Publications by authors named "David C Samuels"

139 Publications

Plasma Arginine and Citrulline are Elevated in Diabetic Retinopathy.

Am J Ophthalmol 2021 Sep 26. Epub 2021 Sep 26.

Vanderbilt Eye Institute, Vanderbilt University Medical Center, 2311 Pierce Avenue, Nashville, TN 37232. Electronic address:

Purpose: To determine if plasma levels of six arginine and citrulline-related metabolites (arginine, citrulline, asymmetric dimethylarginine [ADMA], ornithine, proline, and argininosuccinate) differ between patients with type 2 diabetes and diabetic retinopathy (DR) and type 2 diabetic controls or between patients with proliferative DR (PDR) and non-proliferative DR (NPDR).

Design: Cross-sectional study METHODS: Adults with type 2 diabetes were recruited from the Vanderbilt Eye Institute. Exclusion criteria included non-diabetic retinal disease. Plasma metabolite levels were quantified in 159 diabetic controls and 156 DR patients (92 NPDR, 64 PDR) using isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS). Metabolite levels were compared using Wilcoxon Rank Sum test and logistic regressions adjusting for age, sex, hemoglobin A1c, diabetes duration, statin use, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use. A secondary analysis that included creatinine in the regression model was performed for the subset of patients with available creatinine values (135 diabetic controls, 100 DR patients [58 NPDR, 42 PDR]).

Results: Multivariable logistic regression analyses determined arginine (OR = 1.20, [1.06-1.38], P = 0.0067) and citrulline (OR = 1.53, [1.20-1.98], P = 0.0025) were significantly elevated in DR patients compared to diabetic controls. While ADMA differed between NPDR and PDR patients in the primary analysis (OR = 1.56, [1.15-2.16], P = 0.0051), it was not significantly different when adjusting for creatinine (OR = 1.30, [0.90-1.91], P = 0.15).

Conclusions: Plasma arginine and citrulline were significantly elevated in type 2 diabetic patients with DR compared to diabetic controls. None of the tested metabolites significantly differed between NPDR and PDR patients in the adjusted analysis.
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http://dx.doi.org/10.1016/j.ajo.2021.09.021DOI Listing
September 2021

EditPredict: Prediction of RNA editable sites with convolutional neural network.

Genomics 2021 Sep 23;113(6):3864-3871. Epub 2021 Sep 23.

Comprehensive Cancer Center, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87109, USA. Electronic address:

RNA editing exerts critical impacts on numerous biological processes. While millions of RNA editings have been identified in humans, much more are expected to be discovered. In this work, we constructed Convolutional Neural Network (CNN) models to predict human RNA editing events in both Alu regions and non-Alu regions. With a validation dataset resulting from CRISPR/Cas9 knockout of the ADAR1 enzyme, the validation accuracies reached 99.5% and 93.6% for Alu and non-Alu regions, respectively. We ported our CNN models in a web service named EditPredict. EditPredict not only works on reference genome sequences but can also take into consideration single nucleotide variants in personal genomes. In addition to the human genome, EditPredict tackles other model organisms including bumblebee, fruitfly, mouse, and squid genomes. EditPredict can be used stand-alone to predict novel RNA editing and it can be used to assist in filtering for candidate RNA editing detected from RNA-Seq data.
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http://dx.doi.org/10.1016/j.ygeno.2021.09.016DOI Listing
September 2021

Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models.

J Clin Invest 2021 Jul 22. Epub 2021 Jul 22.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University School of Medicine, Nashville, United States of America.

Alcohol use disorder (AUD) is associated with substantial morbidity, mortality, and societal cost, and pharmacological treatment options for AUD are limited. The endogenous cannabinoid (eCB) signaling system is critically involved in reward processing and alcohol intake is positively correlated with release of the eCB ligand 2-Arachidonoylglycerol (2-AG) within reward neurocircuitry. Here we show that genetic and pharmacological inhibition of diacylglycerol lipase (DAGL), the rate limiting enzyme in the synthesis of 2-AG, reduces alcohol consumption in a variety of preclinical models ranging from a voluntary free-access model to aversion resistant-drinking and dependence-like drinking induced via chronic intermittent ethanol vapor exposure in mice. DAGL inhibition during either chronic alcohol consumption or protracted withdrawal was devoid of anxiogenic and depressive-like behavioral effects. Lastly, DAGL inhibition also prevented ethanol-induced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. These data suggest reducing 2-AG signaling via inhibition of DAGL could represent an effective approach to reduce alcohol consumption across the spectrum of AUD severity.
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http://dx.doi.org/10.1172/JCI146861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409586PMC
July 2021

LYSMD3: A mammalian pattern recognition receptor for chitin.

Cell Rep 2021 Jul;36(3):109392

Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061, USA. Electronic address:

Chitin, a major component of fungal cell walls, has been associated with allergic disorders such as asthma. However, it is unclear how mammals recognize chitin and the principal receptor(s) on epithelial cells that sense chitin remain to be determined. In this study, we show that LYSMD3 is expressed on the surface of human airway epithelial cells and demonstrate that LYSMD3 is able to bind chitin, as well as β-glucan, on the cell walls of fungi. Knockdown or knockout of LYSMD3 also sharply blunts the production of inflammatory cytokines by epithelial cells in response to chitin and fungal spores. Competitive inhibition of the LYSMD3 ectodomain by soluble LYSMD3 protein, multiple ligands, or antibody against LYSMD3 also blocks chitin signaling. Our study reveals LYSMD3 as a mammalian pattern recognition receptor (PRR) for chitin and establishes its role in epithelial cell inflammatory responses to chitin and fungi.
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http://dx.doi.org/10.1016/j.celrep.2021.109392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344708PMC
July 2021

Higher CSF Ferritin Heavy-Chain (Fth1) and Transferrin Predict Better Neurocognitive Performance in People with HIV.

Mol Neurobiol 2021 Oct 30;58(10):4842-4855. Epub 2021 Jun 30.

Genomic Medicine Institute, Cleveland Clinic/Lerner Research Institute, 9500 Euclid Ave/Mail Code R4-008, Cleveland, OH, 44195, USA.

HIV-associated neurocognitive disorder (HAND) remains prevalent despite antiretroviral therapy and involves white matter damage in the brain. Although iron is essential for myelination and myelin maintenance/repair, its role in HAND is largely unexplored. We tested the hypotheses that cerebrospinal fluid (CSF) heavy-chain ferritin (Fth1) and transferrin, proteins integral to iron delivery and myelination, are associated with neurocognitive performance in people with HIV (PWH). Fth1, transferrin, and the pro-inflammatory cytokines TNF-α and IL-6 were quantified in CSF at baseline (entry) in 403 PWH from a prospective observational study who underwent serial, comprehensive neurocognitive assessments. Associations of Fth1 and transferrin with Global Deficit Score (GDS)-defined neurocognitive performance at baseline and 30-42 months of follow-up were evaluated by multivariable regression. While not associated with neurocognitive performance at baseline, higher baseline CSF Fth1 predicted significantly better neurocognitive performance over 30 months in all PWH (p < 0.05), in PWH aged < 50 at 30, 36, and 42 months (all p < 0.05), and in virally suppressed PWH at all three visit time-points (all p < 0.01). Higher CSF transferrin was associated with superior neurocognitive performance at all visits, primarily in viremic individuals (all p < 0.05). All associations persisted after adjustment for neuro-inflammation. In summary, higher CSF Fth1 is neuroprotective over prolonged follow-up in all and virally suppressed PWH, while higher CSF transferrin may be most neuroprotective during viremia. We speculate that higher CSF levels of these critical iron-delivery proteins support improved myelination and consequently, neurocognitive performance in PWH, providing a rationale for investigating their role in interventions to prevent and/or treat HAND.
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http://dx.doi.org/10.1007/s12035-021-02433-7DOI Listing
October 2021

Global Autozygosity Is Associated with Cancer Risk, Mutational Signature and Prognosis.

Cancers (Basel) 2020 Dec 4;12(12). Epub 2020 Dec 4.

Department of Internal Medicine, Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87109, USA.

Global autozygosity quantifies the genome-wide levels of homozygous and heterozygous variants. It is the signature of non-random reproduction, though it can also be driven by other factors, and has been used to assess risk in various diseases. However, the association between global autozygosity and cancer risk has not been studied. From 4057 cancer subjects and 1668 healthy controls, we found strong associations between global autozygosity and risk in ten different cancer types. For example, the heterozygosity ratio was found to be significantly associated with breast invasive carcinoma in Blacks and with male skin cutaneous melanoma in Caucasians. We also discovered eleven associations between global autozygosity and mutational signatures which can explain a portion of the etiology. Furthermore, four significant associations for heterozygosity ratio were revealed in disease-specific survival analyses. This study demonstrates that global autozygosity is effective for cancer risk assessment.
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http://dx.doi.org/10.3390/cancers12123646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761949PMC
December 2020

Mitochondrial DNA haplogroups and weight gain following switch to integrase strand transfer inhibitor-based antiretroviral therapy.

AIDS 2021 03;35(3):439-445

Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) has been associated with excess weight gain in some adults, which may be influenced by genetic factors. We assessed mitochondrial DNA (mtDNA) haplogroups and weight gain following switch to INSTI-based ART.

Methods: All AIDS Clinical Trials Group A5001 and A5322 participants with mtDNA genotyping who switched to INSTI were included. mtDNA haplogroups were derived from prior genotyping algorithms. Race/ethnicity-stratified piecewise linear mixed effects models assessed the relationship between mtDNA haplogroup and weight change slope differences before and after switch to INSTI.

Results: A total of 291 adults switched to INSTI: 78% male, 50% non-Hispanic White, 28% non-Hispanic Black, and 22% Hispanic. The most common European haplogroups were H [n = 66 (45%)] and UK [32 (22%)]. Non-H European haplogroups had a significant increase in weight slope after the switch. This difference was greatest among non-H clade UK on INSTI-based regimens that included tenofovir alafenamide (TAF) [3.67 (95% confidence interval 1.12, 6.21) kg/year; P = 0.005]. Although small sample size limited analyses among non-Hispanic Black and Hispanic persons, similarly significant weight gain was seen among the most common African haplogroup, L3 [n = 29 (39%); slope difference 4.93 (1.54, 8.32) kg/year, P = 0.005], after switching to TAF-containing INSTI-based ART.

Conclusion: Those in European mtDNA haplogroup clade UK and African haplogroup L3 had significantly greater weight gain after switching to INSTI-based ART, especially those receiving TAF. Additional studies in large and diverse populations are needed to clarify the mechanisms and host risk factors for weight gain after switching to INSTI-based ART, with and without TAF.
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http://dx.doi.org/10.1097/QAD.0000000000002771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951953PMC
March 2021

Alternative Applications of Genotyping Array Data Using Multivariant Methods.

Trends Genet 2020 11 6;36(11):857-867. Epub 2020 Aug 6.

Department of Internal Medicine, Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87109, USA. Electronic address:

One of the forerunners that pioneered the revolution of high-throughput genomic technologies is the genotyping microarray technology, which can genotype millions of single-nucleotide variants simultaneously. Owing to apparent benefits, such as high speed, low cost, and high throughput, the genotyping array has gained lasting applications in genome-wide association studies (GWAS) and thus accumulated an enormous amount of data. Empowered by continuous manufactural upgrades and analytical innovation, unconventional applications of genotyping array data have emerged to address more diverse genetic problems, holding promise of boosting genetic research into human diseases through the re-mining of the rich accumulated data. Here, we review several unconventional genotyping array analysis techniques that have been built on the idea of large-scale multivariant analysis and provide empirical application examples. These unconventional outcomes of genotyping arrays include polygenic score, runs of homozygosity (ROH)/heterozygosity ratio, distant pedigree computation, and mitochondrial DNA (mtDNA) copy number inference.
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http://dx.doi.org/10.1016/j.tig.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572808PMC
November 2020

Mitochondria and Human Immunodeficiency Virus: A Troubled Relationship Enters Its Fourth Decade.

Clin Infect Dis 2021 07;73(2):e474-e476

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

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http://dx.doi.org/10.1093/cid/ciaa983DOI Listing
July 2021

Non-canonical RNA-DNA differences and other human genomic features are enriched within very short tandem repeats.

PLoS Comput Biol 2020 06 8;16(6):e1007968. Epub 2020 Jun 8.

Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, United States of America.

Very short tandem repeats bear substantial genetic, evolutional, and pathological significance in genome analyses. Here, we compiled a census of tandem mono-nucleotide/di-nucleotide/tri-nucleotide repeats (MNRs/DNRs/TNRs) in GRCh38, which we term "polytracts" in general. Of the human genome, 144.4 million nucleotides (4.7%) are occupied by polytracts, and 0.47 million single nucleotides are identified as polytract hinges, i.e., break-points of tandem polytracts. Preliminary exploration of the census suggested polytract hinge sites and boundaries of AAC polytracts may bear a higher mapping error rate than other polytract regions. Further, we revealed landscapes of polytract enrichment with respect to nearly a hundred genomic features. We found MNRs, DNRs, and TNRs displayed noticeable difference in terms of locational enrichment for miscellaneous genomic features, especially RNA editing events. Non-canonical and C-to-U RNA-editing events are enriched inside and/or adjacent to MNRs, while all categories of RNA-editing events are under-represented in DNRs. A-to-I RNA-editing events are generally under-represented in polytracts. The selective enrichment of non-canonical RNA-editing events within MNR adjacency provides a negative evidence against their authenticity. To enable similar locational enrichment analyses in relation to polytracts, we developed a software Polytrap which can handle 11 reference genomes. Additionally, we compiled polytracts of four model organisms into a Track Hub which can be integrated into USCS Genome Browser as an official track for convenient visualization of polytracts.
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http://dx.doi.org/10.1371/journal.pcbi.1007968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302867PMC
June 2020

Corrigendum: Genomic Positional Dissection of RNA Editomes in Tumor and Normal Samples.

Front Genet 2020;11:162. Epub 2020 Feb 25.

Department of Internal Medicine, The University of New Mexico, Albuquerque, NM, United States.

[This corrects the article DOI: 10.3389/fgene.2019.00211.].
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http://dx.doi.org/10.3389/fgene.2020.00162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052360PMC
February 2020

Mitochondrial DNA Haplogroups and Frailty in Adults Living with HIV.

AIDS Res Hum Retroviruses 2020 03 14;36(3):214-219. Epub 2020 Jan 14.

Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Mitochondrial DNA (mtDNA) haplogroup has been associated with disease risk and longevity. Among persons with HIV (PWH), mtDNA haplogroup has been associated with AIDS progression, neuropathy, cognitive impairment, and gait speed decline. We sought to determine whether haplogroup is associated with frailty and its components among older PWH. A cross-sectional analysis was performed of AIDS Clinical Trials Group A5322 (HAILO) participants with available genome-wide genotype and frailty assessments. Multivariable logistic regression models adjusted for age, gender, education, smoking, hepatitis C, and prior use of didanosine/stavudine. Among 634 participants, 81% were male, 49% non-Hispanic white, 31% non-Hispanic black, and 20% Hispanic. Mean age was 51.0 (standard deviation 7.5) years and median nadir CD4 count was 212 (interquartile range 72, 324) cells/μL; 6% were frail, 7% had slow gait, and 21% weak grip. H haplogroup participants were more likely to be frail/prefrail ( = .064), have slow gait ( = .09), or weak grip ( = .017) compared with non-H haplogroup participants (not all comparisons reached statistical significance). In adjusted analyses, PWH with haplogroup H had a greater odds of being frail versus nonfrail [odds ratio (OR) 4.0 (95% confidence interval 1.0-15.4)] and having weak grip [OR 2.1 (1.1, 4.1)], but not slow gait [OR 1.6 (0.5, 5.0)] compared with non-H haplogroup. Among black and Hispanic participants, haplogroup was not significantly associated with frailty, grip, or gait. Among antiretroviral therapy (ART)-treated PWH, mtDNA haplogroup H was independently associated with weak grip and frailty. This association could represent a mechanism of weakness and frailty in the setting of HIV and ART.
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http://dx.doi.org/10.1089/AID.2019.0233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133433PMC
March 2020

Mitochondrial DNA Haplogroups and Delirium During Sepsis.

Crit Care Med 2019 08;47(8):1065-1071

Clinical Research, Investigation, and Systems Modeling of Acute illness (CRISMA) Center in the Department of Critical Care Medicine, University of Pittsburgh School of Medicine.

Objectives: Studies suggest that mitochondrial dysfunction underlies some forms of sepsis-induced organ failure. We sought to test the hypothesis that variations in mitochondrial DNA haplogroup affect susceptibility to sepsis-associated delirium, a common manifestation of acute brain dysfunction during sepsis.

Design: Retrospective cohort study.

Setting: Medical and surgical ICUs at a large tertiary care center.

Patients: Caucasian and African American adults with sepsis.

Measurements And Main Results: We determined each patient's mitochondrial DNA haplogroup using single-nucleotide polymorphisms genotyping data in a DNA databank and extracted outcomes from linked electronic medical records. We then used zero-inflated negative binomial regression to analyze age-adjusted associations between mitochondrial DNA haplogroups and duration of delirium, identified using the Confusion Assessment Method for the ICU. Eight-hundred ten patients accounted for 958 sepsis admissions, with 802 (84%) by Caucasians and 156 (16%) by African Americans. In total, 795 patient admissions (83%) involved one or more days of delirium. The 7% of Caucasians belonging to mitochondrial DNA haplogroup clade IWX experienced more delirium than the 49% in haplogroup H, the most common Caucasian haplogroup (age-adjusted rate ratio for delirium 1.36; 95% CI, 1.13-1.64; p = 0.001). Alternatively, among African Americans the 24% in haplogroup L2 experienced less delirium than those in haplogroup L3, the most common African haplogroup (adjusted rate ratio for delirium 0.60; 95% CI, 0.38-0.94; p = 0.03).

Conclusions: Variations in mitochondrial DNA are associated with development of and protection from delirium in Caucasians and African Americans during sepsis. Future studies are now required to determine whether mitochondrial DNA and mitochondrial dysfunction contribute to the pathogenesis of delirium during sepsis so that targeted treatments can be developed.
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http://dx.doi.org/10.1097/CCM.0000000000003810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012366PMC
August 2019

Genomic Positional Dissection of RNA Editomes in Tumor and Normal Samples.

Front Genet 2019 20;10:211. Epub 2019 Mar 20.

Department of Internal Medicine, The University of New Mexico, Albuquerque, NM, United States.

RNA editing is phenomenon that occurs in both protein coding and non-coding RNAs. Increasing evidence have shown that adenosine-to-inosine RNA editing can potentially rendering substantial functional effects throughout the genome. Using RNA editing datasets from two large consortiums: The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) project, we quantitatively analyzed human genome-wide RNA editing events derived from tumor or normal tissues. Generally, a common RNA editing site tends to have a higher editing level in tumors as compared to normal samples. Of the 14 tumor-normal-paired cancer types examined, Eleven of the 14 cancers tested had overall increased RNA editing levels in the tumors. The editomes in cancer or normal tissues were dissected by genomic locations, and significant RNA editing locational difference was found between cancerous and healthy subjects. Additionally, our results indicated a significant correlation between the RNA editing rate and the gene density across chromosomes, highlighted hyper RNA editing clusters through visualization of running RNA editing rates along chromosomes, and identified hyper RNA edited genes (protein-coding genes, lincRNAs, and pseudogenes) that embody a large portion of cancer prognostic predictors. This study reinforces the potential functional effects of RNA editing in protein-coding genes, and also makes a strong foundation for further exploration of RNA editing's roles in non-coding regions.
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http://dx.doi.org/10.3389/fgene.2019.00211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435843PMC
March 2019

Identification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan.

Nat Commun 2019 04 1;10(1):1476. Epub 2019 Apr 1.

Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi, 710069, China.

Early detection and accurate monitoring of chronic kidney disease (CKD) could improve care and retard progression to end-stage renal disease. Here, using untargeted metabolomics in 2155 participants including patients with stage 1-5 CKD and healthy controls, we identify five metabolites, including 5-methoxytryptophan (5-MTP), whose levels strongly correlate with clinical markers of kidney disease. 5-MTP levels decrease with progression of CKD, and in mouse kidneys after unilateral ureteral obstruction (UUO). Treatment with 5-MTP ameliorates renal interstitial fibrosis, inhibits IκB/NF-κB signaling, and enhances Keap1/Nrf2 signaling in mice with UUO or ischemia/reperfusion injury, as well as in cultured human kidney cells. Overexpression of tryptophan hydroxylase-1 (TPH-1), an enzyme involved in 5-MTP synthesis, reduces renal injury by attenuating renal inflammation and fibrosis, whereas TPH-1 deficiency exacerbates renal injury and fibrosis by activating NF-κB and inhibiting Nrf2 pathways. Together, our results suggest that TPH-1 may serve as a target in the treatment of CKD.
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http://dx.doi.org/10.1038/s41467-019-09329-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443780PMC
April 2019

Architectures and accuracy of artificial neural network for disease classification from omics data.

BMC Genomics 2019 Mar 4;20(1):167. Epub 2019 Mar 4.

Department of Internal Medicine, University of New Mexico, Albuquerque, NM, 87131, USA.

Background: Deep learning has made tremendous successes in numerous artificial intelligence applications and is unsurprisingly penetrating into various biomedical domains. High-throughput omics data in the form of molecular profile matrices, such as transcriptomes and metabolomes, have long existed as a valuable resource for facilitating diagnosis of patient statuses/stages. It is timely imperative to compare deep learning neural networks against classical machine learning methods in the setting of matrix-formed omics data in terms of classification accuracy and robustness.

Results: Using 37 high throughput omics datasets, covering transcriptomes and metabolomes, we evaluated the classification power of deep learning compared to traditional machine learning methods. Representative deep learning methods, Multi-Layer Perceptrons (MLP) and Convolutional Neural Networks (CNN), were deployed and explored in seeking optimal architectures for the best classification performance. Together with five classical supervised classification methods (Linear Discriminant Analysis, Multinomial Logistic Regression, Naïve Bayes, Random Forest, Support Vector Machine), MLP and CNN were comparatively tested on the 37 datasets to predict disease stages or to discriminate diseased samples from normal samples. MLPs achieved the highest overall accuracy among all methods tested. More thorough analyses revealed that single hidden layer MLPs with ample hidden units outperformed deeper MLPs. Furthermore, MLP was one of the most robust methods against imbalanced class composition and inaccurate class labels.

Conclusion: Our results concluded that shallow MLPs (of one or two hidden layers) with ample hidden neurons are sufficient to achieve superior and robust classification performance in exploiting numerical matrix-formed omics data for diagnosis purpose. Specific observations regarding optimal network width, class imbalance tolerance, and inaccurate labeling tolerance will inform future improvement of neural network applications on functional genomics data.
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http://dx.doi.org/10.1186/s12864-019-5546-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399893PMC
March 2019

Corrigendum to: Single-nucleotide variants in human RNA: RNA editing and beyond.

Brief Funct Genomics 2019 02;18(1):40

Key Laboratory of Resource Biology and Biotechnology in Western China, School of Life Sciences, Northwest University,Xi'an, Shaanxi, China.

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http://dx.doi.org/10.1093/bfgp/ely041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480416PMC
February 2019

Peripheral Blood Mitochondrial DNA Copy Number Obtained From Genome-Wide Genotype Data Is Associated With Neurocognitive Impairment in Persons With Chronic HIV Infection.

J Acquir Immune Defic Syndr 2019 04;80(4):e95-e102

Vanderbilt University School of Medicine, Nashville, TN.

Background: Mitochondrial DNA (mtDNA) copy number varies by cell type and energy demands. Blood mtDNA copy number has been associated with neurocognitive function in persons without HIV. Low mtDNA copy number may indicate disordered mtDNA replication; high copy number may reflect a response to mitochondrial dysfunction. We hypothesized that blood mtDNA copy number estimated from genome-wide genotyping data is related to neurocognitive impairment (NCI) in persons with HIV.

Methods: In the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, peripheral blood mtDNA copy number was obtained from genome-wide genotyping data as a ratio of mtDNA single-nucleotide polymorphism probe intensities relative to nuclear DNA single-nucleotide polymorphisms. In a multivariable regression model, associations between mtDNA copy number and demographics, blood cell counts, and HIV disease and treatment characteristics were tested. Associations of mtDNA copy number with the global deficit score (GDS), GDS-defined NCI (GDS ≥ 0.5), and HIV-associated neurocognitive disorder (HAND) diagnosis were tested by logistic regression, adjusting for potential confounders.

Results: Among 1010 CHARTER participants, lower mtDNA copy number was associated with longer antiretroviral therapy duration (P < 0.001), but not with d-drug exposure (P = 0.85). mtDNA copy number was also associated with GDS (P = 0.007), GDS-defined NCI (P < 0.001), and HAND (P = 0.002). In all analyses, higher mtDNA copy number was associated with poorer cognitive performance.

Conclusions: Higher mtDNA copy number estimated from peripheral blood genotyping was associated with worse neurocognitive performance in adults with HIV. These results suggest a connection between peripheral blood mtDNA and NCI, and may represent increased mtDNA replication in response to mitochondrial dysfunction.
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http://dx.doi.org/10.1097/QAI.0000000000001930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391216PMC
April 2019

Relationships Between Adipose Mitochondrial Function, Serum Adiponectin, and Insulin Resistance in Persons With HIV After 96 Weeks of Antiretroviral Therapy.

J Acquir Immune Defic Syndr 2019 03;80(3):358-366

Johns Hopkins University, Baltimore, MD.

Objective: Some antiretroviral therapy (ART) and HIV itself confer metabolic risk, perhaps through altered mitochondrial function and adipokines. In AIDS Clinical Trials Group study A5224s, adipose mitochondrial DNA (mtDNA) levels decreased on ART, and electron transport chain complex I (CI) and complex IV (CIV) activity decreased. Another study found decreased serum adiponectin on ART with mtDNA mutation m.10398A>G. We hypothesized that decreased adipose tissue mitochondrial function would be associated with lower adiponectin and insulin sensitivity on ART, and m.10398G would influence these changes.

Design: Retrospective analysis of an ART-naive substudy population from A5224s.

Methods: Analyses included adipose mtDNA levels, CI and CIV activity by immunoassay, visceral adipose tissue by computed tomography, and fasting serum glucose at week 0 and week 96 of ART. Fasting insulin and adiponectin were measured from cryopreserved serum using multiplex bead array. Homeostasis model assessment-2 (HOMA2)-IR and HOMA2-%B estimated insulin resistance and β-cell function, respectively. The m.10398A>G mtDNA variant was available from existing genetic data.

Results: Thirty-seven participants had adipose biopsies at week 0 and week 96. Percent decreases in CIV activity and adiponectin were correlated (Spearman rho 0.41; P = 0.01); this association persisted after controlling for age, sex, body mass index, or visceral adipose tissue in single-covariate regression. HOMA2-IR correlated with decreased CIV (-0.44; P = 0.01) and CI (-0.34; P = 0.05) activity. Among 12 non-Hispanic white persons, m.10398G was associated with decreased adiponectin (P = 0.04).

Conclusions: Decreased adipose mitochondrial activity correlated with changes in adiponectin and glucose homeostasis on ART. Previous findings that a mtDNA mutation modulates adiponectin levels in persons with HIV were replicated.
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http://dx.doi.org/10.1097/QAI.0000000000001926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375746PMC
March 2019

Cancer-specific expression quantitative loci are affected by expression dysregulation.

Brief Bioinform 2018 Nov 23. Epub 2018 Nov 23.

Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.

Expression quantitative trait loci (eQTLs) have been touted as the missing piece that can bridge the gap between genetic variants and phenotypes. Over the past decade, we have witnessed a sharp rise of effort in the identification and application of eQTLs. The successful application of eQTLs relies heavily on their reproducibility. The current eQTL databases such as Genotype-Tissue Expression (GTEx) were populated primarily with eQTLs deriving from germline single nucleotide polymorphisms and normal tissue gene expression. The novel scenarios that employ eQTL models for prediction purposes often involve disease phenotypes characterized by altered gene expressions. To evaluate eQTL reproducibility across diverse data sources and the effect of disease-specific gene expression alteration on eQTL identification, we conducted an eQTL study using 5178 samples from The Cancer Genome Atlas (TCGA). We found that the reproducibility of eQTLs between normal and tumor tissues was low in terms of the number of shared eQTLs. However, among the shared eQTLs, the effect directions were generally concordant. This suggests that the source of the gene expression (normal or tumor tissue) has a strong effect on the detectable eQTLs and the effect direction of the eQTLs. Additional analyses demonstrated good directional concordance of eQTLs between GTEx and TCGA. Furthermore, we found that multi-tissue eQTLs may exert opposite effects across multiple tissue types. In summary, our results suggest that eQTL prediction models need to carefully address tissue and disease dependency of eQTLs. Tissue-disease-specific eQTL databases can afford more accurate prediction models for future studies.
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http://dx.doi.org/10.1093/bib/bby108DOI Listing
November 2018

Bi-stream CNN Down Syndrome screening model based on genotyping array.

BMC Med Genomics 2018 Nov 20;11(Suppl 5):105. Epub 2018 Nov 20.

School of Medicine,The University of New Mexico, Albuquerque, 87131, NM, USA.

Background: Human Down syndrome (DS) is usually caused by genomic micro-duplications and dosage imbalances of human chromosome 21. It is associated with many genomic and phenotype abnormalities. Even though human DS occurs about 1 per 1,000 births worldwide, which is a very high rate, researchers haven't found any effective method to cure DS. Currently, the most efficient ways of human DS prevention are screening and early detection.

Methods: In this study, we used deep learning techniques and analyzed a set of Illumina genotyping array data. We built a bi-stream convolutional neural networks model to screen/predict the occurrence of DS. Firstly, we built image input data by converting the intensities of each SNP site into chromosome SNP maps. Next, we proposed a bi-stream convolutional neural network (CNN) architecture with nine layers and two branch models. We further merged two CNN branch models into one model in the fourth convolutional layer, and output the prediction in the last layer.

Results: Our bi-stream CNN model achieved 99.3% average accuracies, and very low false-positive and false-negative rates, which was necessary for further applications in disease prediction and medical practice. We further visualized the feature maps and learned filters from intermediate convolutional layers, which showed the genomic patterns and correlated SNPs variations in human DS genomes. We also compared our methods with other CNN and traditional machine learning models. We further analyzed and discussed the characteristics and strengths of our bi-stream CNN model.

Conclusions: Our bi-stream model used two branch CNN models to learn the local genome features and regional patterns among adjacent genes and SNP sites from two chromosomes simultaneously. It achieved the best performance in all evaluating metrics when compared with two single-stream CNN models and three traditional machine-learning algorithms. The visualized feature maps also provided opportunities to study the genomic markers and pathway components associated with Human DS, which provided insights for gene therapy and genomic medicine developments.
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http://dx.doi.org/10.1186/s12920-018-0416-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245487PMC
November 2018

Single-nucleotide variants in human RNA: RNA editing and beyond.

Brief Funct Genomics 2019 02;18(1):30-39

Key Laboratory of Resource Biology and Biotechnology in Western China, School of Life Sciences, Northwest University,Xi'an, Shaanxi, China.

Through analysis of paired high-throughput DNA-Seq and RNA-Seq data, researchers quickly recognized that RNA-Seq can be used for more than just gene expression quantification. The alternative applications of RNA-Seq data are abundant, and we are particularly interested in its usefulness for detecting single-nucleotide variants, which arise from RNA editing, genomic variants and other RNA modifications. A stunning discovery made from RNA-Seq analyses is the unexpectedly high prevalence of RNA-editing events, many of which cannot be explained by known RNA-editing mechanisms. Over the past 6-7 years, substantial efforts have been made to maximize the potential of RNA-Seq data. In this review we describe the controversial history of mining RNA-editing events from RNA-Seq data and the corresponding development of methodologies to identify, predict, assess the quality of and catalog RNA-editing events as well as genomic variants.
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http://dx.doi.org/10.1093/bfgp/ely032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962770PMC
February 2019

Hemochromatosis (HFE) Gene Variants Are Associated with Increased Mitochondrial DNA Levels During HIV-1 Infection and Antiretroviral Therapy.

AIDS Res Hum Retroviruses 2018 11 22;34(11):942-949. Epub 2018 Aug 22.

9 Icahn School of Medicine of Mount Sinai , New York, New York.

Some HIV-associated complications involve mitochondrial dysfunction and may be less common in individuals with iron-loading HFE (hemochromatosis gene) variants. We evaluated HFE 845A and 187G alleles in relation to mitochondrial DNA (mtDNA) levels in peripheral blood mononuclear cells from 85 individuals with HIV infection on uninterrupted antiretroviral therapy (ART) for 15 or more consecutive weeks. Carriers of HFE gene variants (N = 24) had significantly higher mtDNA levels than noncarriers (N = 61), after adjusting for age, race, sex, and type of ART [adjusted β-coefficient 297, p-value < .001 for at least one HFE variant], but mtDNA declined among all individuals on study during 48 weeks on ART. Increased cellular mtDNA content may represent a compensatory response to mitochondrial stress that is influenced by iron-loading HFE variants.
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http://dx.doi.org/10.1089/AID.2018.0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421985PMC
November 2018

Relation of Body Mass Index to Symptom Burden in Patients withAtrial Fibrillation.

Am J Cardiol 2018 07 1;122(2):235-241. Epub 2018 May 1.

Department of Medicine, University of Illinois at Chicago, Jesse Brown VA Medical Center, Chicago, Illinois; Departments of Medicine and Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee. Electronic address:

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity and increased mortality. As body mass index (BMI) is increasingly recognized as an important risk factor for the development of AF, we tested the hypothesis that BMI modulates symptomatic AF burden. Cross-sectional data collected from 1,382 patients in the Vanderbilt AF Registry were analyzed. AF severity was assessed using the Toronto atrial fibrillation severity scale (AFSS). BMI was categorized according to World Health Organization guidelines and patients were grouped according to their present AF treatment regimen: no treatment (n = 185), rate control therapy with atrioventricular nodal blocking agents (n = 351), rhythm control with antiarrhythmic drugs (n = 636), and previous AF ablation (n = 210). Patients with BMI >35 kg/m had higher AFSS scores than those with BMI <30 kg/m in the rate control (43.57 vs 38.21: p = 0.0057), rhythm control (46.61 vs 41.08: p = 1.6 × 10), and ablation (44.01 vs 39.02: p = 0.047) groups. Inunivariate linear models, BMI was associated with an increase in the AFSS score in the rate control (0.27, 95% confidence interval [CI] 0.05 to 0.5, p = 0.02), rhythm control (0.38, 95% CI 0.21 to 0.56, p = 2.49 × 10), and ablation (0.38, 95% CI 0.03 to 0.73, p = 0.03) groups. The association remained significant in the rhythm control groups after adjusting for age, gender, race, and comorbidities (0.29, 95% CI 0.11 to 0.49, p = 0.002). In conclusion, increasing BMI was directly associated with patient reported measures of AF symptom severity, burden, and quality of life. This was most significant in patients treated with rhythm-control strategies.
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http://dx.doi.org/10.1016/j.amjcard.2018.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028292PMC
July 2018

Quality and concordance of genotyping array data of 12,064 samples from 5840 cancer patients.

Genomics 2019 07 11;111(4):950-957. Epub 2018 Jun 11.

Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA. Electronic address:

Genotyping arrays characterize genome-wide SNPs for a study cohort and were the primary technology behind genome wide association studies over the last decade. The Cancer Genome Atlas (TCGA) is one of the largest cancer consortium studies, and it collected genotyping data for all of its participants. Using TCGA SNP data genotyped using the Affymetrix 6.0 SNP array from 12,064 samples, we conducted a comprehensive comparisons across DNA sources (tumor tissue, normal tissue, and blood) and sample storage protocols (formalin-fixed paraffin-embedded (FFPE) vs. freshly frozen (FF)), examining genotypes, transition/transversion ratios, and mutation catalogues. During the analysis, we made important observations in relevance to the data quality issues. SNP concordance was excellent between blood and normal tissues, and slightly lower between blood and tumor tissue due to potential somatic mutations in the tumors. The observed poor SNP concordance between FFPE and FF samples suggested a batch effect. The transition/transversion ratio, a metric commonly used for quality control purpose in exome sequencing projects, appeared less applicable for genotyping array data due to the whole-genome coverage built into the array design. Moreover, there were substantially more loss of heterozygosity events than gain of heterozygosity when comparing tumors relative to normal tissues and blood. This might be a consequence of extensive copy number deletions in tumors. In summary, our thorough evaluation calls for more adequate quality control practices and provides guidelines for improved application of TCGA genotyping data.
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http://dx.doi.org/10.1016/j.ygeno.2018.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546549PMC
July 2019

Mutation-specific effects in germline transmission of pathogenic mtDNA variants.

Hum Reprod 2018 07;33(7):1331-1341

Department of Genetics and Cell Biology, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, the Netherlands.

Study Question: Does germline selection (besides random genetic drift) play a role during the transmission of heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations in humans?

Summary Answer: We conclude that inheritance of mtDNA is mutation-specific and governed by a combination of random genetic drift and negative and/or positive selection.

What Is Known Already: mtDNA inherits maternally through a genetic bottleneck, but the underlying mechanisms are largely unknown. Although random genetic drift is recognized as an important mechanism, selection mechanisms are thought to play a role as well.

Study Design, Size, Duration: We determined the mtDNA mutation loads in 160 available oocytes, zygotes, and blastomeres of five carriers of the m.3243A>G mutation, one carrier of the m.8993T>G mutation, and one carrier of the m.14487T>C mutation.

Participants/materials, Setting, Methods: Mutation loads were determined in PGD samples using PCR assays and analysed mathematically to test for random sampling effects. In addition, a meta-analysis has been performed on mutation load transmission data in the literature to confirm the results of the PGD samples.

Main Results And The Role Of Chance: By applying the Kimura distribution, which assumes random mechanisms, we found that mtDNA segregations patterns could be explained by variable bottleneck sizes among all our carriers (moment estimates ranging from 10 to 145). Marked differences in the bottleneck size would determine the probability that a carrier produces offspring with mutations markedly different than her own. We investigated whether bottleneck sizes might also be influenced by non-random mechanisms. We noted a consistent absence of high mutation loads in all our m.3243A>G carriers, indicating non-random events. To test this, we fitted a standard and a truncated Kimura distribution to the m.3243A>G segregation data. A Kimura distribution truncated at 76.5% heteroplasmy has a significantly better fit (P-value = 0.005) than the standard Kimura distribution. For the m.8993T>G mutation, we suspect a skewed mutation load distribution in the offspring. To test this hypothesis, we performed a meta-analysis on published blood mutation levels of offspring-mother (O-M) transmission for the m.3243A>G and m.8993T>G mutations. This analysis revealed some evidence that the O-M ratios for the m.8993T>G mutation are different from zero (P-value <0.001), while for the m.3243A>G mutation there was little evidence that the O-M ratios are non-zero. Lastly, for the m.14487T>G mutation, where the whole range of mutation loads was represented, we found no indications for selective events during its transmission.

Large Scale Data: All data are included in the Results section of this article.

Limitations, Reason For Caution: The availability of human material for the mutations is scarce, requiring additional samples to confirm our findings.

Wider Implications Of The Findings: Our data show that non-random mechanisms are involved during mtDNA segregation. We aimed to provide the mechanisms underlying these selection events. One explanation for selection against high m.3243A>G mutation loads could be, as previously reported, a pronounced oxidative phosphorylation (OXPHOS) deficiency at high mutation loads, which prohibits oogenesis (e.g. progression through meiosis). No maximum mutation loads of the m.8993T>G mutation seem to exist, as the OXPHOS deficiency is less severe, even at levels close to 100%. In contrast, high mutation loads seem to be favoured, probably because they lead to an increased mitochondrial membrane potential (MMP), a hallmark on which healthy mitochondria are being selected. This hypothesis could provide a possible explanation for the skewed segregation pattern observed. Our findings are corroborated by the segregation pattern of the m.14487T>C mutation, which does not affect OXPHOS and MMP significantly, and its transmission is therefore predominantly determined by random genetic drift. Our conclusion is that mutation-specific selection mechanisms occur during mtDNA inheritance, which has implications for PGD and mitochondrial replacement therapy.

Study Funding/competing Interest(s): This work has been funded by GROW-School of Oncology and Developmental Biology. The authors declare no competing interests.
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http://dx.doi.org/10.1093/humrep/dey114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551225PMC
July 2018

Genomic and transcriptomic characterization of the mitochondrial-rich oncocytic phenotype on a thyroid carcinoma background.

Mitochondrion 2019 05 6;46:123-133. Epub 2018 Apr 6.

Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal; Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal; Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal. Electronic address:

We conducted the first systematic omics study of the oncocytic phenotype in 488 papillary thyroid carcinomas (PTC) from The Cancer Genome Atlas. Oncocytic phenotype is secondary to PTC, being unrelated to several pathologic scores. The nuclear genome had low impact on this phenotype (except in specific copy number variation), which was mostly driven by the significant accumulation of mitochondrial DNA non-synonymous and frameshift mutations at high heteroplasmy levels. Energy and mitochondrial-related pathways were significantly enriched in oncocytic tumors that also displayed increased levels of expression for genes involved in autophagy and fusion of mitochondria. Our in vitro tests confirmed that autophagy is increased and functional while mitophagy is decreased in these tumors.
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http://dx.doi.org/10.1016/j.mito.2018.04.001DOI Listing
May 2019

The Role of Mitochondrial DNA Variation in Age-Related Decline in Gait Speed Among Older Men Living With Human Immunodeficiency Virus.

Clin Infect Dis 2018 08;67(5):778-784

Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.

Background: Age-related gait speed decline is accelerated in men with human immunodeficiency virus (HIV). Mitochondrial genetic variation is associated with frailty and mortality in the general population and may provide insight into mechanisms of functional decline in people aging with HIV.

Methods: Gait speed was assessed semiannually in the Multicenter AIDS Cohort Study. Mitochondrial DNA (mtDNA) haplogroups were extracted from genome-wide genotyping data, classifying men aged ≥50 years into 5 groups: mtDNA haplogroup H, J, T, Uk, and other. Differences in gait speed by haplogroups were assessed as rate of gait speed decline per year, probability of slow gait speed (<1.0 m/s), and hazard of slow gait using multivariable linear mixed-effects models, mixed-effects logistic regression models, and the Andersen-Gill model, controlling for hepatitis C virus infection, previous AIDS diagnosis, thymidine analogues exposure, education, body composition, smoking, and peripheral neuropathy. Age was further controlled for in the mixed-effects logistic regression models.

Results: A total of 455 HIV-positive white men aged ≥50 years contributed 3283 person-years of follow-up. Among them, 70% had achieved HIV viral suppression. In fully adjusted models, individuals with haplogroup J had more rapid decline in gait speed (adjusted slopes, 0.018 m/s/year vs 0.011 m/s/year, pinteraction = 0.012) and increased risk of developing slow gait (adjusted odds ratio, 2.97; 95% confidence interval, 1.24-7.08) compared to those with other haplogroups.

Conclusions: Among older, HIV-infected men, mtDNA haplogroup J was an independent risk factor for more rapid age-related gait speed decline.
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http://dx.doi.org/10.1093/cid/ciy151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093993PMC
August 2018

Mitochondrial Haplogroups Modify the Effect of Diabetes Duration and HbA1c on Proliferative Diabetic Retinopathy Risk in Patients With Type 2 Diabetes.

Invest Ophthalmol Vis Sci 2017 12;58(14):6481-6488

Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, United States.

Purpose: We previously demonstrated an association between European mitochondrial haplogroups and proliferative diabetic retinopathy (PDR). The purpose of this study was to determine how the relationship between these haplogroups and both diabetes duration and hyperglycemia, two major risk factors for diabetic retinopathy (DR), affect PDR prevalence.

Methods: Our population consisted of patients with type 2 diabetes with (n = 377) and without (n = 480) DR. A Kruskal-Wallis test was used to compare diabetes duration and hemoglobin A1c (HbA1c) among mitochondrial haplogroups. Logistic regressions were performed to investigate diabetes duration and HbA1c as risk factors for PDR in the context of European mitochondrial haplogroups.

Results: Neither diabetes duration nor HbA1c differed among mitochondrial haplogroups. Among DR patients from haplogroup H, longer diabetes duration and increasing HbA1c were significant risk factors for PDR (P = 0.0001 and P = 0.011, respectively). Neither diabetes duration nor HbA1c was a significant risk factor for PDR in DR patients from haplogroup UK.

Conclusions: European mitochondrial haplogroups modify the effects of diabetes duration and HbA1c on PDR risk in patients with type 2 diabetes. In our patient population, longer diabetes duration and higher HbA1c increased PDR risk in patients from haplogroup H, but did not affect PDR risk in patients from haplogroup UK. This relationship has not been previously demonstrated and may explain, in part, why some patients with nonproliferative DR develop PDR and others do not, despite similar diabetes duration and glycemic control.
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http://dx.doi.org/10.1167/iovs.17-22804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749245PMC
December 2017

Current Research on Non-Coding Ribonucleic Acid (RNA).

Genes (Basel) 2017 Dec 5;8(12). Epub 2017 Dec 5.

Key Laboratory of Resource Biology and Biotechnology in Western China, School of Life Sciences, Northwest University, Xi'an 710069, Shaanxi, China.

Non-coding ribonucleic acid (RNA) has without a doubt captured the interest of biomedical researchers. The ability to screen the entire human genome with high-throughput sequencing technology has greatly enhanced the identification, annotation and prediction of the functionality of non-coding RNAs. In this review, we discuss the current landscape of non-coding RNA research and quantitative analysis. Non-coding RNA will be categorized into two major groups by size: long non-coding RNAs and small RNAs. In long non-coding RNA, we discuss regular long non-coding RNA, pseudogenes and circular RNA. In small RNA, we discuss miRNA, transfer RNA, piwi-interacting RNA, small nucleolar RNA, small nuclear RNA, Y RNA, single recognition particle RNA, and 7SK RNA. We elaborate on the origin, detection method, and potential association with disease, putative functional mechanisms, and public resources for these non-coding RNAs. We aim to provide readers with a complete overview of non-coding RNAs and incite additional interest in non-coding RNA research.
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http://dx.doi.org/10.3390/genes8120366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748684PMC
December 2017
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