Biology subjects

Cox, L. A.

Publications and source records attributed to Cox, L. A..

28 records · Page 2Linked to original sources

bioRxiv2021

Blood pressure and the kidney cortex transcriptome response to high sodium diet challenge in female nonhuman primates

Blood pressure (BP) is influenced by genetic variation and sodium intake. Ninety percent of Americans consume more than the AHA recommended amount of sodium. Studies on the impact of genetic variation and sodium intake on BP in nonhuman primates (NHP) to date have focused on males. We hypothesized that variation in renal transcriptional networks correlate with BP response to high dietary sodium in female baboons. Sodium-naive female baboons (n=7) were fed a low-sodium (LS) diet for 6 weeks followed by a high sodium (HS) diet for 6 weeks. Sodium intake, serum 17 betaestradiol, and ultrasound-guided kidney biopsies for RNA-Seq BP were collected at the end of each diet. BP was continuously measured for 64-hour periods throughout the study by implantable telemetry devices. On the LS diet, Na+ intake and serum 17 beta-estradiol concentration correlated with BP. Kidney transcriptomes differed by diet; analysis by unbiased weighted gene co-expression network analysis revealed modules of genes correlated with BP on the HS diet. Cell type composition of renal biopsies was consistent among all animals for both diets. Network analysis of module genes showed causal networks linking hormone receptors, proliferation and differentiation, methylation, hypoxia, insulin and lipid regulation, and inflammation as regulators underlying variation in BP on the HS diet. Our results show variation in BP correlated with novel kidney gene networks with master regulators PPARG and MYC in female baboons on a HS diet. Identification of mechanisms underlying regulators that influence BP will inform better therapies towards greater precision medicine for women.

genomics↗

bioRxiv2021

Maternal obesity causes fetal cardiac hypertrophy and alters adult offspring myocardial metabolism in mice

Obesity in pregnant women causes fetal cardiac dysfunction and increases offspring cardiovascular disease risk but its effect on myocardial metabolism is unknown. We hypothesised that maternal obesity alters fetal cardiac expression of metabolism-related genes and shifts offspring myocardial substrate preference from glucose towards lipids. Female mice were fed control or obesogenic diets before and during pregnancy. Fetal hearts were studied in late gestation (embryonic day, E18.5; term{approx}E21) and offspring were studied at 3, 6, 9 or 24 months postnatally. Maternal obesity increased heart weight and peroxisome proliferator activated receptor {gamma} (Pparg) expression in female and male fetuses and caused left ventricular diastolic dysfunction in the adult offspring. Cardiac dysfunction progressively worsened with age in female, not male, offspring of obese dams, compared to age-matched controls. In 6-month-old offspring, exposure to maternal obesity increased cardiac palmitoyl carnitine-supported mitochondrial respiration in males and reduced myocardial 18F-fluorodeoxyglucose uptake in females. Cardiac Pparg expression remained higher in adult offspring of obese than control dams and correlated with contractile and metabolic function. Maternal obesity did not affect cardiac palmitoyl carnitine respiration in females or 18F-fluorodeoxyglucose uptake in males, or alter cardiac 3H-oleic acid uptake, pyruvate respiration, lipid content or fatty acid/glucose transporter abundance in offspring of either sex. The results support our hypothesis and show that maternal obesity affects offspring cardiac metabolism in a sex-dependent manner. Persistent upregulation of Pparg expression in response to overnutrition in utero may mechanistically underpin programmed cardiac impairments and contribute to cardiovascular disease risk in children of women with obesity.

physiology↗

bioRxiv2021

Integrated Omics Analysis Reveals Sirtuin Signaling is Central to Hepatic Response to a High Fructose Diet

BackgroundDietary high fructose (HFr) is a known metabolic disruptor contributing to development of obesity and diabetes in Western societies. Initial molecular changes from exposure to HFr on liver metabolism may be essential to understand the perturbations leading to insulin resistance and abnormalities in lipid and carbohydrate metabolism. We studied vervet monkeys (Clorocebus aethiops sabaeus) fed a HFr (n=5) or chow diet (n=5) for 6 weeks, and obtained clinical measures of liver function, blood insulin, cholesterol and triglycerides. In addition, we performed untargeted global transcriptomics, proteomics, and metabolomics analyses on liver biopsies to determine the molecular impact of a HFr diet on coordinated pathways and networks that differed by diet. ResultsWe show that integration of omics data sets improved statistical significance for some pathways and networks, and decreased significance for others, suggesting that multiple omics datasets enhance confidence in relevant pathway and network identification. Specifically, we found that sirtuin signaling and a peroxisome proliferator activated receptor alpha (PPARA) regulatory network were significantly altered in hepatic response to HFr. Integration of metabolomics and miRNAs data further strengthened our findings. ConclusionsOur integrated analysis of three types of omics data with pathway and regulatory network analysis demonstrates the usefulness of this approach for discovery of molecular networks central to a biological response. In addition, metabolites aspartic acid and docosahexaenoic acid (DHA), protein ATG3, and genes ATG7, HMGCS2 link sirtuin signaling and the PPARA network suggesting molecular mechanisms for altered hepatic gluconeogenesis from consumption of a HFr diet.

systems biology↗

bioRxiv2021

Sulfonylureas target the neurovascular response to decrease Alzheimer's pathology

Hyperexcitability is a defining feature of Alzheimers disease (AD), where aberrant neuronal activity is both a cause and consequence of AD. Therefore, identifying novel targets that modulate cellular excitability is an important strategy for treating AD. ATP-sensitive potassium (KATP) channels are metabolic sensors that modulate cellular excitability. Sulfonylureas are KATP channel antagonists traditionally used to combat hyperglycemia in diabetic patients by inhibiting pancreatic KATP channels, thereby stimulating insulin release. However, KATP channels are not limited to the pancreas and systemic modulation of KATP channels has pleotropic physiological effects, including profound effects on vascular function. Here, we demonstrate that human AD patients have higher cortical expression of vascular KATP channels, important modulators of vasoreactivity. We demonstrate that peripheral treatment with the sulfonylurea and KATP channel inhibitor, glyburide, reduced the aggregation and activity-dependent production of amyloid-beta (A{beta}), a hallmark of AD, in mice. Since glyburide does not readily cross the blood brain barrier, our data suggests that glyburide targets vascular KATP channel activity to reduce arterial stiffness, improve vasoreactivity, and normalize pericyte-endothelial cell morphology, offering a novel therapeutic target for AD. Graphical abstractTargeting vascular KATP channel activity for the treatment of Alzheimers disease pathology. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗

bioRxiv2021

Assessment of label-free quantification and missing value imputation for proteomics in non-human primates

IntroductionReliable and effective label-free quantification (LFQ) analyses are dependent not only on the method of data acquisition in the mass spectrometer, but also on the downstream data processing, including software tools, query database, data normalization and imputation. In non-human primates (NHP), LFQ is challenging because the query databases for NHP are limited since the genomes of these species are not comprehensively annotated. This invariably results in limited discovery of proteins and associated Post Translational Modifications (PTMs) and a higher fraction of missing data points. While identification of fewer proteins and PTMs due to database limitations can negatively impact uncovering important and meaningful biological information, missing data also limits downstream analyses (e.g., multivariate analyses), decreases statistical power, biases statistical inference, and makes biological interpretation of the data more challenging. In this study we attempted to address both issues: first, we used the MetaMorphues proteomics search engine to counter the limits of NHP query databases and maximize the discovery of proteins and associated PTMs, and second, we evaluated different imputation methods for accurate data inference. ResultsUsing the MetaMorpheus proteomics search engine we obtained quantitative data for 1,622 proteins and 10,634 peptides including 58 different PTMs (biological, metal and artifacts) across a diverse age range of NHP brain frontal cortex. However, among the 1,622 proteins identified, only 293 proteins were quantified across all samples with no missing values, emphasizing the importance of implementing an accurate and statiscaly valid imputation method to fill in missing data. In our imputation analysis we demonstrate that Single Imputation methods that borrow information from correlated proteins such as Generalized Ridge Regression (GRR), Random Forest (RF), local least squares (LLS), and a Bayesian Principal Component Analysis methods (BPCA), are able to estimate missing protein abundance values with great accuracy. ConclusionsOverall, this study offers a detailed comparative analysis of LFQ data generated in NHP and proposes strategies for improved LFQ in NHP proteomics data.

genomics↗

bioRxiv2021

High-resolution estimates of crossover and noncrossover recombination from a captive baboon colony

Homologous recombination has been extensively studied in humans and a handful of model organisms. Much less is known about recombination in other species, including non-human primates. Here we present a study of crossovers and non-crossover (NCO) recombination in olive baboons (Papio anubis) from two pedigrees containing a total of 20 paternal and 17 maternal meioses, and compare these results to linkage-disequlibrium (LD) based recombination estimates from 36 unrelated olive baboons. We demonstrate how crossovers, combined with LD-based recombination estimates, can be used to identify genome assembly errors. We also quantify sex-specific differences in recombination rates, including elevated male crossover and reduced female crossover rates near telomeres. Finally, we add to the increasing body of evidence suggesting that while most NCO recombination tracts in mammals are short (e.g., < 500 bp), there are a non-negligible fraction of longer (e.g., > 1 Kb) NCO tracts. We fit a mixture-of-two-geometric distributions model to the NCO tract length distribution and estimate that >99% of all NCO tracts are very short (mean 24 bp), but the remaining tracts can be quite long (mean 11 Kb). A single geometric distribution model for NCO tract lengths is incompatible with the data, suggesting that LD-based methods for estimating NCO recombination rates that make this assumption may need to be modified. SignificanceMost homologous recombination events are noncrossovers (NCO), but little is known about NCO conversion tract lengths. Here we utilize whole-genome sequence data from large baboon pedigrees to estimate the NCO tract length distribution and to study other aspects of recombination.

genomics↗

bioRxiv2020

Postnatal persistence of sex-dependent renal developmentally programmed structural and molecular changes in nonhuman primates

BackgroundPoor nutrition during development programs kidney function. No studies on postnatal consequences of decreased perinatal nutrition exist in nonhuman primates (NHP) for translation to human renal disease. Our baboon model of moderate maternal nutrient restriction (MNR) produces intrauterine growth restricted (IUGR) and programs renal fetal phenotype. We hypothesized that the IUGR phenotype persists postnatally, influencing responses to a high-fat, high-carbohydrate, high-salt (HFCS) diet. MethodsPregnant baboons ate chow (Control; CON) or 70% of control intake (MNR) from 0.16 gestation through lactation. MNR offspring were IUGR at birth. At weaning, all offspring (CON and IUGR females and males, n=3/group) ate chow. At ~4.5 years of age, blood, urine, and kidney biopsies were collected before and after a 7-week HFCS diet challenge. Kidney function, unbiased kidney gene expression, and untargeted urine metabolomics were evaluated. ResultsIUGR female and male kidney transcriptome and urine metabolome differed from CON at 3.5 years, prior to HFCS. After the challenge, we observed sex-specific and fetal exposure-specific responses in urine creatinine, urine metabolites, and renal signaling pathways. ConclusionsWe previously showed mTOR signaling dysregulation in IUGR fetal kidneys. Before HFCS, gene expression analysis indicated that dysregulation persists postnatally in IUGR females. IUGR male offspring response to HFCS showed uncoordinated signaling pathway responses suggestive of proximal tubule injury. To our knowledge, this is the first study comparing CON and IUGR postnatal juvenile NHP and the impact of fetal and postnatal life caloric mismatch. Perinatal history needs to be taken into account when assessing renal disease risk.

genomics↗

bioRxiv2019

Accurate assembly of the olive baboon (Papio anubis) genome using long-read and Hi-C data

Besides macaques, baboons are the most commonly used nonhuman primate in biomedical research. Despite this importance, the genomic resources for baboons are quite limited. In particular, the current baboon reference genome Panu_3.0 is a highly fragmented, reference-guided (i.e., not fully de novo) assembly, and its poor quality inhibits our ability to conduct downstream genomic analyses. Here we present a truly de novo genome assembly of the olive baboon (Papio anubis) that uses data from several recently developed single-molecule technologies. Our assembly, Panubis1.0, has an N50 contig size of ~1.46 Mb (as opposed to 139 Kb for Panu_3.0), and has single scaffolds that span each of the 20 autosomes and the X chromosome. We highlight multiple lines of evidence (including Bionano Genomics data, pedigree linkage information, and linkage disequilibrium data) suggesting that there are several large assembly errors in Panu_3.0, which have been corrected in Panubis1.0.

genomics↗

bioRxiv2019

Metabolic Reprogramming: Short-term Western Diet Exposure Induces Sustained Changes in Plasma Metabolites

Dietary patterns are well known to contribute to the metabolic syndrome and related disorders. We evaluated the impact of a short-term Westernized diet (WD) exposure on systemic plasma metabolomic changes in a cohort of adult male baboons. In this pilot study, five male baboons (n=5) raised and maintained on a standard monkey chow diet (high complex carbohydrates, low fat) were exposed to a challenge WD (high in saturated fats and simple carbohydrates) for 7 weeks (49 d), followed by a 57-day washout period on monkey chow (106 d). In addition to monitoring clinical measures, we used a comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (2D GC-ToF-MS) platform to assess the metabolomic changes in plasma at three time points. Twenty-three metabolites were changed in response to the WD (49 d), but the response across the animals was highly variable. All animals presented a very different metabolic profile than at baseline (0 d), and the washout period resulted in a relatively homogenous metabolic state across all animals. A short-term exposure to a WD led to long-term changes in the metabolic profile, suggesting a "reset" of the metabolic program.

systems biology↗

bioRxiv2018

Analysis of 100 high coverage genomes from a pedigreed captive baboon colony

Baboons (genus Papio) are broadly studied in the wild and in captivity. They are widely used as a non-human primate model for biomedical studies, and the Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute has maintained a large captive baboon colony for more than 50 years. Unlike other model organisms though, the genomic resources for baboons are severely lacking. This has hindered the progress of studies using baboons as a model for basic biology or human disease. Here, we describe a dataset of 100 high-coverage whole-genome sequences obtained from the mixed colony of olive (P. anubis) and yellow (P. cynocephalus) baboons housed at the SNPRC. These data provide a comprehensive catalog of common genetic variation in baboons, as well as a fine-scale genetic map. We show how the data can be used to learn about ancestry and admixture, and to correct errors in the colony records. Finally, we investigated the consequences of inbreeding within the SNPRC colony and found clear evidence for increased rates of juvenile mortality and increased homozygosity of putatively deleterious alleles in inbred individuals.

genomics↗