Publications by authors named "R J Andrews"

1,610 Publications

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Single-Nucleus RNA Sequencing Identifies New Classes of Proximal Tubular Epithelial Cells in Kidney Fibrosis.

J Am Soc Nephrol 2021 Jun 21. Epub 2021 Jun 21.

D Fraser, Wales Kidney Research Unit, Cardiff University, Cardiff, United Kingdom of Great Britain and Northern Ireland

Background: Proximal tubular cells (PTCs) are the most abundant cell type in the kidney. PTCs are central to normal kidney function and to regeneration versus organ fibrosis following injury. This study used single-nucleus RNA sequencing (snRNA-seq) to describe the phenotype of PTCs in renal fibrosis.

Methods: Kidneys were harvested from naïve mice and from mice with renal fibrosis induced by chronic aristolochic acid administration. Nuclei were isolated using Nuclei EZ Lysis buffer. Libraries were prepared on the 10X platform and snRNA-seq completed using the Illumina NextSeq 550 System. Genome mapping was carried out with high-performance computing.

Results: A total of 23,885 nuclei were analysed. PTCs were found in five abundant clusters, mapping to S1, S1-2, S2, S2-cortical S3, and medullary S3 segments. Additional cell clusters ("new PTC clusters") were at low abundance in normal kidney and in increased number in kidneys undergoing regeneration/fibrosis following injury. These clusters exhibited clear molecular phenotypes, permitting labelling as proliferating, New-PT1, New-PT2, and (present only following injury) New-PT3. Each cluster exhibited a unique gene expression signature, including multiple genes previously associated with renal injury response and fibrosis progression. Comprehensive pathway analyses revealed metabolic reprogramming, enrichment of cellular communication and cell motility, and various immune activations in new PTC clusters. In ligand-receptor analysis, new PTC clusters promoted fibrotic signaling to fibroblasts and inflammatory activation to macrophages.

Conclusion: These data identify unrecognized PTC phenotype heterogeneity and reveal novel PTCs associated with kidney fibrosis.
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http://dx.doi.org/10.1681/ASN.2020081143DOI Listing
June 2021

Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer's disease.

Brain 2021 Jun 18. Epub 2021 Jun 18.

The Rockefeller University, New York, NY, 10065 USA.

Dysregulation of glutamatergic neural circuits has been implicated in a cycle of toxicity, believed among the neurobiological underpinning of Alzheimer's disease. Previously, we reported preclinical evidence that the glutamate modulator riluzole, which is FDA-approved for the treatment of amyotrophic lateral sclerosis, has potential benefits on cognition, structural and molecular markers of aging and Alzheimer's disease. The objective of this study was to evaluate in a pilot clinical trial, using neuroimaging biomarkers, the potential efficacy and safety of riluzole in patients with Alzheimer's disease as compared to placebo. A 6-month phase 2 double-blind, randomized, placebo-controlled study was conducted at two sites. Participants consisted of males and females, 50 to 95 years of age, with a clinical diagnosis of probable Alzheimer's disease, and Mini-Mental State Examination between 19 and 27. Ninety-four participants were screened, fifty subjects that met inclusion criteria were randomly assigned to receive 50 mg riluzole (n = 26) or placebo (n = 24) twice a day. Twenty-two riluzole-treated and 20 placebo participants completed the study. Primary endpoints were baseline to 6 months changes in a) cerebral glucose metabolism as measured with fluorodeoxyglucose-positron emission tomography in pre-specified regions of interest (hippocampus, posterior cingulate, precuneus, lateral temporal, inferior parietal, frontal) and b) changes in posterior cingulate levels of the neuronal viability marker N-acetylaspartate as measured with in vivo proton magnetic resonance spectroscopy. Secondary outcome measures were neuropsychological testing for correlation with neuroimaging biomarkers and in vivo measures of glutamate in posterior cingulate measured with magnetic resonance spectroscopy as a potential marker of target engagement. Measures of cerebral glucose metabolism, a well-established Alzheimer's disease biomarker and predictor of disease progression, declined significantly less in several pre-specified regions of interest with the most robust effect in posterior cingulate, and effects in precuneus, lateral temporal, right hippocampus and frontal cortex in riluzole-treated subjects in comparison to placebo group. No group effect was found in measures of N-acetylaspartate levels. A positive correlation was observed between cognitive measures and regional cerebral glucose metabolism. A group by visit interaction was observed in glutamate levels in posterior cingulate, potentially suggesting engagement of glutamatergic system by riluzole. In vivo glutamate levels positively correlated with cognitive performance. These findings support our main primary hypothesis that cerebral glucose metabolism would be better preserved in the riluzole treated group than in the placebo group and investigations in future larger and longer studies to test riluzole as a potential novel therapeutic intervention for Alzheimer's disease.
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http://dx.doi.org/10.1093/brain/awab222DOI Listing
June 2021

Fur seals do, but sea lions don't - cross taxa insights into exhalation during ascent from dives.

Philos Trans R Soc Lond B Biol Sci 2021 Aug 14;376(1830):20200219. Epub 2021 Jun 14.

Sea Mammal Research Unit, Scottish Oceans Institute, University of St Andrews, Fife KY16 8LB, UK.

Management of gases during diving is not well understood across marine mammal species. Prior to diving, phocid (true) seals generally exhale, a behaviour thought to assist with the prevention of decompression sickness. Otariid seals (fur seals and sea lions) have a greater reliance on their lung oxygen stores, and inhale prior to diving. One otariid, the Antarctic fur seal (), then exhales during the final 50-85% of the return to the surface, which may prevent another gas management issue: shallow-water blackout. Here, we compare data collected from animal-attached tags (video cameras, hydrophones and conductivity sensors) deployed on a suite of otariid seal species to examine the ubiquity of ascent exhalations for this group. We find evidence for ascent exhalations across four fur seal species, but that such exhalations are absent for three sea lion species. Fur seals and sea lions are no longer genetically separated into distinct subfamilies, but are morphologically distinguished by the thick underfur layer of fur seals. Together with their smaller size and energetic dives, we suggest their air-filled fur might underlie the need to perform these exhalations, although whether to reduce buoyancy and ascent speed, for the avoidance of shallow-water blackout or to prevent other cardiovascular management issues in their diving remains unclear. This article is part of the theme issue 'Measuring physiology in free-living animals (Part I)'.
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http://dx.doi.org/10.1098/rstb.2020.0219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200655PMC
August 2021

Ambulatory Phlebectomy and Sclerotherapy as Tools for the Treatment of Varicose Veins and Telangiectasias.

Semin Intervent Radiol 2021 Jun 3;38(2):160-166. Epub 2021 Jun 3.

Interventional Radiology Program, University of North Carolina School of Medicine, Chapel Hill, North Carolina.

Treatment of chronic venous disease is a fascinating and rewarding undertaking. Once the truncal reflux is addressed, several options are available that can be used to treat the associated ulcers, varicosities, reticular veins, and telangiectasias. This review will focus on two widely employed procedures: ambulatory phlebectomy and sclerotherapy.
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http://dx.doi.org/10.1055/s-0041-1727151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175112PMC
June 2021

Menopause impacts human brain structure, connectivity, energy metabolism, and amyloid-beta deposition.

Sci Rep 2021 Jun 9;11(1):10867. Epub 2021 Jun 9.

Departments of Pharmacology and Neurology, College of Medicine, University of Arizona, Tucson, AZ, USA.

All women undergo the menopause transition (MT), a neuro-endocrinological process that impacts aging trajectories of multiple organ systems including brain. The MT occurs over time and is characterized by clinically defined stages with specific neurological symptoms. Yet, little is known of how this process impacts the human brain. This multi-modality neuroimaging study indicates substantial differences in brain structure, connectivity, and energy metabolism across MT stages (pre-menopause, peri-menopause, and post-menopause). These effects involved brain regions subserving higher-order cognitive processes and were specific to menopausal endocrine aging rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized post-menopause, and gray matter volume (GMV) recovered in key brain regions for cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance post-menopause, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri-menopausal and post-menopausal women carrying apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer's disease, relative to genotype-matched males. These data show that human menopause is a dynamic neurological transition that significantly impacts brain structure, connectivity, and metabolic profile during midlife endocrine aging of the female brain.
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http://dx.doi.org/10.1038/s41598-021-90084-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190071PMC
June 2021