the groundwater types can be classified into Na–SO4 and Na–Cl types. Only one groundwater sample was Na–HCO3 type. The dominant cations for all samples were Na+. However, the dominant anions varied from HCO3− to SO42−, and as well Cl−. The mean total dissolved solid (TDS) content of groundwater in the region was 1889 mg/L. Thus, only 20% of groundwater samples meet Chinese drinking water standards (< 1000 mg/L). Principal component analysis (PCA) combined with hierarchical cluster analysis (HCA) and self-organizing maps (SOM) were applied for the classification of the groundwater geochemistry. The three first principal components explained 58, 20, and 16% of the variance, respectively. The first component reflects sulfate minerals (gypsum, anhydrite) and halite dissolution, and/or evaporation in the shallow aquifer. The second and third components are interpreted as carbonate rock dissolution. The reason for two factors is that the different aquifers give rise to different degree of hydrogeochemical evolution (different travel distances and travel times). Identified clusters for evolution characteristic and influencing factors were confirmed by the PCA–HCA methods. Using information from eight ion components and SOM, formation mechanisms and influencing factors for the present groundwater quality were determined

Coordinated generation of multiple ocular-like cell lineages and fabrication of functional corneal epithelial cell sheets from human iPS cells

We describe a protocol for the generation of a functional and transplantable corneal epithelium derived from human induced pluripotent stem (iPS) cells. When this protocol is followed, a proportion of iPS cells spontaneously form circular colonies, each of which is composed of four concentric zones. Cells in these zones have different morphologies and immunostaining characteristics, resembling neuroectoderm, neural crest, ocular-surface ectoderm, or surface ectoderm. We have named this 2D colony a 'SEAM' (self-formed ectodermal autonomous multizone), and previously demonstrated that cells within the SEAM have the potential to give rise to anlages of different ocular lineages, including retinal cells, lens cells, and ocular-surface ectoderm. To investigate the translational potential of the SEAM, cells within it that resemble ocular-surface epithelia can be isolated by pipetting and FACS sorting into a population of corneal epithelial-like progenitor cells. These can be expanded and differentiated to form an epithelial layer expressing K12 and PAX6, and able to recover function in an animal model of corneal epithelial dysfunction after surgical transplantation. The whole protocol, encompassing human iPS cell preparation, autonomous differentiation, purification, and subsequent differentiation, takes between 100 and 120 d, and is of potential use to researchers with an interest in eye development and/or ocular-surface regeneration. Experience with human iPS cell culture and sorting via FACS will be of benefit for researchers performing this protocol

Cognitive style modulates semantic interference effects: evidence from field dependency

The so-called semantic interference effect is a delay in selecting an appropriate target word in a context where semantic neighbours are strongly activated. Semantic interference effect has been described to vary from one individual to another. These differences in the susceptibility to semantic interference may be due to either differences in the ability to engage in lexical-specific selection mechanisms or to differences in the ability to engage more general, top-down inhibition mechanisms which suppress unwanted responses based on task-demands. However, semantic interference may also be modulated by an individual’s disposition to separate relevant perceptual signals from noise, such as a field-independent (FI) or a field-dependent (FD) cognitive style. We investigated the relationship between semantic interference in picture naming and in an STM probe task and both the ability to inhibit responses top-down (measured through a Stroop task) and a FI/FD cognitive style measured through the embedded figures test (EFT). We found a significant relationship between semantic interference in picture naming and cognitive style—with semantic interference increasing as a function of the degree of field dependence—but no associations with the semantic probe and the Stroop task. Our results suggest that semantic interference can be modulated by cognitive style, but not by differences in the ability to engage top-down control mechanisms, at least as measured by the Stroop task

The Stimulatory Gαs Protein Is Involved in Olfactory Signal Transduction in Drosophila

Seven-transmembrane receptors typically mediate olfactory signal transduction by coupling to G-proteins. Although insect odorant receptors have seven transmembrane domains like G-protein coupled receptors, they have an inverted membrane topology, constituting a key difference between the olfactory systems of insects and other animals. While heteromeric insect ORs form ligand-activated non-selective cation channels in recombinant expression systems, the evidence for an involvement of cyclic nucleotides and G-proteins in odor reception is inconsistent. We addressed this question in vivo by analyzing the role of G-proteins in olfactory signaling using electrophysiological recordings. We found that Gαs plays a crucial role for odorant induced signal transduction in OR83b expressing olfactory sensory neurons, but not in neurons expressing CO2 responsive proteins GR21a/GR63a. Moreover, signaling of Drosophila ORs involved Gαs also in a heterologous expression system. In agreement with these observations was the finding that elevated levels of cAMP result in increased firing rates, demonstrating the existence of a cAMP dependent excitatory signaling pathway in the sensory neurons. Together, we provide evidence that Gαs plays a role in the OR mediated signaling cascade in Drosophila

Cognitive performance in healthy older adults relates to spontaneous switching between states of functional connectivity during rest

Growing evidence has shown that brain activity at rest slowly wanders through a repertoire of different states, where whole-brain functional connectivity (FC) temporarily settles into distinct FC patterns. Nevertheless, the functional role of resting-state activity remains unclear. Here, we investigate how the switching behavior of resting-state FC relates with cognitive performance in healthy older adults. We analyse resting-state fMRI data from 98 healthy adults previously categorized as being among the best or among the worst performers in a cohort study of >1000 subjects aged 50+ who underwent neuropsychological assessment. We use a novel approach focusing on the dominant FC pattern captured by the leading eigenvector of dynamic FC matrices. Recurrent FC patterns - or states - are detected and characterized in terms of lifetime, probability of occurrence and switching profiles. We find that poorer cognitive performance is associated with weaker FC temporal similarity together with altered switching between FC states. These results provide new evidence linking the switching dynamics of FC during rest with cognitive performance in later life, reinforcing the functional role of resting-state activity for effective cognitive processing.This project was financed by the Fundação Calouste Gulbenkian (Portugal) (Contract grant number: P-139977; project “Better mental health during ageing based on temporal prediction of individual brain ageing trajectories (TEMPO)”), co-financed by Portuguese North Regional Operational Program (ON.2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER) as well as the Projecto Estratégico co-funded by FCT (PEst-C/SAU/LA0026-/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298) and under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020) under the Portugal 2020 Partnership Agreement through the European Regional Development Fundinfo:eu-repo/semantics/publishedVersio

Acetaminophen Modulates the Transcriptional Response to Recombinant Interferon-β

BACKGROUND: Recombinant interferon treatment can result in several common side effects including fever and injection-site pain. Patients are often advised to use acetaminophen or other over-the-counter pain medications as needed. Little is known regarding the transcriptional changes induced by such co-administration. METHODOLOGY/PRINCIPAL FINDINGS: We tested whether the administration of acetaminophen causes a change in the response normally induced by interferon-beta treatment. CD-1 mice were administered acetaminophen (APAP), interferon-beta (IFN-beta) or a combination of IFN-beta+APAP and liver and serum samples were collected for analysis. Differential gene expression was determined using an Agilent 22 k whole mouse genome microarray. Data were analyzed by several methods including Gene Ontology term clustering and Gene Set Enrichment Analysis. We observed a significant change in the transcription profile of hepatic cells when APAP was co-administered with IFN-beta. These transcriptional changes included a marked up-regulation of genes involved in signal transduction and cell differentiation and down-regulation of genes involved in cellular metabolism, trafficking and the IkappaBK/NF-kappaB cascade. Additionally, we observed a large decrease in the expression of several IFN-induced genes including Ifit-3, Isg-15, Oasl1, Zbp1 and predicted gene EG634650 at both early and late time points. CONCLUSIONS/SIGNIFICANCE: A significant change in the transcriptional response was observed following co-administration of IFN-beta+APAP relative to IFN-beta treatment alone. These results suggest that administration of acetaminophen has the potential to modify the efficacy of IFN-beta treatment

A biophysical model of dynamic balancing of excitation and inhibition in fast oscillatory large-scale networks

Over long timescales, neuronal dynamics can be robust to quite large perturbations, such as changes in white matter connectivity and grey matter structure through processes including learning, aging, development and certain disease processes. One possible explanation is that robust dynamics are facilitated by homeostatic mechanisms that can dynamically rebalance brain networks. In this study, we simulate a cortical brain network using the Wilson-Cowan neural mass model with conduction delays and noise, and use inhibitory synaptic plasticity (ISP) to dynamically achieve a spatially local balance between excitation and inhibition. Using MEG data from 55 subjects we find that ISP enables us to simultaneously achieve high correlation with multiple measures of functional connectivity, including amplitude envelope correlation and phase locking. Further, we find that ISP successfully achieves local E/I balance, and can consistently predict the functional connectivity computed from real MEG data, for a much wider range of model parameters than is possible with a model without ISP

A Thalamocortical Neural Mass Model of the EEG during NREM Sleep and Its Response to Auditory Stimulation

Few models exist that accurately reproduce the complex rhythms of the thalamocortical system that are apparent in measured scalp EEG and at the same time, are suitable for large-scale simulations of brain activity. Here, we present a neural mass model of the thalamocortical system during natural non-REM sleep, which is able to generate fast sleep spindles (12–15 Hz), slow oscillations (<1 Hz) and K-complexes, as well as their distinct temporal relations, and response to auditory stimuli. We show that with the inclusion of detailed calcium currents, the thalamic neural mass model is able to generate different firing modes, and validate the model with EEG-data from a recent sleep study in humans, where closed-loop auditory stimulation was applied. The model output relates directly to the EEG, which makes it a useful basis to develop new stimulation protocols

Mechanisms and models of somatic cell reprogramming

Whitehead Institute for Biomedical Research (Jerome and Florence Brill Graduate Student Fellowship)National Institutes of Health (U.S.) (US NIH grant RO1-CA087869)National Institutes of Health (U.S.) (US NIH grant R37-CA084198)National Science Foundation (U.S.) (NSF Graduate Research Fellowship)National Institutes of Health (U.S.) ((NIH) Kirschstein National Research Service Award,1 F32 GM099153-01A1)Vertex Pharmaceuticals Incorporated (Vertex Scholar