62 research outputs found
Metabolic consequences of interleukin-6 challenge in developing neurons and astroglia
Abstract Background: Maternal immune activation and subsequent interleukin-6 (IL-6) induction disrupt normal brain development and predispose the offspring to developing autism and schizophrenia. While several proteins have been identified as having some link to these developmental disorders, their prevalence is still small and their causative role, if any, is not well understood. However, understanding the metabolic consequences of environmental predisposing factors could shed light on disorders such as autism and schizophrenia. Methods: To gain a better understanding of the metabolic consequences of IL-6 exposure on developing central nervous system (CNS) cells, we separately exposed developing neuron and astroglia cultures to IL-6 for 2 hours while collecting effluent from our gravity-fed microfluidic chambers. By coupling microfluidic technologies to ultra-performance liquid chromatography-ion mobility-mass spectrometry (UPLC-IM-MS), we were able to characterize the metabolic response of these CNS cells to a narrow window of IL-6 exposure. Results: Our results revealed that 1) the use of this technology, due to its superb media volume:cell volume ratio, is ideally suited for analysis of cell-type-specific exometabolome signatures; 2) developing neurons have low secretory activity at baseline, while astroglia show strong metabolic activity; 3) both neurons and astroglia respond to IL-6 exposure in a cell type-specific fashion; 4) the astroglial response to IL-6 stimulation is predominantly characterized by increased levels of metabolites, while neurons mostly depress their metabolic activity; and 5) disturbances in glycerophospholipid metabolism and tryptophan/kynurenine metabolite secretion are two putative mechanisms by which IL-6 affects the developing nervous system. Conclusions: Our findings are potentially critical for understanding the mechanism by which IL-6 disrupts brain function, and they provide information about the molecular cascade that links maternal immune activation to developmental brain disorders
Mediterranean-climate streams and rivers: geographically separated but ecologically comparable freshwater systems
Streams and rivers in mediterranean-climate regions (med-rivers in med-regions) are ecologically unique, with flow regimes reflecting precipitation patterns. Although timing of drying and flooding is predictable, seasonal and annual intensity of these events is not. Sequential flooding and drying, coupled with anthropogenic influences make these med-rivers among the most stressed riverine habitat worldwide. Med-rivers are hotspots for biodiversity in all med-regions. Species in med-rivers require different, often opposing adaptive mechanisms to survive drought and flood conditions or recover from them. Thus, metacommunities undergo seasonal differences, reflecting cycles of river fragmentation and connectivity, which also affect ecosystem functioning. River conservation and management is challenging, and trade-offs between environmental and human uses are complex, especially under future climate change scenarios. This overview of a Special Issue on med-rivers synthesizes information presented in 21 articles covering the five med-regions worldwide: Mediterranean Basin, coastal California, central Chile, Cape region of South Africa, and southwest and southern Australia. Research programs to increase basic knowledge in less-developed med-regions should be prioritized to achieve increased abilities to better manage med-rivers
Mediterranean-climate streams and rivers: geographically separated but ecologically comparable freshwater systems
Structuring Microbial Metabolic Responses to Multiplexed Stimuli via Self-Organizing Metabolomics Maps
SummarySecondary metabolite biosynthesis in microorganisms responds to discrete chemical and biological stimuli; however, untargeted identification of these responses presents a significant challenge. Herein we apply multiplexed stimuli to Streptomyces coelicolor and collect the resulting response metabolomes via ion mobility-mass spectrometric analysis. Self-organizing map (SOM) analytics adapted for metabolomic data demonstrate efficient characterization of the subsets of primary and secondary metabolites that respond similarly across stimuli. Over 60% of all metabolic features inventoried from responses are either not observed under control conditions or produced at greater than 2-fold increase in abundance in response to at least one of the multiplexing conditions, reflecting how metabolites encode phenotypic changes in an organism responding to multiplexed challenges. Using abundance as an additional filter, each of 16 known S. coelicolor secondary metabolites is prioritized via SOM and observed at increased levels (1.2- to 22-fold compared with unperturbed) in response to one or more challenge conditions
Structural Mass Spectrometry: Rapid Methods for Separation and Analysis of Peptide Natural Products
A significant challenge in natural product discovery
is the initial
discrimination of discrete secondary metabolites alongside functionally
similar primary metabolic cellular components within complex biological
samples. A property that has yet to be fully exploited for natural
product identification and characterization is the gas-phase collision
cross section, or, more generally, the mobilityâmass correlation.
Peptide natural products possess many of the properties that distinguish
natural products, as they are frequently characterized by a high degree
of intramolecular bonding and possess extended and compact conformations
among other structural modifications. This report describes a rapid
structural mass spectrometry technique based on ion mobilityâmass
spectrometry for the comparison of peptide natural products to their
primary metabolic congeners using mobilityâmass correlation.
This property is empirically determined using ion mobilityâmass
spectrometry, applied to the analysis of linear versus modified peptides,
and used to discriminate peptide natural products in a crude microbial
extract. Complementary computational approaches are utilized to understand
the structural basis for the separation of primary metabolism derived
linear peptides from secondary metabolite cyclic and modified cyclic
species. These findings provide a platform for enhancing the identification
of secondary metabolic peptides with distinct mobilityâmass
ratios within complex biological samples
Distance Geometry Protocol to Generate Conformations of Natural Products to Structurally Interpret Ion Mobility-Mass Spectrometry Collision Cross Sections
Ion mobility-mass spectrometry (IM-MS)
allows the separation of
ionized molecules based on their charge-to-surface area (IM) and mass-to-charge
ratio (MS), respectively. The IM drift time data that is obtained
is used to calculate the ion-neutral collision cross section (CCS)
of the ionized molecule with the neutral drift gas, which is directly
related to the ion conformation and hence molecular size and shape.
Studying the conformational landscape of these ionized molecules computationally
provides interpretation to delineate the potential structures that
these CCS values could represent, or conversely, structural motifs
not consistent with the IM data. A challenge in the IM-MS community
is the ability to rapidly compute conformations to interpret natural
product data, a class of molecules exhibiting a broad range of biological
activity. The diversity of biological activity is, in part, related
to the unique structural characteristics often observed for natural
products. Contemporary approaches to structurally interpret IM-MS
data for peptides and proteins typically utilize molecular dynamics
(MD) simulations to sample conformational space. However, MD calculations
are computationally expensive, they require a force field that accurately
describes the molecule of interest, and there is no simple metric
that indicates when sufficient conformational sampling has been achieved.
Distance geometry is a computationally inexpensive approach that creates
conformations based on sampling different pairwise distances between
the atoms within the molecule and therefore does not require a force
field. Progressively larger distance bounds can be used in distance
geometry calculations, providing in principle a strategy to assess
when all plausible conformations have been sampled. Our results suggest
that distance geometry is a computationally efficient and potentially
superior strategy for conformational analysis of natural products
to interpret gas-phase CCS data
Ion mobility-mass spectrometry strategies for untargeted systems, synthetic, and chemical biology
Wavelet-Based Peak Detection and a New Charge Inference Procedure for MS/MS Implemented in ProteoWizardâs msConvert
We
report the implementation of high-quality signal processing
algorithms into ProteoWizard, an efficient, open-source software package
designed for analyzing proteomics tandem mass spectrometry data. Specifically,
a new wavelet-based peak-picker (CantWaiT) and a precursor charge
determination algorithm (Turbocharger) have been implemented. These
additions into ProteoWizard provide universal tools that are independent
of vendor platform for tandem mass spectrometry analyses and have
particular utility for intralaboratory studies requiring the advantages
of different platforms convergent on a particular workflow or for
interlaboratory investigations spanning multiple platforms. We compared
results from these tools to those obtained using vendor and commercial
software, finding that in all cases our algorithms resulted in a comparable
number of identified peptides for simple and complex samples measured
on Waters, Agilent, and AB SCIEX quadrupole time-of-flight and Thermo
Q-Exactive mass spectrometers. The mass accuracy of matched precursor
ions also compared favorably with vendor and commercial tools. Additionally,
typical analysis runtimes (âŒ1â100 ms per MS/MS spectrum)
were short enough to enable the practical use of these high-quality
signal processing tools for large clinical and research data sets
Systems-level view of cocaine addiction: The interconnection of the immune and nervous systems
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