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"Cunningham, Greg P"
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Journey to Jupiter
The King of Planets, Jupiter is both the largest planet in our solar system and one of the most interesting. This book examines how Jupiter formed, its atmosphere and major features, its many moons, and the history of its human exploration.
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Age‐associated change in pyruvate metabolism investigated with hyperpolarized 13C‐MRI of the human brain
In this study, hyperpolarized 13C MRI (HP‐13C MRI) was used to investigate changes in the uptake and metabolism of pyruvate with age. Hyperpolarized 13C‐pyruvate was administered to healthy aging individuals (N = 35, ages 21–77) and whole‐brain spatial distributions of 13C‐lactate and 13C‐bicarbonate production were measured. Linear mixed‐effects regressions were performed to compute the regional percentage change per decade, showing a significant reduction in both normalized 13C‐lactate and normalized 13C‐bicarbonate production with age: −7%±2% per decade for 13C‐lactate and −9%±4% per decade for 13C‐bicarbonate. Certain regions, such as the right medial precentral gyrus, showed greater rates of change while the left caudate nucleus had a flat 13C‐lactate versus age and a slightly increasing 13C‐bicarbonate versus age. The results show that both the production of lactate (visible as 13C‐lactate signal) as well as the consumption of monocarboxylates to make acetyl‐CoA (visible as 13C‐bicarbonate signal) decrease with age and that the rate of change varies by brain region. In this work, hyperpolarized 13C MRI was used to investigate lactate and bicarbonate production in the brain versus age. The results show that both the production of lactate (visible as 13C‐lactate signal) as well as the consumption of monocarboxylates to make acetyl‐CoA (visible as 13C‐bicarbonate signal) decrease with age and that the rate of change varies by brain region.
Journal Article
Stimulus onset quenches neural variability: a widespread cortical phenomenon
The authors measured the variability of neuronal responses across a large number of datasets and cortical areas. They found that variability decreased in response to all stimuli tested, whether the animal was awake, behaving or anesthetized, suggesting that the stabilization of cortex in response to an input is a general cortical property.
Neural responses are typically characterized by computing the mean firing rate, but response variability can exist across trials. Many studies have examined the effect of a stimulus on the mean response, but few have examined the effect on response variability. We measured neural variability in 13 extracellularly recorded datasets and one intracellularly recorded dataset from seven areas spanning the four cortical lobes in monkeys and cats. In every case, stimulus onset caused a decline in neural variability. This occurred even when the stimulus produced little change in mean firing rate. The variability decline was observed in membrane potential recordings, in the spiking of individual neurons and in correlated spiking variability measured with implanted 96-electrode arrays. The variability decline was observed for all stimuli tested, regardless of whether the animal was awake, behaving or anaesthetized. This widespread variability decline suggests a rather general property of cortex, that its state is stabilized by an input.
Journal Article
Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms
Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both by inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of mitochondrial membrane potential is observed in primary and immortalized mammalian cells as well as in Drosophila . These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial function even in defective mitochondria.
Journal Article
Age‐associated change in pyruvate metabolism investigated with hyperpolarized 13 C‐MRI of the human brain
In this study, hyperpolarized 13 C MRI (HP‐ 13 C MRI) was used to investigate changes in the uptake and metabolism of pyruvate with age. Hyperpolarized 13 C‐pyruvate was administered to healthy aging individuals ( N = 35, ages 21–77) and whole‐brain spatial distributions of 13 C‐lactate and 13 C‐bicarbonate production were measured. Linear mixed‐effects regressions were performed to compute the regional percentage change per decade, showing a significant reduction in both normalized 13 C‐lactate and normalized 13 C‐bicarbonate production with age: per decade for 13 C‐lactate and per decade for 13 C‐bicarbonate. Certain regions, such as the right medial precentral gyrus, showed greater rates of change while the left caudate nucleus had a flat 13 C‐lactate versus age and a slightly increasing 13 C‐bicarbonate versus age. The results show that both the production of lactate (visible as 13 C‐lactate signal) as well as the consumption of monocarboxylates to make acetyl‐CoA (visible as 13 C‐bicarbonate signal) decrease with age and that the rate of change varies by brain region.
Journal Article
Dynamics and predicted distribution of an irrupting ‘sleeper’ population: fallow deer in Tasmania
Sleeper populations of non-native species can remain at low abundance for decades before irrupting. For over a century, fallow deer (Dama dama) in the island state of Tasmania, Australia, remained at low abundance and close to the region in which they were released. Recently, there are indications the population has increased in abundance and distribution. Here, we spatially quantify the population change using a time series of annual spotlight counts from 1985 to 2019 (up to 172 transects annually, totalling of 5756 transect counts). Next, we predict the potential for further range expansion, using global occurrences to characterise the species’ climatic niche, and remote-camera surveys (3225 camera sites) to model fine-grained habitat suitability. Spotlight counts of fallow deer increased by 11.5% annually, resulting in a 40-fold increase from 1985 to 2019. The core distribution increased 2.9-fold during this 35-year period, and now spans c. 27% of Tasmania’s land area. Satellite populations have established in locations where farmed deer have escaped or been released, suggesting that humans have facilitated range expansion via new introduction events. Based on climate and habitat suitability, our models predict that 56% of Tasmania is suitable under the current climate. This suggests range expansion is likely to continue unless the population is actively managed, which could include the eradication of satellite populations and containment of core populations. This case study cautions that despite over a century of slow population growth, sleeper populations of non-native species can abruptly increase.
Journal Article
Detecting microstructural deviations in individuals with deep diffusion MRI tractometry
Most diffusion magnetic resonance imaging studies of disease rely on statistical comparisons between large groups of patients and healthy participants to infer altered tissue states in the brain; however, clinical heterogeneity can greatly challenge their discriminative power. There is currently an unmet need to move away from the current approach of group-wise comparisons to methods with the sensitivity to detect altered tissue states at the individual level. This would ultimately enable the early detection and interpretation of microstructural abnormalities in individual patients, an important step towards personalized medicine in translational imaging. To this end, Detect was developed to advance diffusion magnetic resonance imaging tractometry towards single-patient analysis. By operating on the manifold of white-matter pathways and learning normative microstructural features, our framework captures idiosyncrasies in patterns along white-matter pathways. Our approach paves the way from traditional group-based comparisons to true personalized radiology, taking microstructural imaging from the bench to the bedside.
Journal Article
New Resources for Marine Genomics: Bacterial Artificial Chromosome Libraries for the Eastern and Pacific Oysters (Crassostrea virginica and C. gigas)
Large-insert genomic bacterial artificial chromosome (BAC) libraries of two culturally and economically important oyster species, Crassostrea virginica and C. gigas, have been developed as part of an international effort to develop tools and reagents that will advance our ability to conduct genetic and genomic research. A total of 73,728 C. gigas clones with an average insert size of 152 kb were picked and arrayed representing an 11.8-fold genome coverage. A total of 55,296 clones with an average insert size of 150 kb were picked and arrayed for C. virginica, also representing an 11.8-fold genome coverage. The C. gigas and C. virginica libraries were screened with probes derived from selected oyster genes using high-density BAC colony filter arrays. The probes identified 4 to 25 clones per gene for C. virginica and 5 to 50 clones per gene for C. gigas. We conducted a preliminary analysis of genetic polymorphism represented in the C. gigas library. The results suggest that the degree of divergence among similar sequences is highly variable and concentrated in intronic regions. Evidence supporting allelic polymorphism is reported for two genes and allelic and/or locus specific polymorphism for several others. Classical inheritance studies are needed to confirm the nature of these polymorphisms. The oyster BAC libraries are publicly available to the research community on a cost-recovery basis at www.genome.clemson.edu.
Journal Article
Mapping the Morphology of DNA on Carbon Nanotube-Based Sensors in Solution using X-ray Scattering Interferometry
Single-walled carbon nanotubes (SWCNTs) with adsorbed single-stranded DNA (ssDNA) are applied as sensors to investigate biological systems, with applications ranging from clinical diagnostics to agricultural biotechnology. Unique ssDNA sequences render SWCNTs selectively responsive to target analytes. However, it remains unclear how the ssDNA conformation on the SWCNT surface contributes to their ultimate functionality, as observations have been constrained to computational models or experiments under dehydrated states that differ substantially from the aqueous biological environments in which the nanosensors are applied. Herein, we demonstrate a direct mode of measuring in-solution ssDNA geometries on SWCNTs via X-ray scattering interferometry (XSI), which leverages the interference pattern produced by AuNP tags conjugated to ssDNA on the SWCNT surface. We employ XSI to quantify distinct surface-adsorbed morphologies for two ssDNA oligomer lengths, conformational changes as a function of ionic strength, and the mechanism of dopamine sensing for a previously established ssDNA-SWCNT nanosensor, with corresponding ab initio modeling for visualization. We show that the shorter oligomer, (GT)6, adopts a highly ordered structure of stacked rings along the SWCNT axis, compared to the longer, less periodic (GT)15 wrapping. The presence of dopamine elicits a simultaneous axial elongation and radial constriction of the ssDNA closer to the SWCNT surface. Application of XSI to probe solution-phase morphologies of nanoparticle-based tools will yield insights into sensing mechanisms and inform future design strategies for polymer-functionalized SWCNT technologies.
Paper
Tractometry-based Anomaly Detection for Single-subject White Matter Analysis
There is an urgent need for a paradigm shift from group-wise comparisons to individual diagnosis in diffusion MRI (dMRI) to enable the analysis of rare cases and clinically-heterogeneous groups. Deep autoencoders have shown great potential to detect anomalies in neuroimaging data. We present a framework that operates on the manifold of white matter (WM) pathways to learn normative microstructural features, and discriminate those at genetic risk from controls in a paediatric population.
Paper