48 research outputs found
Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data
From inflammaging to healthy aging by dietary lifestyle choices: is epigenetics the key to personalized nutrition?
Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping
The suprachiasmatic nuclei (SCN), the central circadian pacemakers in mammals, comprise a multiscale neuronal system that times daily events. We use recent advances in graphics processing unit computing to generate a multiscale model for the SCN that resolves cellular electrical activity down to the timescale of individual action potentials and the intracellular molecular events that generate circadian rhythms. We use the model to study the role of the neurotransmitter GABA in synchronizing circadian rhythms among individual SCN neurons, a topic of much debate in the circadian community. The model predicts that GABA signaling has two components: phasic (fast) and tonic (slow). Phasic GABA postsynaptic currents are released after action potentials, and can both increase or decrease firing rate, depending on their timing in the interspike interval, a modeling hypothesis we experimentally validate; this allows flexibility in the timing of circadian output signals. Phasic GABA, however, does not significantly affect molecular timekeeping. The tonic GABA signal is released when cells become very excited and depolarized; it changes the excitability of neurons in the network, can shift molecular rhythms, and affects SCN synchrony. We measure which neurons are excited or inhibited by GABA across the day and find GABA-excited neurons are synchronized by—and GABA-inhibited neurons repelled from—this tonic GABA signal, which modulates the synchrony in the SCN provided by other signaling molecules. Our mathematical model also provides an important tool for circadian research, and a model computational system for the many multiscale projects currently studying brain function
Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping
The suprachiasmatic nuclei (SCN), the central circadian pacemakers in mammals, comprise a multiscale neuronal system that times daily events. We use recent advances in graphics processing unit computing to generate a multiscale model for the SCN that resolves cellular electrical activity down to the timescale of individual action potentials and the intracellular molecular events that generate circadian rhythms. We use the model to study the role of the neurotransmitter GABA in synchronizing circadian rhythms among individual SCN neurons, a topic of much debate in the circadian community. The model predicts that GABA signaling has two components: phasic (fast) and tonic (slow). Phasic GABA postsynaptic currents are released after action potentials, and can both increase or decrease firing rate, depending on their timing in the interspike interval, a modeling hypothesis we experimentally validate; this allows flexibility in the timing of circadian output signals. Phasic GABA, however, does not significantly affect molecular timekeeping. The tonic GABA signal is released when cells become very excited and depolarized; it changes the excitability of neurons in the network, can shift molecular rhythms, and affects SCN synchrony. We measure which neurons are excited or inhibited by GABA across the day and find GABA-excited neurons are synchronized by—and GABA-inhibited neurons repelled from—this tonic GABA signal, which modulates the synchrony in the SCN provided by other signaling molecules. Our mathematical model also provides an important tool for circadian research, and a model computational system for the many multiscale projects currently studying brain function
Estimating the Potential Toxicity of Chemicals Associated with Hydraulic Fracturing Operations Using Quantitative Structure–Activity Relationship Modeling
The United States
Environmental Protection Agency (EPA) identified
1173 chemicals associated with hydraulic fracturing fluids, flowback,
or produced water, of which 1026 (87%) lack chronic oral toxicity
values for human health assessments. To facilitate the ranking and
prioritization of chemicals that lack toxicity values, it may be useful
to employ toxicity estimates from quantitative structure–activity
relationship (QSAR) models. Here we describe an approach for applying
the results of a QSAR model from the TOPKAT program suite, which provides
estimates of the rat chronic oral lowest-observed-adverse-effect level
(LOAEL). Of the 1173 chemicals, TOPKAT was able to generate LOAEL
estimates for 515 (44%). To address the uncertainty associated with
these estimates, we assigned qualitative confidence scores (high,
medium, or low) to each TOPKAT LOAEL estimate, and found 481 to be
high-confidence. For 48 chemicals that had both a high-confidence
TOPKAT LOAEL estimate and a chronic oral reference dose from EPA’s
Integrated Risk Information System (IRIS) database, Spearman rank
correlation identified 68% agreement between the two values (permutation
p-value =1 × 10<sup>–11</sup>). These results provide
support for the use of TOPKAT LOAEL estimates in identifying and prioritizing
potentially hazardous chemicals. High-confidence TOPKAT LOAEL estimates
were available for 389 of 1026 hydraulic fracturing-related chemicals
that lack chronic oral RfVs and OSFs from EPA-identified sources,
including a subset of chemicals that are frequently used in hydraulic
fracturing fluids
Overview of Chronic Oral Toxicity Values for Chemicals Present in Hydraulic Fracturing Fluids, Flowback, and Produced Waters
Concerns
have been raised about potential public health effects
that may arise if hydraulic fracturing-related chemicals were to impact
drinking water resources. This study presents an overview of the chronic
oral toxicity valuesspecifically, chronic oral reference values
(RfVs) for noncancer effects, and oral slope factors (OSFs) for cancerthat
are available for a list of 1173 chemicals that the United States
(U.S.) Environmental Protection Agency (EPA) identified as being associated
with hydraulic fracturing, including 1076 chemicals used in hydraulic
fracturing fluids and 134 chemicals detected in flowback or produced
waters from hydraulically fractured wells. The EPA compiled RfVs and
OSFs using six governmental and intergovernmental data sources. Ninety
(8%) of the 1076 chemicals reported in hydraulic fracturing fluids
and 83 (62%) of the 134 chemicals reported in flowback/produced water
had a chronic oral RfV or OSF available from one or more of the six
sources. Furthermore, of the 36 chemicals reported in hydraulic fracturing
fluids in at least 10% of wells nationwide (identified from EPA’s
analysis of the FracFocus Chemical Disclosure Registry 1.0), 8 chemicals
(22%) had an available chronic oral RfV. The lack of chronic oral
RfVs and OSFs for the majority of these chemicals highlights the significant
knowledge gap that exists to assess the potential human health hazards
associated with hydraulic fracturing