146 results on '"Kidd JM"'
Search Results
2. Exome capture from saliva produces high quality genomic and metagenomic data
- Author
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Wall, Jeffrey, Pollard, Katherine, Kidd, JM, Sharpton, TJ, Bobo, D, Norman, PJ, Martin, AR, Carpenter, ML, Sikora, M, Gignoux, CR, Nemat-Gorgani, N, and Adams, A
- Abstract
Background: Targeted capture of genomic regions reduces sequencing cost while generating higher coverage by allowing biomedical researchers to focus on specific loci of interest, such as exons. Targeted capture also has the potential to facilitate the gene
- Published
- 2014
3. Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network
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Mcconnell, Mj, Moran, Jv, Abyzov, A, Akbarian, S, Bae, T, Cortes-Ciriano, I, Erwin, Ja, Fasching, L, Flasch, Da, Freed, D, Ganz, J, Jaffe, Ae, Kwan, Ky, Kwon, M, Lodato, Ma, Mills, Re, Paquola, Acm, Rodin, Re, Rosenbluh, C, Sestan, N, Sherman, Ma, Shin, Jh, Song, S, Straub, Re, Thorpe, J, Weinberger, Dr, Urban, Ae, Zhou, B, Gage, Fh, Lehner, T, Senthil, G, Walsh, Ca, Chess, A, Courchesne, E, Gleeson, Jg, Kidd, Jm, Park, Pj, Pevsner, J, Vaccarino, Fm, Barton, Ar, Bekiranov, S, Bohrson, Cl, Burbulis, Ie, Chronister, W, Coppola, G, Daily, K, D'Gama, Am, Emery, Sb, Frisbie, Tj, Gao, T, Gulyás-Kovács, A, Haakenson, M, Keil, Jm, Kopera, Hc, Lam, Mm, Lee, Ea, Marques-Bonet, T, Mathern, Gw, Moldovan, Jb, Oetjens, Mt, Omberg, L, Peters, Ma, Pochareddy, S, Pramparo, T, Ratan, A, Sanavia, T, Shi, L, Skarica, M, Wang, J, Wang, M, Wang, Y, Wierman, M, Wolpert, M, Woodworth, M, Zhao, X, and Zhou, W
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DNA Replication ,0301 basic medicine ,DNA Repair ,Brain Somatic Mosaicism ,Somatic cell ,DNA Mutational Analysis ,Genomics ,Disease ,Biology ,Article ,Germline ,03 medical and health sciences ,Neural Stem Cells ,Humans ,Copy-number variation ,Neurons ,Genetics ,Multidisciplinary ,Genome, Human ,Mosaicism ,Mental Disorders ,Brain ,Phenotype ,Germ Cells ,030104 developmental biology ,Human genome ,Nerve Net ,Nervous System Diseases ,Cell Division ,Neurotypical ,DNA Damage - Abstract
BACKGROUND Elucidating the genetic architecture of neuropsychiatric disorders remains a major scientific and medical challenge. Emerging genomic technologies now permit the analysis of somatic mosaicism in human tissues. The measured frequencies of single-nucleotide variants (SNVs), small insertion/deletion (indel) mutations, structural variants [including copy number variants (CNVs), inversions, translocations, and whole-chromosome gains or losses], and mobile genetic element insertions (MEIs) indicate that each neuron may harbor hundreds of somatic mutations. Given the long life span of neurons and their central role in neural circuits and behavior, somatic mosaicism represents a potential mechanism that may contribute to neuronal diversity and the etiology of numerous neuropsychiatric disorders. ADVANCES Somatic mutations that confer cellular proliferative or cellular survival phenotypes have been identified in patients with cortical malformations. These data have led to the hypothesis that somatic mutations may also confer phenotypes to subsets of neurons, which could increase the risk of developing certain neuropsychiatric disorders. Genomic technologies, including advances in long-read, next-generation DNA sequencing technologies, single-cell genomics, and cutting-edge bioinformatics, can now make it possible to determine the types and frequencies of somatic mutations within the human brain. However, a comprehensive understanding of the contribution of somatic mosaicism to neurotypical brain development and neuropsychiatric disease requires a coordinated, multi-institutional effort. The National Institute of Mental Health (NIMH) has formed a network of 18 investigative teams representing 15 institutions called the Brain Somatic Mosaicism Network (BSMN). Each research team will use an array of genomic technologies to exploit well-curated human tissue repositories in an effort to define the frequency and pattern of somatic mutations in neurotypical individuals and in schizophrenia, autism spectrum disorder, bipolar disorder, Tourette syndrome, and epilepsy patient populations. Collectively, these efforts are estimated to generate a community resource of more than 10,000 DNA-sequencing data sets and will enable a cross-platform integrated analysis with other NIMH initiatives, such as the PsychENCODE project and the CommonMind Consortium. OUTLOOK A fundamental open question in neurodevelopmental genetics is whether and how somatic mosaicism may contribute to neuronal diversity within the neurotypical spectrum and in diseased brains. Healthy individuals may harbor known pathogenic somatic mutations at subclinical frequencies, and the local composition of neural cell types may be altered by mutations conferring prosurvival phenotypes in subsets of neurons. By extension, the neurotypical architecture of somatic mutations may confer circuit-level differences that would not be present if every neuron had an identical genome. Given the apparent abundance of somatic mutations within neurons, an in-depth understanding of how different types of somatic mosaicism affect neural function could yield mechanistic insight into the etiology of neurodevelopmental and neuropsychiatric disorders. The BSMN will examine large collections of postmortem brain tissue from neurotypical individuals and patients with neuropsychiatric disorders. By sequencing brain DNA and single neuronal genomes directly, rather than genomic DNA derived from peripheral blood or other somatic tissues, the BSMN will test the hypothesis that brain somatic variants contribute to neuropsychiatric disease. Notably, it is also possible that some inherited germline variants confer susceptibility to disease, which is later exacerbated by somatic mutations. Confirming such a scenario could increase our understanding of the genetic risk architecture of neuropsychiatric disease and may, in part, explain discordant neuropsychiatric phenotypes between identical twins. Results from these studies may lead to the discovery of biomarkers and genetic targets to improve the treatment of neuropsychiatric disease and may offer hope for improving the lives of patients and their families.
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- 2017
4. Great ape genetic diversity and population history
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Prado-Martinez J, Sudmant PH, Kidd JM, Li H, Kelley JL, Lorente-Galdos B, Veeramah KR, Woerner AE, O'Connor TD, Santpere G, Cagan A, Theunert C, Casals F, Laayouni H, Munch K, Hobolth A, Halager AE, Malig M, Hernandez-Rodriguez J, Hernando-Herraez I, Prxfcfer K, Pybus M, Johnstone L, Lachmann M, Alkan C, Twigg D, Petit N, Baker C, Hormozdiari F, Fernandez-Callejo M, Dabad M, Wilson ML, Stevison L, Camprubxed C, Carvalho T, Ruiz-Herrera A, Vives L, Mele M, Abello T, Kondova I, Bontrop RE, Pusey A, Lankester F, and K
- Published
- 2013
5. An integrated map of genetic variation from 1,092 human genomes
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Altshuler, DM, Durbin, RM, Abecasis, GR, Bentley, DR, Chakravarti, A, Clark, AG, Donnelly, P, Eichler, EE, Flicek, P, Gabriel, SB, Gibbs, RA, Green, ED, Hurles, ME, Knoppers, BM, Korbel, JO, Lander, ES, Lee, C, Lehrach, H, Mardis, ER, Marth, GT, McVean, GA, Nickerson, DA, Schmidt, JP, Sherry, ST, Wang, J, Wilson, RK, Dinh, H, Kovar, C, Lee, S, Lewis, L, Muzny, D, Reid, J, Wang, M, Fang, X, Guo, X, Jian, M, Jiang, H, Jin, X, Li, G, Li, J, Li, Y, Li, Z, Liu, X, Lu, Y, Ma, X, Su, Z, Tai, S, Tang, M, Wang, B, Wang, G, Wu, H, Wu, R, Yin, Y, Zhang, W, Zhao, J, Zhao, M, Zheng, X, Zhou, Y, Gupta, N, Clarke, L, Leinonen, R, Smith, RE, Zheng-Bradley, X, Grocock, R, Humphray, S, James, T, Kingsbury, Z, Sudbrak, R, Albrecht, MW, Amstislavskiy, VS, Borodina, TA, Lienhard, M, Mertes, F, Sultan, M, Timmermann, B, Yaspo, M-L, Fulton, L, Fulton, R, Weinstock, GM, Balasubramaniam, S, Burton, J, Danecek, P, Keane, TM, Kolb-Kokocinski, A, McCarthy, S, Stalker, J, Quail, M, Davies, CJ, Gollub, J, Webster, T, Wong, B, Zhan, Y, Auton, A, Yu, F, Bainbridge, M, Challis, D, Evani, US, Lu, J, Nagaswamy, U, Sabo, A, Wang, Y, Yu, J, Coin, LJM, Fang, L, Li, Q, Lin, H, Liu, B, Luo, R, Qin, N, Shao, H, Xie, Y, Ye, C, Yu, C, Zhang, F, Zheng, H, Zhu, H, Garrison, EP, Kural, D, Lee, W-P, Leong, WF, Ward, AN, Wu, J, Zhang, M, Griffin, L, Hsieh, C-H, Mills, RE, Shi, X, Von Grotthuss, M, Zhang, C, Daly, MJ, DePristo, MA, Banks, E, Bhatia, G, Carneiro, MO, Del Angel, G, Genovese, G, Handsaker, RE, Hartl, C, McCarroll, SA, Nemesh, JC, Poplin, RE, Schaffner, SF, Shakir, K, Yoon, SC, Lihm, J, Makarov, V, Jin, H, Kim, W, Kim, KC, Rausch, T, Beal, K, Cunningham, F, Herrero, J, McLaren, WM, Ritchie, GRS, Gottipati, S, Keinan, A, Rodriguez-Flores, JL, Sabeti, PC, Grossman, SR, Tabrizi, S, Tariyal, R, Cooper, DN, Ball, EV, Stenson, PD, Barnes, B, Bauer, M, Cheetham, RK, Cox, T, Eberle, M, Kahn, S, Murray, L, Peden, J, Shaw, R, Ye, K, Batzer, MA, Konkel, MK, Walker, JA, MacArthur, DG, Lek, M, Herwig, R, Shriver, MD, Bustamante, CD, Byrnes, JK, De la Vega, FM, Gravel, S, Kenny, EE, Kidd, JM, Lacroute, P, Maples, BK, Moreno-Estrada, A, Zakharia, F, Halperin, E, Baran, Y, Craig, DW, Christoforides, A, Homer, N, Izatt, T, Kurdoglu, AA, Sinari, SA, Squire, K, Xiao, C, Sebat, J, Bafna, V, Burchard, EG, Hernandez, RD, Gignoux, CR, Haussler, D, Katzman, SJ, Kent, WJ, Howie, B, Ruiz-Linares, A, Dermitzakis, ET, Lappalainen, T, Devine, SE, Maroo, A, Tallon, LJ, Rosenfeld, JA, Michelson, LP, Kang, HM, Anderson, P, Angius, A, Bigham, A, Blackwell, T, Busonero, F, Cucca, F, Fuchsberger, C, Jones, C, Jun, G, Lyons, R, Maschio, A, Porcu, E, Reinier, F, Sanna, S, Schlessinger, D, Sidore, C, Tan, A, Trost, MK, Awadalla, P, Hodgkinson, A, Lunter, G, Marchini, JL, Myers, S, Churchhouse, C, Delaneau, O, Gupta-Hinch, A, Iqbal, Z, Mathieson, I, Rimmer, A, Xifara, DK, Oleksyk, TK, Fu, Y, Xiong, M, Jorde, L, Witherspoon, D, Xing, J, Browning, BL, Alkan, C, Hajirasouliha, I, Hormozdiari, F, Ko, A, Sudmant, PH, Chen, K, Chinwalla, A, Ding, L, Dooling, D, Koboldt, DC, McLellan, MD, Wallis, JW, Wendl, MC, Zhang, Q, Tyler-Smith, C, Albers, CA, Ayub, Q, Chen, Y, Coffey, AJ, Colonna, V, Huang, N, Jostins, L, Li, H, Scally, A, Walter, K, Xue, Y, Zhang, Y, Gerstein, MB, Abyzov, A, Balasubramanian, S, Chen, J, Clarke, D, Habegger, L, Harmanci, AO, Jin, M, Khurana, E, Mu, XJ, Sisu, C, Degenhardt, J, Stuetz, AM, Church, D, Michaelson, JJ, Ben, B, Lindsay, SJ, Ning, Z, Frankish, A, Harrow, J, Fowler, G, Hale, W, Kalra, D, Barker, J, Kelman, G, Kulesha, E, Radhakrishnan, R, Roa, A, Smirnov, D, Streeter, I, Toneva, I, Vaughan, B, Ananiev, V, Belaia, Z, Beloslyudtsev, D, Bouk, N, Chen, C, Cohen, R, Cook, C, Garner, J, Hefferon, T, Kimelman, M, Liu, C, Lopez, J, Meric, P, O'Sullivan, C, Ostapchuk, Y, Phan, L, Ponomarov, S, Schneider, V, Shekhtman, E, Sirotkin, K, Slotta, D, Zhang, H, Barnes, KC, Beiswanger, C, Cai, H, Cao, H, Gharani, N, Henn, B, Jones, D, Kaye, JS, Kent, A, Kerasidou, A, Mathias, R, Ossorio, PN, Parker, M, Reich, D, Rotimi, CN, Royal, CD, Sandoval, K, Su, Y, Tian, Z, Tishkoff, S, Toji, LH, Via, M, Yang, H, Yang, L, Zhu, J, Bodmer, W, Bedoya, G, Ming, CZ, Yang, G, You, CJ, Peltonen, L, Garcia-Montero, A, Orfao, A, Dutil, J, Martinez-Cruzado, JC, Brooks, LD, Felsenfeld, AL, McEwen, JE, Clemm, NC, Duncanson, A, Dunn, M, Guyer, MS, Peterson, JL, 1000 Genomes Project Consortium, Dermitzakis, Emmanouil, Universitat de Barcelona, Massachusetts Institute of Technology. Department of Biology, Altshuler, David, and Lander, Eric S.
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Natural selection ,LOCI ,Genome-wide association study ,Evolutionary biology ,Continental Population Groups/genetics ,Human genetic variation ,VARIANTS ,Genoma humà ,Binding Sites/genetics ,0302 clinical medicine ,RARE ,Sequence Deletion/genetics ,WIDE ASSOCIATION ,ddc:576.5 ,Copy-number variation ,MUTATION ,Exome sequencing ,transcription factor ,Conserved Sequence ,Human evolution ,Sequence Deletion ,Genetics ,RISK ,0303 health sciences ,Multidisciplinary ,Continental Population Groups ,1000 Genomes Project Consortium ,Genetic analysis ,Genomics ,Polymorphism, Single Nucleotide/genetics ,Research Highlight ,3. Good health ,Algorithm ,Multidisciplinary Sciences ,Genetic Variation/genetics ,Map ,Science & Technology - Other Topics ,Conserved Sequence/genetics ,Integrated approach ,General Science & Technology ,Genetics, Medical ,Haplotypes/genetics ,Biology ,Polymorphism, Single Nucleotide ,Evolution, Molecular ,03 medical and health sciences ,Genetic variation ,Humans ,Transcription Factors/metabolism ,POPULATION-STRUCTURE ,1000 Genomes Project ,Polymorphism ,Nucleotide Motifs ,Alleles ,030304 developmental biology ,COPY NUMBER VARIATION ,Science & Technology ,Binding Sites ,Human genome ,Genome, Human ,Racial Groups ,Genetic Variation ,Genetics, Population ,Haplotypes ,Genome, Human/genetics ,untranslated RNA ,030217 neurology & neurosurgery ,Transcription Factors ,Genome-Wide Association Study - Abstract
By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations., National Institutes of Health (U.S.) (Grant RC2HL102925), National Institutes of Health (U.S.) (Grant U54HG3067)
- Published
- 2012
6. Frailty and Prehabilitation: Navigating the Road to a Successful Transplant.
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Kirkman DL, Kidd JM, Carbone S, Pontinha VM, Tanriover B, Kumar D, and Gupta G
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- 2024
- Full Text
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7. Mobile element insertions affect human pigmentation and skin cancer risk.
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Kidd JM
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- Humans, Genetic Predisposition to Disease, Mutagenesis, Insertional, Risk Factors, DNA Transposable Elements genetics, Skin Neoplasms genetics, Skin Pigmentation genetics
- Published
- 2024
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8. Uremic stomatitis.
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Kidd JM, Patrick K, and Sriperumbuduri S
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- Humans, Stomatitis etiology, Stomatitis diagnosis, Stomatitis pathology, Renal Dialysis, Male, Female, Middle Aged, Uremia complications, Uremia therapy, Uremia diagnosis, Uremia etiology
- Published
- 2024
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9. A map of canine sequence variation relative to a Greenland wolf outgroup.
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Nguyen AK, Schall PZ, and Kidd JM
- Abstract
For over 15 years, canine genetics research relied on a reference assembly from a Boxer breed dog named Tasha (i.e., canFam3.1). Recent advances in long-read sequencing and genome assembly have led to the development of numerous high-quality assemblies from diverse canines. These assemblies represent notable improvements in completeness, contiguity, and the representation of gene promoters and gene models. Although genome graph and pan-genome approaches have promise, most genetic analyses in canines rely upon the mapping of Illumina sequencing reads to a single reference. The Dog10K consortium, and others, have generated deep catalogs of genetic variation through an alignment of Illumina sequencing reads to a reference genome obtained from a German Shepherd Dog named Mischka (i.e., canFam4, UU_Cfam_GSD_1.0). However, alignment to a breed-derived genome may introduce bias in genotype calling across samples. Since the use of an outgroup reference genome may remove this effect, we have reprocessed 1929 samples analyzed by the Dog10K consortium using a Greenland wolf (mCanLor1.2) as the reference. We efficiently performed remapping and variant calling using a GPU-implementation of common analysis tools. The resulting call set removes the variability in genetic differences seen across samples and breed relationships revealed by principal component analysis are not affected by the choice of reference genome. Using this sequence data, we inferred the history of population sizes and found that village dog populations experienced a 9-13 fold reduction in historic effective population size relative to wolves., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2024
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10. Variable patterns of retrotransposition in different HeLa strains provide mechanistic insights into SINE RNA mobilization processes.
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Moldovan JB, Kopera HC, Liu Y, Garcia-Canadas M, Catalina P, Leone PE, Sanchez L, Kitzman JO, Kidd JM, Garcia-Perez JL, and Moran JV
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- Humans, HeLa Cells, Short Interspersed Nucleotide Elements genetics, Animals, Retroelements genetics, RNA genetics, RNA metabolism, RNA, Transfer genetics, RNA, Transfer metabolism, Zebrafish genetics, Alu Elements genetics, Long Interspersed Nucleotide Elements genetics
- Abstract
Alu elements are non-autonomous Short INterspersed Elements (SINEs) derived from the 7SL RNA gene that are present at over one million copies in human genomic DNA. Alu mobilizes by a mechanism known as retrotransposition, which requires the Long INterspersed Element-1 (LINE-1) ORF2-encoded protein (ORF2p). Here, we demonstrate that HeLa strains differ in their capacity to support Alu retrotransposition. Human Alu elements retrotranspose efficiently in HeLa-HA and HeLa-CCL2 (Alu-permissive) strains, but not in HeLa-JVM or HeLa-H1 (Alu-nonpermissive) strains. A similar pattern of retrotransposition was observed for other 7SL RNA-derived SINEs and tRNA-derived SINEs. In contrast, mammalian LINE-1s, a zebrafish LINE, a human SINE-VNTR-Alu (SVA) element, and an L1 ORF1-containing mRNA can retrotranspose in all four HeLa strains. Using an in vitro reverse transcriptase-based assay, we show that Alu RNAs associate with ORF2p and are converted into cDNAs in both Alu-permissive and Alu-nonpermissive HeLa strains, suggesting that 7SL- and tRNA-derived SINEs use strategies to 'hijack' L1 ORF2p that are distinct from those used by SVA elements and ORF1-containing mRNAs. These data further suggest ORF2p associates with the Alu RNA poly(A) tract in both Alu-permissive and Alu-nonpermissive HeLa strains, but that Alu retrotransposition is blocked after this critical step in Alu-nonpermissive HeLa strains., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2024
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11. Duplications and Retrogenes Are Numerous and Widespread in Modern Canine Genomic Assemblies.
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Nguyen AK, Blacksmith MS, and Kidd JM
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- Dogs genetics, Animals, Genomics, Evolution, Molecular, Retroelements, Gene Duplication, Genome
- Abstract
Recent years have seen a dramatic increase in the number of canine genome assemblies available. Duplications are an important source of evolutionary novelty and are also prone to misassembly. We explored the duplication content of nine canine genome assemblies using both genome self-alignment and read-depth approaches. We find that 8.58% of the genome is duplicated in the canFam4 assembly, derived from the German Shepherd Dog Mischka, including 90.15% of unplaced contigs. Highlighting the continued difficulty in properly assembling duplications, less than half of read-depth and assembly alignment duplications overlap, but the mCanLor1.2 Greenland wolf assembly shows greater concordance. Further study shows the presence of multiple segments that have alignments to four or more duplicate copies. These high-recurrence duplications correspond to gene retrocopies. We identified 3,892 candidate retrocopies from 1,316 parental genes in the canFam4 assembly and find that ∼8.82% of duplicated base pairs involve a retrocopy, confirming this mechanism as a major driver of gene duplication in canines. Similar patterns are found across eight other recent canine genome assemblies, with metrics supporting a greater quality of the PacBio HiFi mCanLor1.2 assembly. Comparison between the wolf and other canine assemblies found that 92% of retrocopy insertions are shared between assemblies. By calculating the number of generations since genome divergence, we estimate that new retrocopy insertions appear, on average, in 1 out of 3,514 births. Our analyses illustrate the impact of retrogene formation on canine genomes and highlight the variable representation of duplicated sequences among recently completed canine assemblies., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)
- Published
- 2024
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12. Podocyte-specific silencing of acid sphingomyelinase gene to abrogate hyperhomocysteinemia-induced NLRP3 inflammasome activation and glomerular inflammation.
- Author
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Huang D, Kidd JM, Zou Y, Wu X, Li N, Gehr TWB, Li PL, and Li G
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- Animals, Kidney Glomerulus pathology, Kidney Glomerulus metabolism, Glomerulonephritis pathology, Glomerulonephritis metabolism, Glomerulonephritis genetics, Gene Silencing, Mice, Mice, Inbred C57BL, Extracellular Vesicles metabolism, Male, Disease Models, Animal, Sphingomyelin Phosphodiesterase genetics, Sphingomyelin Phosphodiesterase metabolism, Podocytes metabolism, Podocytes pathology, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Hyperhomocysteinemia metabolism, Hyperhomocysteinemia complications, Hyperhomocysteinemia genetics, Inflammasomes metabolism, Inflammasomes genetics, Mice, Knockout
- Abstract
Acid sphingomyelinase (ASM) has been reported to increase tissue ceramide and thereby mediate hyperhomocysteinemia (hHcy)-induced glomerular nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation, inflammation, and sclerosis. In the present study, we tested whether somatic podocyte-specific silencing of Smpd1 gene (mouse ASM gene code) attenuates hHcy-induced NLRP3 inflammasome activation and associated extracellular vesicle (EV) release in podocytes and thereby suppresses glomerular inflammatory response and injury. In vivo, somatic podocyte-specific Smpd1 gene silencing almost blocked hHcy-induced glomerular NLRP3 inflammasome activation in Podo
cre (podocyte-specific expression of cre recombinase) mice compared with control littermates. By nanoparticle tracking analysis (NTA), floxed Smpd1 shRNA transfection was found to abrogate hHcy-induced elevation of urinary EV excretion in Podocre mice. In addition, Smpd1 gene silencing in podocytes prevented hHcy-induced immune cell infiltration into glomeruli, proteinuria, and glomerular sclerosis in Podocre mice. Such protective effects of podocyte-specific Smpd1 gene silencing were mimicked by global knockout of Smpd1 gene in Smpd1-/- mice. On the contrary, podocyte-specific Smpd1 gene overexpression exaggerated hHcy-induced glomerular pathological changes in Smpd1trg /Podocre (podocyte-specific Smpd1 gene overexpression) mice, which were significantly attenuated by transfection of floxed Smpd1 shRNA. In cell studies, we also confirmed that Smpd1 gene knockout or silencing prevented homocysteine (Hcy)-induced elevation of EV release in the primary cultures of podocyte isolated from Smpd1-/- mice or podocytes of Podocre mice transfected with floxed Smpd1 shRNA compared with WT/WT podocytes. Smpd1 gene overexpression amplified Hcy-induced EV secretion from podocytes of Smpd1trg /Podocre mice, which was remarkably attenuated by transfection of floxed Smpd1 shRNA. Mechanistically, Hcy-induced elevation of EV release from podocytes was blocked by ASM inhibitor (amitriptyline, AMI), but not by NLRP3 inflammasome inhibitors (MCC950 and glycyrrhizin, GLY). Super-resolution microscopy also showed that ASM inhibitor, but not NLRP3 inflammasome inhibitors, prevented the inhibition of lysosome-multivesicular body interaction by Hcy in podocytes. Moreover, we found that podocyte-derived inflammatory EVs (released from podocytes treated with Hcy) induced podocyte injury, which was exaggerated by T cell coculture. Interstitial infusion of inflammatory EVs into renal cortex induced glomerular injury and immune cell infiltration. In conclusion, our findings suggest that ASM in podocytes plays a crucial role in the control of NLRP3 inflammasome activation and inflammatory EV release during hHcy and that the development of podocyte-specific ASM inhibition or Smpd1 gene silencing may be a novel therapeutic strategy for treatment of hHcy-induced glomerular disease with minimized side effect. NEW & NOTEWORTHY In the present study, we tested whether podocyte-specific silencing of Smpd1 gene attenuates hyperhomocysteinemia (hHcy)-induced nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation and associated inflammatory extracellular vesicle (EV) release in podocytes and thereby suppresses glomerular inflammatory response and injury. Our findings suggest that acid sphingomyelinase (ASM) in podocytes plays a crucial role in the control of NLRP3 inflammasome activation and inflammatory EV release during hHcy. Based on our findings, it is anticipated that the development of podocyte-specific ASM inhibition or Smpd1 gene silencing may be a novel therapeutic strategy for treatment of hHcy-induced glomerular disease with minimized side effects.- Published
- 2024
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13. Mapping recurrent mosaic copy number variation in human neurons.
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Sun C, Kathuria K, Emery SB, Kim B, Burbulis IE, Shin JH, Weinberger DR, Moran JV, Kidd JM, Mills RE, and McConnell MJ
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- Humans, Alleles, DNA Copy Number Variations, Neurons metabolism, Mosaicism
- Abstract
When somatic cells acquire complex karyotypes, they often are removed by the immune system. Mutant somatic cells that evade immune surveillance can lead to cancer. Neurons with complex karyotypes arise during neurotypical brain development, but neurons are almost never the origin of brain cancers. Instead, somatic mutations in neurons can bring about neurodevelopmental disorders, and contribute to the polygenic landscape of neuropsychiatric and neurodegenerative disease. A subset of human neurons harbors idiosyncratic copy number variants (CNVs, "CNV neurons"), but previous analyses of CNV neurons are limited by relatively small sample sizes. Here, we develop an allele-based validation approach, SCOVAL, to corroborate or reject read-depth based CNV calls in single human neurons. We apply this approach to 2,125 frontal cortical neurons from a neurotypical human brain. SCOVAL identifies 226 CNV neurons, which include a subclass of 65 CNV neurons with highly aberrant karyotypes containing whole or substantial losses on multiple chromosomes. Moreover, we find that CNV location appears to be nonrandom. Recurrent regions of neuronal genome rearrangement contain fewer, but longer, genes., (© 2024. The Author(s).)
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- 2024
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14. Genomic data resources of the Brain Somatic Mosaicism Network for neuropsychiatric diseases.
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Garrison MA, Jang Y, Bae T, Cherskov A, Emery SB, Fasching L, Jones A, Moldovan JB, Molitor C, Pochareddy S, Peters MA, Shin JH, Wang Y, Yang X, Akbarian S, Chess A, Gage FH, Gleeson JG, Kidd JM, McConnell M, Mills RE, Moran JV, Park PJ, Sestan N, Urban AE, Vaccarino FM, Walsh CA, Weinberger DR, Wheelan SJ, and Abyzov A
- Subjects
- Humans, Autism Spectrum Disorder genetics, Brain, Genomics, Mosaicism, Genome, Human, Mental Disorders genetics
- Abstract
Somatic mosaicism is defined as an occurrence of two or more populations of cells having genomic sequences differing at given loci in an individual who is derived from a single zygote. It is a characteristic of multicellular organisms that plays a crucial role in normal development and disease. To study the nature and extent of somatic mosaicism in autism spectrum disorder, bipolar disorder, focal cortical dysplasia, schizophrenia, and Tourette syndrome, a multi-institutional consortium called the Brain Somatic Mosaicism Network (BSMN) was formed through the National Institute of Mental Health (NIMH). In addition to genomic data of affected and neurotypical brains, the BSMN also developed and validated a best practices somatic single nucleotide variant calling workflow through the analysis of reference brain tissue. These resources, which include >400 terabytes of data from 1087 subjects, are now available to the research community via the NIMH Data Archive (NDA) and are described here., (© 2023. The Author(s).)
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- 2023
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15. Author Correction: Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture.
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Meadows JRS, Kidd JM, Wang GD, Parker HG, Schall PZ, Bianchi M, Christmas MJ, Bougiouri K, Buckley RM, Hitte C, Nguyen AK, Wang C, Jagannathan V, Niskanen JE, Frantz LAF, Arumilli M, Hundi S, Lindblad-Toh K, Ginja C, Agustina KK, André C, Boyko AR, Davis BW, Drögemüller M, Feng XY, Gkagkavouzis K, Iliopoulos G, Harris AC, Hytönen MK, Kalthof DC, Liu YH, Lymberakis P, Poulakakis N, Pires AE, Racimo F, Ramos-Almodovar F, Savolainen P, Venetsani S, Tammen I, Triantafyllidis A, vonHoldt B, Wayne RK, Larson G, Nicholas FW, Lohi H, Leeb T, Zhang YP, and Ostrander EA
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- 2023
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16. Genome-wide methylation patterns from canine nanopore assemblies.
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Schall PZ, Winkler PA, Petersen-Jones SM, Yuzbasiyan-Gurkan V, and Kidd JM
- Subjects
- Dogs, Animals, Methylation, Genome, Sequence Analysis, DNA, Software, High-Throughput Nucleotide Sequencing, Nanopores
- Abstract
Recent advances in long-read sequencing have enabled the creation of reference-quality genome assemblies for multiple individuals within a species. In particular, 8 long-read genome assemblies have recently been published for the canine model (dogs and wolves). These assemblies were created using a range of sequencing and computational approaches, with only limited comparisons described among subsets of the assemblies. Here we present 3 high-quality de novo reference assemblies based upon Oxford Nanopore long-read sequencing: 2 Bernese Mountain Dogs (BD & OD) and a Cairn terrier (CA611). These breeds are of particular interest due to the enrichment of unresolved genetic disorders. Leveraging advancement in software technologies, we utilized published data of Labrador Retriever (Yella) to generate a new assembly, resulting in a ∼280-fold increase in continuity (N50 size of 91 kbp vs 25.75 Mbp). In conjunction with these 4 new assemblies, we uniformly assessed 8 existing assemblies for generalized quality metrics, sequence divergence, and a detailed BUSCO assessment. We identified a set of ∼400 conserved genes during the BUSCO analysis missing in all assemblies. Genome-wide methylation profiles were generated from the nanopore sequencing, resulting in broad concordance with existing whole-genome and reduced-representation bisulfite sequencing, while highlighting superior overage of mobile elements. These analyses demonstrate the ability of Nanopore sequencing to resolve the sequence and epigenetic profile of canine genomes., Competing Interests: Conflicts of interest The author(s) declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)
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- 2023
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17. Regulation of NLRP3 Inflammasome Activation and Inflammatory Exosome Release in Podocytes by Acid Sphingomyelinase During Obesity.
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Huang D, Kidd JM, Zou Y, Wu X, Gehr TWB, Li PL, and Li G
- Subjects
- Animals, Mice, Ceramides metabolism, Inflammasomes metabolism, Inflammation metabolism, Nicotinamide Phosphoribosyltransferase metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Obesity metabolism, Sphingomyelin Phosphodiesterase, Exosomes metabolism, Podocytes metabolism
- Abstract
The activation of nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome has been reported to importantly contribute to glomerular inflammation and injury under different pathological conditions such as obesity. However, the mechanism mediating NLRP3 inflammasome activation in podocytes and subsequent glomerular injury remains poorly understood. Given that the ceramide signaling pathway has been reported to be implicated in obesity-related glomerulopathy (ORG), the present study was designed to test whether the ceramide-producing enzyme, acid sphingomyelinase (ASM), determines NLRP3 inflammasome activation and inflammatory exosome release in podocytes leading to glomerular inflammation and injury during ORG. In Smpd1
trg /Podocre mice, podocyte-specific overexpression of Smpd1 gene which encodes ASM significantly exaggerated high-fat diet (HFD)-induced NLRP3 inflammasome activation in podocytes and immune cell infiltration in glomeruli compared to WT/WT mice. Smpd1 gene deletion, however, blocked these pathological changes induced by HFD in Smpd1-/- mice. Accompanied with NLRP3 inflammasome activation and glomerular inflammation, urinary excretion of exosomes containing podocyte marker and NLRP3 inflammasome products (IL-1β and IL-18) in Smpd1trg /Podocre mice on the HFD was much higher than that in WT/WT mice. In contrast, Smpd1-/- mice on the HDF had significantly lower urinary exosome excretion than WT/WT mice. Correspondingly, HFD-induced podocyte injury, glomerular sclerosis, and proteinuria were more severe in Smpd1trg /Podocre mice, but milder in Smpd1-/- mice compared to WT/WT mice. Using podocytes isolated from these mice, we demonstrated that visfatin, a prototype pro-inflammatory adipokine, induced NLRP3 inflammasome activation and enrichment of multivesicular bodies (MVBs) containing IL-1β in podocytes, which was much stronger in podocytes from Smpd1trg /Podocre mice, but weaker in those from Smpd1-/- mice than WT/WT podocytes. By quantitative analysis of exosomes, it was found that upon visfatin stimulation, podocytes from Smpd1trg /Podocre mice released much more exosomes containing NLRP3 inflammasome products, but podocytes from Smpd1-/- mice released much less exosomes compared to WT/WT podocytes. Super-resolution microscopy demonstrated that visfatin inhibited lysosome-MVB interaction in podocytes, indicating impaired MVB degradation by lysosome. The inhibition of lysosome-MVB interaction by visfatin was amplified by Smpd1 gene overexpression but attenuated by Smpd1 gene deletion. Taken together, our results suggest that ASM in podocytes is a crucial regulator of NLRP3 inflammasome activation and inflammatory exosome release that instigate glomerular inflammation and injury during obesity., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2023
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18. Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture.
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Meadows JRS, Kidd JM, Wang GD, Parker HG, Schall PZ, Bianchi M, Christmas MJ, Bougiouri K, Buckley RM, Hitte C, Nguyen AK, Wang C, Jagannathan V, Niskanen JE, Frantz LAF, Arumilli M, Hundi S, Lindblad-Toh K, Ginja C, Agustina KK, André C, Boyko AR, Davis BW, Drögemüller M, Feng XY, Gkagkavouzis K, Iliopoulos G, Harris AC, Hytönen MK, Kalthoff DC, Liu YH, Lymberakis P, Poulakakis N, Pires AE, Racimo F, Ramos-Almodovar F, Savolainen P, Venetsani S, Tammen I, Triantafyllidis A, vonHoldt B, Wayne RK, Larson G, Nicholas FW, Lohi H, Leeb T, Zhang YP, and Ostrander EA
- Subjects
- Dogs, Animals, Chromosome Mapping, Alleles, Polymorphism, Single Nucleotide, Nucleotides, Demography, Wolves genetics
- Abstract
Background: The international Dog10K project aims to sequence and analyze several thousand canine genomes. Incorporating 20 × data from 1987 individuals, including 1611 dogs (321 breeds), 309 village dogs, 63 wolves, and four coyotes, we identify genomic variation across the canid family, setting the stage for detailed studies of domestication, behavior, morphology, disease susceptibility, and genome architecture and function., Results: We report the analysis of > 48 M single-nucleotide, indel, and structural variants spanning the autosomes, X chromosome, and mitochondria. We discover more than 75% of variation for 239 sampled breeds. Allele sharing analysis indicates that 94.9% of breeds form monophyletic clusters and 25 major clades. German Shepherd Dogs and related breeds show the highest allele sharing with independent breeds from multiple clades. On average, each breed dog differs from the UU_Cfam_GSD_1.0 reference at 26,960 deletions and 14,034 insertions greater than 50 bp, with wolves having 14% more variants. Discovered variants include retrogene insertions from 926 parent genes. To aid functional prioritization, single-nucleotide variants were annotated with SnpEff and Zoonomia phyloP constraint scores. Constrained positions were negatively correlated with allele frequency. Finally, the utility of the Dog10K data as an imputation reference panel is assessed, generating high-confidence calls across varied genotyping platform densities including for breeds not included in the Dog10K collection., Conclusions: We have developed a dense dataset of 1987 sequenced canids that reveals patterns of allele sharing, identifies likely functional variants, informs breed structure, and enables accurate imputation. Dog10K data are publicly available., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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19. A first-in-class inhibitor of Hsp110 molecular chaperones of pathogenic fungi.
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Hu L, Sun C, Kidd JM, Han J, Fang X, Li H, Liu Q, May AE, Li Q, Zhou L, and Liu Q
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- Humans, Molecular Chaperones, Protein Folding, Antifungal Agents pharmacology, Candida albicans
- Abstract
Proteins of the Hsp110 family are molecular chaperones that play important roles in protein homeostasis in eukaryotes. The pathogenic fungus Candida albicans, which causes infections in humans, has a single Hsp110, termed Msi3. Here, we provide proof-of-principle evidence supporting fungal Hsp110s as targets for the development of new antifungal drugs. We identify a pyrazolo[3,4-b] pyridine derivative, termed HLQ2H (or 2H), that inhibits the biochemical and chaperone activities of Msi3, as well as the growth and viability of C. albicans. Moreover, the fungicidal activity of 2H correlates with its inhibition of in vivo protein folding. We propose 2H and related compounds as promising leads for development of new antifungals and as pharmacological tools for the study of the molecular mechanisms and functions of Hsp110s., (© 2023. The Author(s).)
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- 2023
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20. Mapping the Complex Genetic Landscape of Human Neurons.
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Sun C, Kathuria K, Emery SB, Kim B, Burbulis IE, Shin JH, Weinberger DR, Moran JV, Kidd JM, Mills RE, and McConnell MJ
- Abstract
When somatic cells acquire complex karyotypes, they are removed by the immune system. Mutant somatic cells that evade immune surveillance can lead to cancer. Neurons with complex karyotypes arise during neurotypical brain development, but neurons are almost never the origin of brain cancers. Instead, somatic mutations in neurons can bring about neurodevelopmental disorders, and contribute to the polygenic landscape of neuropsychiatric and neurodegenerative disease. A subset of human neurons harbors idiosyncratic copy number variants (CNVs, "CNV neurons"), but previous analyses of CNV neurons have been limited by relatively small sample sizes. Here, we developed an allele-based validation approach, SCOVAL, to corroborate or reject read-depth based CNV calls in single human neurons. We applied this approach to 2,125 frontal cortical neurons from a neurotypical human brain. This approach identified 226 CNV neurons, as well as a class of CNV neurons with complex karyotypes containing whole or substantial losses on multiple chromosomes. Moreover, we found that CNV location appears to be nonrandom. Recurrent regions of neuronal genome rearrangement contained fewer, but longer, genes., Competing Interests: Competing interests J.V.M. is an inventor on patent US6150160, is a paid consultant for Gilead Sciences, serves on the scientific advisory board of Tessera Therapeutics Inc. (where he is paid as a consultant and has equity options), has licensed reagents to Merck Pharmaceutical, and recently served on the American Society of Human Genetics Board of Directors. The other authors do not declare competing interests.
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- 2023
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21. Rapid Progression of Focal Segmental Glomerulosclerosis in Patients with High-Risk APOL1 Genotypes.
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Kallash M, Wang Y, Smith A, Trachtman H, Gbadegesin R, Nester C, Canetta P, Wang C, Hunley TE, Sperati CJ, Selewski D, Ayoub I, Srivastava T, Mottl AK, Kopp J, Gillespie B, Robinson B, Chen D, Steinke J, Twombley K, Reidy K, Mucha K, Greenbaum LA, Blazius B, Helmuth M, Yonatan P, Parekh RS, Hogan S, Royal V, D'Agati V, Chishti A, Falk R, Gharavi A, Holzman L, Klein J, Smoyer W, Kretzler M, Gipson D, and Kidd JM
- Subjects
- Humans, Apolipoprotein L1 genetics, Cohort Studies, Risk Factors, Genotype, Apolipoproteins genetics, Glomerulosclerosis, Focal Segmental genetics, Glomerulosclerosis, Focal Segmental diagnosis
- Abstract
Background: FSGS is a heterogeneous diagnosis with a guarded prognosis. Polymorphisms in the apolipoprotein L1 ( APOL1 ) gene are associated with developing FSGS and faster progression to kidney failure in affected patients. Better understanding the natural history of patients with FSGS and APOL1 risk alleles is essential to improve patient care and support the design and interpretation of interventional studies. The objective of this study was to evaluate the quantitative association between APOL1 and kidney disease progression and the interaction with other clinical and laboratory factors., Methods: CureGN cohort study participants with biopsy diagnosis of FSGS, regardless of self-identified race, were included. The exposure of interest was two APOL1 risk alleles (high risk) versus zero to one risk alleles (low risk). The primary outcome was eGFR slope categorized as rapid progressor (eGFR slope ≤-5 ml/min per year), intermediate progressor (slope between 0 and -5), or nonprogressor (slope ≥0). Multivariable ordinal logistic and linear regressions were used for adjusted analyses. Missing data were addressed using multiple imputation., Results: Of 650 participants, 476 (73%) had genetic testing, among whom 87 (18%) were high risk. High-risk participants were more likely to have lower median eGFR (62 [interquartile range, 36-81] versus low-risk participants 76 ml/min per 1.73 m 2 [interquartile range, 44-106]; P <0.01). In adjusted analysis, the odds of more rapid progression of eGFR was 2.75 times higher (95% confidence interval, 1.67 to 4.53; P <0.001) in the high-risk versus low-risk groups., Conclusions: In patients with FSGS, high-risk APOL1 genotype is the predominant factor associated with more rapid loss of kidney function., (Copyright © 2023 by the American Society of Nephrology.)
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- 2023
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22. Recent, full-length gene retrocopies are common in canids.
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Batcher K, Varney S, York D, Blacksmith M, Kidd JM, Rebhun R, Dickinson P, and Bannasch D
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- Animals, Dogs, Retroelements, Male, Genome, Humans, DNA Copy Number Variations
- Abstract
Gene retrocopies arise from the reverse transcription and insertion into the genome of processed mRNA transcripts. Although many retrocopies have acquired mutations that render them functionally inactive, most mammals retain active LINE-1 sequences capable of producing new retrocopies. New retrocopies, referred to as retro copy number variants (retroCNVs), may not be identified by standard variant calling techniques in high-throughput sequencing data. Although multiple functional FGF4 retroCNVs have been associated with skeletal dysplasias in dogs, the full landscape of canid retroCNVs has not been characterized. Here, retroCNV discovery was performed on a whole-genome sequencing data set of 293 canids from 76 breeds. We identified retroCNV parent genes via the presence of mRNA-specific 30-mers, and then identified retroCNV insertion sites through discordant read analysis. In total, we resolved insertion sites for 1911 retroCNVs from 1179 parent genes, 1236 of which appeared identical to their parent genes. Dogs had on average 54.1 total retroCNVs and 1.4 private retroCNVs. We found evidence of expression in testes for 12% (14/113) of the retroCNVs identified in six Golden Retrievers, including four chimeric transcripts, and 97 retroCNVs also had significantly elevated F
ST across dog breeds, possibly indicating selection. We applied our approach to a subset of human genomes and detected an average of 4.2 retroCNVs per sample, highlighting a 13-fold relative increase of retroCNV frequency in dogs. Particularly in canids, retroCNVs are a largely unexplored source of genetic variation that can contribute to genome plasticity and that should be considered when investigating traits and diseases., (© 2022 Batcher et al.; Published by Cold Spring Harbor Laboratory Press.)- Published
- 2022
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23. Author Correction: Comparative and demographic analysis of orang-utan genomes.
- Author
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Locke DP, Hillier LW, Warren WC, Worley KC, Nazareth LV, Muzny DM, Yang SP, Wang Z, Chinwalla AT, Minx P, Mitreva M, Cook L, Delehaunty KD, Fronick C, Schmidt H, Fulton LA, Fulton RS, Nelson JO, Magrini V, Pohl C, Graves TA, Markovic C, Cree A, Dinh HH, Hume J, Kovar CL, Fowler GR, Lunter G, Meader S, Heger A, Ponting CP, Marques-Bonet T, Alkan C, Chen L, Cheng Z, Kidd JM, Eichler EE, White S, Searle S, Vilella AJ, Chen Y, Flicek P, Ma J, Raney B, Suh B, Burhans R, Herrero J, Haussler D, Faria R, Fernando O, Darré F, Farré D, Gazave E, Oliva M, Navarro A, Roberto R, Capozzi O, Archidiacono N, Della Valle G, Purgato S, Rocchi M, Konkel MK, Walker JA, Ullmer B, Batzer MA, Smit AFA, Hubley R, Casola C, Schrider DR, Hahn MW, Quesada V, Puente XS, Ordoñez GR, López-Otín C, Vinar T, Brejova B, Ratan A, Harris RS, Miller W, Kosiol C, Lawson HA, Taliwal V, Martins AL, Siepel A, RoyChoudhury A, Ma X, Degenhardt J, Bustamante CD, Gutenkunst RN, Mailund T, Dutheil JY, Hobolth A, Schierup MH, Ryder OA, Yoshinaga Y, de Jong PJ, Weinstock GM, Rogers J, Mardis ER, Gibbs RA, and Wilson RK
- Published
- 2022
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24. Canis familiaris (Great Dane domestic dog).
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Halo JV and Kidd JM
- Subjects
- Animals, Dogs, Dog Diseases
- Published
- 2022
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25. Bimodal Expression Patterns, and Not Viral Burst Sizes, Predict the Effects of Vpr on HIV-1 Proviral Populations in Jurkat Cells.
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Atindaana E, Kissi-Twum A, Emery S, Burnett C, Pitcher J, Visser M, Kidd JM, and Telesnitsky A
- Subjects
- Humans, Jurkat Cells, Proviruses genetics, vpr Gene Products, Human Immunodeficiency Virus genetics, vpr Gene Products, Human Immunodeficiency Virus metabolism, HIV Seropositivity, HIV-1 physiology
- Abstract
Integration site landscapes, clonal dynamics, and latency reversal with or without vpr were compared in HIV-1-infected Jurkat cell populations, and the properties of individual clones were defined. Clones differed in fractions of long terminal repeat (LTR)-active daughter cells, with some clones containing few to no LTR-active cells, while almost all cells were LTR active for others. Clones varied over 4 orders of magnitude in virus release per active cell. Proviruses in largely LTR-active clones were closer to preexisting enhancers and promoters than low-LTR-active clones. Unsurprisingly, major vpr
+ clones contained fewer LTR-active cells than vpr- clones, and predominant vpr+ proviruses were farther from enhancers and promoters than those in vpr- pools. Distances to these marks among intact proviruses previously reported for antiretroviral therapy (ART)-suppressed patients revealed that patient integration sites were more similar to those in the vpr+ pool than to vpr- integrants. Complementing vpr -defective proviruses with vpr led to the rapid loss of highly LTR-active clones, indicating that the effect of Vpr on proviral populations occurred after integration. However, major clones in the complemented pool and its vpr- parent population did not differ in burst sizes. When the latency reactivation agents prostratin and JQ1 were applied separately or in combination, vpr+ and vpr- population-wide trends were similar, with dual-treatment enhancement being due in part to reactivated clones that did not respond to either drug applied separately. However, the expression signatures of individual clones differed between populations. These observations highlight how Vpr, exerting selective pressure on proviral epigenetic variation, can shape integration site landscapes, proviral expression patterns, and reactivation properties. IMPORTANCE A bedrock assumption in HIV-1 population modeling is that all active cells release the same amount of virus. However, the findings here revealed that when HIV-infected cells expand into clones, each clone differs in virus production. Reasoning that this variation in expression patterns constituted a population of clones from which differing subsets would prevail under differing environmental conditions, the cytotoxic HIV-1 protein Vpr was introduced, and population dynamics and expression properties were compared in the presence and absence of Vpr. The results showed that whereas most clones produced fairly continuous levels of virus in the absence of Vpr, its presence selected for a distinct subset of clones with properties reminiscent of persistent populations in patients, suggesting the possibility that the interclonal variation in expression patterns observed in culture may contribute to proviral persistence in vivo .- Published
- 2022
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26. Racial-ethnic differences in health-related quality of life among adults and children with glomerular disease.
- Author
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Krissberg JR, Helmuth ME, Almaani S, Cai Y, Cattran D, Chatterjee D, Gbadegesin RA, Gibson KL, Glenn DA, Greenbaum LA, Iragorri S, Jain K, Khalid M, Kidd JM, Kopp JB, Lafayette R, Nestor JG, Parekh RS, Reidy KJ, David T Selewski, John Sperati C, Tuttle KR, Twombley K, Vasylyeva TL, Weaver DJ Jr, Wenderfer SE, and O'Shaughnessy MM
- Abstract
Introduction: Disparities in health-related quality of life (HRQOL) have been inadequately studied in patients with glomerular disease. The aim of this study was to identify relationships between race/ethnicity, socioeconomic status, disease severity, and HRQOL in an ethnically and racially diverse cohort of patients with glomerular disease., Methods: Cure Glomerulonephropathy (CureGN) is a multinational cohort study of patients with biopsy-proven glomerular disease. Associations between race/ethnicity and HRQOL were determined by the following: 1. Missed school or work due to kidney disease; 2. Responses to Patient Reported Outcomes Measurement Information System (PROMIS) questionnaires. We adjusted for demographics, socioeconomic status, and disease characteristics using multivariable logistic and linear regression., Results: Black and Hispanic participants had worse socioeconomic status and more severe glomerular disease than White or Asian participants. Black adults missed work or school most frequently due to kidney disease (30% versus 16-23% in the other three groups, p=0.04), and had the worst self-reported global physical health (median score 44.1 versus 48.0-48.2, p<0.001) and fatigue (53.8 versus 48.5-51.1, p=0.002), compared to other racial/ethnic groups. However, these findings were not statistically significant with adjustment for socioeconomic status and disease severity, both of which were strongly associated with HRQOL in adults. Among children, disease severity but not race/ethnicity or socioeconomic status were associated with HRQOL., Conclusions: Among patients with glomerular disease enrolled in CureGN, the worse HRQOL reported by Black adults was attributable to lower socioeconomic status and more severe glomerular disease. No racial/ethnic differences in HRQOL were observed in children., Competing Interests: Conflicts of Interest: Dr. Greenbaum reports receiving research support from Vertex Pharmaceuticals, Apellis Pharmaceuticals, Reata Pharmaceuticals, Alexion Pharmaceuticals and an honorarium from Alexion Pharmaceuticals. Dr. Almaani is a consultant for Aurinia Pharmaceuticals Inc. Dr. Reidy is a primary investigator for Complexa and Advicenne studies unrelated to this current manuscript. Dr. Gibson holds advisory roles for Aurinia Inc., Reata Inc., and Retrophin, Inc. Dr. Tuttle has received research support from Goldfinch Bio and Travere/Retrophin and holds an advisory role for Goldfinch Bio. Dr. Sperati reports receiving research support for clinical trials from Alexion Pharmaceuticals and Alnylam, and honoraria for serving as chair of DSMB. All other authors declare that they have no known competing financial interests personal relationships that could appear to influence the work reported in this paper. Results of this paper have not been published previously in whole or part, with the exception of abstract format (ASN Kidney Week 2019).
- Published
- 2021
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27. Patiromer and Sodium Zirconium Cyclosilicate in Treatment of Hyperkalemia: A Systematic Review and Meta-Analysis.
- Author
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Shrestha DB, Budhathoki P, Sedhai YR, Baniya R, Cable CA, Kashiouris MG, Dixon DL, Kidd JM, Adhikari Y, Marasini A, and Bhandari S
- Abstract
Background: Patiromer and sodium zirconium cyclosilicate (SZC) are newer options for hyperkalemia treatment. This systematic review and meta-analysis were conducted to assess the safety and side effect profile of patiromer and SZC compared with placebo or other standards of care in the management of hyperkalemia., Methods: We searched electronic databases for relevant articles. The screening was performed independently and data were extracted among the selected studies. We performed a statistical analysis on Revman 5.4 software. The odds ratio (OR) was used for outcome estimation with a 95% CI., Results: Patiromer had lower rates of hyperkalemia (OR = 0.44; 95% CI, 0.22-0.89) compared with standard of care. The analysis showed no significant differences between the 2 groups in terms of overall adverse effects, any serious/specific adverse effects, or treatment discontinuation as a result of adverse effects. Comparing the SZC-10 group with standard of care showed no significant differences in the occurrence of hyperkalemia during treatment, overall adverse effects, any serious/specific adverse effects, or treatment discontinuation as a result of adverse effects but showed a higher rate of edema in the treatment group (OR = 6.77; 95% CI, 1.03-44.25). Similarly, no significant differences were seen between the 2 SZC doses for the occurrence of any adverse effects, hyperkalemia, constipation, diarrhea, or urinary tract infection, whereas edema was higher among patients receiving SZC-10 (OR = 3.13; 95% CI, 1.19-8.27)., Conclusions: In patients with acute hyperkalemia, SZC is the drug of choice due to its more rapid reduction of serum potassium level, whereas in patients with chronic hyperkalemia, patiromer appears to be the drug of choice because SZC is associated with an increase in edema, likely due to an increase in sodium absorption, which could have important adverse consequences in patients with chronic kidney disease and or heart failure. Thus, both drugs were found to be safe while treating hyperkalemia. (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX)., (© 2021 The Author(s).)
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- 2021
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28. From Surviving Sepsis to Surviving Sepsis-Associated Acute Kidney Injury: Focusing on Risk Stratification of Acute Kidney Injury / Acute Kidney Disease After Sepsis.
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Kothari NR, Gipson GT, and Kidd JM
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- 2021
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29. Dog10K_Boxer_Tasha_1.0: A Long-Read Assembly of the Dog Reference Genome.
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Jagannathan V, Hitte C, Kidd JM, Masterson P, Murphy TD, Emery S, Davis B, Buckley RM, Liu YH, Zhang XQ, Leeb T, Zhang YP, Ostrander EA, and Wang GD
- Subjects
- Animals, Contig Mapping, Molecular Sequence Annotation, Dogs genetics, Genome
- Abstract
The domestic dog has evolved to be an important biomedical model for studies regarding the genetic basis of disease, morphology and behavior. Genetic studies in the dog have relied on a draft reference genome of a purebred female boxer dog named "Tasha" initially published in 2005. Derived from a Sanger whole genome shotgun sequencing approach coupled with limited clone-based sequencing, the initial assembly and subsequent updates have served as the predominant resource for canine genetics for 15 years. While the initial assembly produced a good-quality draft, as with all assemblies produced at the time, it contained gaps, assembly errors and missing sequences, particularly in GC-rich regions, which are found at many promoters and in the first exons of protein-coding genes. Here, we present Dog10K_Boxer_Tasha_1.0, an improved chromosome-level highly contiguous genome assembly of Tasha created with long-read technologies that increases sequence contiguity >100-fold, closes >23,000 gaps of the CanFam3.1 reference assembly and improves gene annotation by identifying >1200 new protein-coding transcripts. The assembly and annotation are available at NCBI under the accession GCF_000002285.5.
- Published
- 2021
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30. Comprehensive identification of somatic nucleotide variants in human brain tissue.
- Author
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Wang Y, Bae T, Thorpe J, Sherman MA, Jones AG, Cho S, Daily K, Dou Y, Ganz J, Galor A, Lobon I, Pattni R, Rosenbluh C, Tomasi S, Tomasini L, Yang X, Zhou B, Akbarian S, Ball LL, Bizzotto S, Emery SB, Doan R, Fasching L, Jang Y, Juan D, Lizano E, Luquette LJ, Moldovan JB, Narurkar R, Oetjens MT, Rodin RE, Sekar S, Shin JH, Soriano E, Straub RE, Zhou W, Chess A, Gleeson JG, Marquès-Bonet T, Park PJ, Peters MA, Pevsner J, Walsh CA, Weinberger DR, Vaccarino FM, Moran JV, Urban AE, Kidd JM, Mills RE, and Abyzov A
- Subjects
- Alleles, Chromosome Mapping, Computational Biology methods, Genomics methods, Germ Cells metabolism, High-Throughput Nucleotide Sequencing, Humans, Organ Specificity genetics, Polymorphism, Single Nucleotide, Brain metabolism, Genetic Association Studies methods, Genetic Variation
- Abstract
Background: Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells., Results: Here, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees., Conclusions: This study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.
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- 2021
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31. Long-read assembly of a Great Dane genome highlights the contribution of GC-rich sequence and mobile elements to canine genomes.
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Halo JV, Pendleton AL, Shen F, Doucet AJ, Derrien T, Hitte C, Kirby LE, Myers B, Sliwerska E, Emery S, Moran JV, Boyko AR, and Kidd JM
- Subjects
- Animals, Dogs classification, Long Interspersed Nucleotide Elements, Short Interspersed Nucleotide Elements, Species Specificity, Dogs genetics, GC Rich Sequence, Genome, Interspersed Repetitive Sequences
- Abstract
Technological advances have allowed improvements in genome reference sequence assemblies. Here, we combined long- and short-read sequence resources to assemble the genome of a female Great Dane dog. This assembly has improved continuity compared to the existing Boxer-derived (CanFam3.1) reference genome. Annotation of the Great Dane assembly identified 22,182 protein-coding gene models and 7,049 long noncoding RNAs, including 49 protein-coding genes not present in the CanFam3.1 reference. The Great Dane assembly spans the majority of sequence gaps in the CanFam3.1 reference and illustrates that 2,151 gaps overlap the transcription start site of a predicted protein-coding gene. Moreover, a subset of the resolved gaps, which have an 80.95% median GC content, localize to transcription start sites and recombination hotspots more often than expected by chance, suggesting the stable canine recombinational landscape has shaped genome architecture. Alignment of the Great Dane and CanFam3.1 assemblies identified 16,834 deletions and 15,621 insertions, as well as 2,665 deletions and 3,493 insertions located on secondary contigs. These structural variants are dominated by retrotransposon insertion/deletion polymorphisms and include 16,221 dimorphic canine short interspersed elements (SINECs) and 1,121 dimorphic long interspersed element-1 sequences (LINE-1_Cfs). Analysis of sequences flanking the 3' end of LINE-1_Cfs (i.e., LINE-1_Cf 3'-transductions) suggests multiple retrotransposition-competent LINE-1_Cfs segregate among dog populations. Consistent with this conclusion, we demonstrate that a canine LINE-1_Cf element with intact open reading frames can retrotranspose its own RNA and that of a SINEC_Cf consensus sequence in cultured human cells, implicating ongoing retrotransposon activity as a driver of canine genetic variation., Competing Interests: Competing interest statement: J.V.M. is an inventor on patent US6150160, is a paid consultant for Gilead Sciences, serves on the scientific advisory board of Tessera Therapeutics Inc. (where he is paid as a consultant and has equity options), and currently serves on the American Society of Human Genetics Board of Directors. A.R.B. is the cofounder and Chief Science Officer of Embark Veterinary., (Copyright © 2021 the Author(s). Published by PNAS.)
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- 2021
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32. The Chronic Kidney Disease Phenotype of HFpEF: Unique Cardiac Characteristics.
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Kirkman DL, Carbone S, Canada JM, Trankle C, Kadariya D, Buckley L, Billingsley H, Kidd JM, Van Tassell BW, and Abbate A
- Subjects
- Aged, Blood Flow Velocity, Case-Control Studies, Echocardiography, Doppler, Electric Impedance, Exercise Test, Exercise Tolerance, Female, Functional Status, Galectin 3 metabolism, Heart Failure complications, Heart Failure diagnostic imaging, Heart Failure metabolism, Humans, Male, Middle Aged, Mitral Valve diagnostic imaging, Mitral Valve physiopathology, Natriuretic Peptide, Brain metabolism, Oxygen Consumption, Peptide Fragments metabolism, Phenotype, Quality of Life, Renal Insufficiency, Chronic complications, Body Composition, Glomerular Filtration Rate, Heart Failure physiopathology, Renal Insufficiency, Chronic metabolism, Stroke Volume physiology
- Published
- 2021
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33. Exercise intolerance in kidney diseases: physiological contributors and therapeutic strategies.
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Kirkman DL, Bohmke N, Carbone S, Garten RS, Rodriguez-Miguelez P, Franco RL, Kidd JM, and Abbate A
- Subjects
- Anemia, Iron-Deficiency complications, Fatigue therapy, Humans, Muscular Diseases complications, Sympathetic Nervous System physiology, Fatigue etiology, Kidney Failure, Chronic complications
- Abstract
Exertional fatigue, defined as the overwhelming and debilitating sense of sustained exhaustion that impacts the ability to perform activities of daily living, is highly prevalent in chronic kidney disease (CKD) and end-stage renal disease (ESRD). Subjective reports of exertional fatigue are paralleled by objective measurements of exercise intolerance throughout the spectrum of the disease. The prevalence of exercise intolerance is clinically noteworthy, as it leads to increased frailty, worsened quality of life, and an increased risk of mortality. The physiological underpinnings of exercise intolerance are multifaceted and still not fully understood. This review aims to provide a comprehensive outline of the potential physiological contributors, both central and peripheral, to kidney disease-related exercise intolerance and highlight current and prospective interventions to target this symptom. In this review, the CKD-related metabolic derangements, cardiac and pulmonary dysfunction, altered physiological responses to oxygen consumption, vascular derangements, and sarcopenia are discussed in the context of exercise intolerance. Lifestyle interventions to improve exertional fatigue, such as aerobic and resistance exercise training, are discussed, and the lack of dietary interventions to improve exercise tolerance is highlighted. Current and prospective pharmaceutical and nutraceutical strategies to improve exertional fatigue are also broached. An extensive understanding of the pathophysiological mechanisms of exercise intolerance will allow for the development of more targeted therapeutic approached to improve exertional fatigue and health-related quality of life in CKD and ESRD.
- Published
- 2021
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34. Genomic Copy Number Variation Study of Nine Macaca Species Provides New Insights into Their Genetic Divergence, Adaptation, and Biomedical Application.
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Li J, Fan Z, Shen F, Pendleton AL, Song Y, Xing J, Yue B, Kidd JM, and Li J
- Subjects
- Animals, Adaptation, Biological, Biological Evolution, DNA Copy Number Variations, Gene Duplication, Macaca genetics
- Abstract
Copy number variation (CNV) can promote phenotypic diversification and adaptive evolution. However, the genomic architecture of CNVs among Macaca species remains scarcely reported, and the roles of CNVs in adaptation and evolution of macaques have not been well addressed. Here, we identified and characterized 1,479 genome-wide hetero-specific CNVs across nine Macaca species with bioinformatic methods, along with 26 CNV-dense regions and dozens of lineage-specific CNVs. The genes intersecting CNVs were overrepresented in nutritional metabolism, xenobiotics/drug metabolism, and immune-related pathways. Population-level transcriptome data showed that nearly 46% of CNV genes were differentially expressed across populations and also mainly consisted of metabolic and immune-related genes, which implied the role of CNVs in environmental adaptation of Macaca. Several CNVs overlapping drug metabolism genes were verified with genomic quantitative polymerase chain reaction, suggesting that these macaques may have different drug metabolism features. The CNV-dense regions, including 15 first reported here, represent unstable genomic segments in macaques where biological innovation may evolve. Twelve gains and 40 losses specific to the Barbary macaque contain genes with essential roles in energy homeostasis and immunity defense, inferring the genetic basis of its unique distribution in North Africa. Our study not only elucidated the genetic diversity across Macaca species from the perspective of structural variation but also provided suggestive evidence for the role of CNVs in adaptation and genome evolution. Additionally, our findings provide new insights into the application of diverse macaques to drug study., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)
- Published
- 2020
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35. Glycosuria and Acute Kidney Injury: A Rare Presentation of Acute Interstitial Nephritis.
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Schwartz BA and Kidd JM
- Abstract
Acute interstitial nephritis (AIN) is often induced by drugs and is a common cause of acute kidney injury. Clinically diagnosing AIN can often be challenging because these signs and symptoms rarely present in concert. The inflammatory pathology of AIN leads to renal tubule dysregulation, which can be clinically observed as glycosuria, eosinophilia, leukocytes or white blood cell casts, and proteinuria. We present a case of an otherwise healthy woman in her 30s with AIN presenting with acute kidney injury and glycosuria without pyuria. This patient had an atypical presentation of AIN that lacked classic diagnostic laboratory features and has been rarely reported. She had profound glycosuria in the setting of normoglycemia, which resolved following a course of corticosteroids. Glycosuria was most likely due to proximal tubule damage from AIN. This case supports previous hypotheses that drug-induced AIN can cause proximal tubule dysfunction resulting in glycosuria in the absence of other identifiable proximal tubule dysregulations. We hypothesize that resolution of AIN involves the repair and restoration of sodium-dependent glucose cotransporter function., (© 2020 The Authors.)
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- 2020
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36. TypeTE: a tool to genotype mobile element insertions from whole genome resequencing data.
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Goubert C, Thomas J, Payer LM, Kidd JM, Feusier J, Watkins WS, Burns KH, Jorde LB, and Feschotte C
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- Databases, Genetic, Gene Frequency genetics, Genetic Loci, Genetics, Population, Genome, Human, Genotype, Humans, Interspersed Repetitive Sequences genetics, Mutagenesis, Insertional genetics, Software, Whole Genome Sequencing methods
- Abstract
Alu retrotransposons account for more than 10% of the human genome, and insertions of these elements create structural variants segregating in human populations. Such polymorphic Alus are powerful markers to understand population structure, and they represent variants that can greatly impact genome function, including gene expression. Accurate genotyping of Alus and other mobile elements has been challenging. Indeed, we found that Alu genotypes previously called for the 1000 Genomes Project are sometimes erroneous, which poses significant problems for phasing these insertions with other variants that comprise the haplotype. To ameliorate this issue, we introduce a new pipeline - TypeTE - which genotypes Alu insertions from whole-genome sequencing data. Starting from a list of polymorphic Alus, TypeTE identifies the hallmarks (poly-A tail and target site duplication) and orientation of Alu insertions using local re-assembly to reconstruct presence and absence alleles. Genotype likelihoods are then computed after re-mapping sequencing reads to the reconstructed alleles. Using a high-quality set of PCR-based genotyping of >200 loci, we show that TypeTE improves genotype accuracy from 83% to 92% in the 1000 Genomes dataset. TypeTE can be readily adapted to other retrotransposon families and brings a valuable toolbox addition for population genomics., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2020
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37. Commentary on Metabolic Acidosis in a Pediatric Patient with Leukemia and Fungal Infection.
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Kidd JM
- Subjects
- Child, Humans, Acidosis diagnosis, Leukemia complications, Mycoses complications, Mycoses diagnosis
- Published
- 2020
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38. The difficulties of identifying and treating Enterobacterales with OXA-48-like carbapenemases.
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Kidd JM, Livermore DM, and Nicolau DP
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- Bacterial Proteins metabolism, Enterobacteriaceae enzymology, beta-Lactamases metabolism
- Published
- 2020
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39. Persistent Disease Activity in Patients With Long-Standing Glomerular Disease.
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Delbarba E, Marasa M, Canetta PA, Piva SE, Chatterjee D, Kil BH, Mu X, Gibson KL, Hladunewich MA, Hogan JJ, Julian BA, Kidd JM, Laurin LP, Nachman PH, Rheault MN, Rizk DV, Sanghani NS, Trachtman H, Wenderfer SE, Gharavi AG, and Bomback AS
- Abstract
Introduction: Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease., Methods: Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy <5 years before enrollment drawn from the Cure Glomerulonephropathy Network (CureGN cohort, n = 1182; CUMC-CureGN cohort, n = 362). Disease activity was defined by (i) Kidney Disease: Improving Global Outcomes-recommended threshold criteria for initiation of immunosuppression in primary glomerulonephropathy (GN) and (ii) CureGN's Disease Activity Working Group definitions for activity., Results: No significant differences were detected among the 3 cohorts in terms of age, sex, serum creatinine, and urinary protein-to-creatinine ratio. For each GN subtype, disease activity in the OLD cohort was comparable with disease activity in the entire CureGN and the CUMC-CureGN cohort. When limiting our comparisons to disease activity in incident CUMC-CureGN patients (first diagnostic biopsy within 6 months of enrollment), OLD patients demonstrated similar activity rates as incident patients., Conclusion: Disease activity did not differ among patients with shorter versus longer duration of disease. Such survivor patients, with long-term but persistent disease, are potentially highly informative for understanding the clinical course and pathogenesis of GN and may help identify factors mediating more chronic subtypes of disease., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)
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- 2020
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40. Identification and characterization of occult human-specific LINE-1 insertions using long-read sequencing technology.
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Zhou W, Emery SB, Flasch DA, Wang Y, Kwan KY, Kidd JM, Moran JV, and Mills RE
- Subjects
- Cell Line, Genome, Human, Humans, Polymorphism, Genetic, Single-Cell Analysis, Software, Whole Genome Sequencing, Long Interspersed Nucleotide Elements, Sequence Analysis, DNA methods
- Abstract
Long Interspersed Element-1 (LINE-1) retrotransposition contributes to inter- and intra-individual genetic variation and occasionally can lead to human genetic disorders. Various strategies have been developed to identify human-specific LINE-1 (L1Hs) insertions from short-read whole genome sequencing (WGS) data; however, they have limitations in detecting insertions in complex repetitive genomic regions. Here, we developed a computational tool (PALMER) and used it to identify 203 non-reference L1Hs insertions in the NA12878 benchmark genome. Using PacBio long-read sequencing data, we identified L1Hs insertions that were absent in previous short-read studies (90/203). Approximately 81% (73/90) of the L1Hs insertions reside within endogenous LINE-1 sequences in the reference assembly and the analysis of unique breakpoint junction sequences revealed 63% (57/90) of these L1Hs insertions could be genotyped in 1000 Genomes Project sequences. Moreover, we observed that amplification biases encountered in single-cell WGS experiments led to a wide variation in L1Hs insertion detection rates between four individual NA12878 cells; under-amplification limited detection to 32% (65/203) of insertions, whereas over-amplification increased false positive calls. In sum, these data indicate that L1Hs insertions are often missed using standard short-read sequencing approaches and long-read sequencing approaches can significantly improve the detection of L1Hs insertions present in individual genomes., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2020
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41. Monte Carlo Simulation Methodologies for β-Lactam/β-Lactamase Inhibitor Combinations: Effect on Probability of Target Attainment Assessments.
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Kidd JM, Stein GE, Nicolau DP, and Kuti JL
- Subjects
- Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents therapeutic use, Azabicyclo Compounds therapeutic use, Ceftazidime therapeutic use, Computer Simulation, Drug Administration Schedule, Drug Combinations, Humans, Microbial Sensitivity Tests, Models, Biological, Models, Statistical, beta-Lactamase Inhibitors therapeutic use, beta-Lactams therapeutic use, Azabicyclo Compounds administration & dosage, Azabicyclo Compounds pharmacokinetics, Ceftazidime administration & dosage, Ceftazidime pharmacokinetics, Monte Carlo Method, beta-Lactamase Inhibitors administration & dosage, beta-Lactamase Inhibitors pharmacokinetics, beta-Lactams administration & dosage, beta-Lactams pharmacokinetics
- Abstract
Monte Carlo simulations (MCSs) are used in antibiotic development to predict the probability of pharmacodynamic target attainment (PTA) for a dosing regimen. However, for β-lactam/β-lactamase inhibitor combinations (BL-BLICs), methods for linking simulated concentration profiles of the β-lactam (BL) and β-lactamase inhibitor (BLI) components are rarely described. Using a previously defined pharmacokinetic model of ceftazidime/avibactam from critically ill patients, we performed four 5000-patient MCSs using different methods of increasing complexity to couple the BL and BLI components and compared PTA for ceftazidime and avibactam targets of >70% fT>MIC and >70% fT>1 mg/L, respectively, at MICs from 1 to 128 mg/L. Method A ignored all covariates and correlations, whereas methods B, C, and D enhanced associations by adding (B) pharmacokinetic parameter correlation within each drug only; (C) pharmacokinetic parameter correlation within each drug and creatinine clearance (CRCL); and (D) pharmacokinetic parameter correlation within each drug, CRCL, and pharmacokinetic parameter correlation between drugs. Method D produced a simulated patient population that best recapitulated the observed relationships between pharmacokinetic parameters in actual patients. Ceftazidime/avibactam PTA at MIC 8 mg/L (the susceptibility break point) and 16 mg/L ranged from 92.4% to 98.3% and 80.2% to 88.4%, respectively. PTA was lowest with method A, whereas PTA estimates were similar for all other methods. Compared with ignoring all pharmacokinetic parameter associations, the inclusion of covariate relationships and parameter correlation between both components of ceftazidime/avibactam leads to fewer patients with discordant pharmacokinetic parameters and results in higher PTA. Consideration of these methodologies should guide future MCS analyses for BL-BLIC., (© 2019, The American College of Clinical Pharmacology.)
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- 2020
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42. Rapid, Paralog-Sensitive CNV Analysis of 2457 Human Genomes Using QuicK-mer2.
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Shen F and Kidd JM
- Subjects
- Algorithms, Evolution, Molecular, Gene Duplication, Genome, Human, Humans, Computational Biology methods, DNA Copy Number Variations, Sequence Analysis, DNA methods
- Abstract
Gene duplication is a major mechanism for the evolution of gene novelty, and copy-number variation makes a major contribution to inter-individual genetic diversity. However, most approaches for studying copy-number variation rely upon uniquely mapping reads to a genome reference and are unable to distinguish among duplicated sequences. Specialized approaches to interrogate specific paralogs are comparatively slow and have a high degree of computational complexity, limiting their effective application to emerging population-scale data sets. We present QuicK-mer2, a self-contained, mapping-free approach that enables the rapid construction of paralog-specific copy-number maps from short-read sequence data. This approach is based on the tabulation of unique k-mer sequences from short-read data sets, and is able to analyze a 20X coverage human genome in approximately 20 min. We applied our approach to newly released sequence data from the 1000 Genomes Project, constructed paralog-specific copy-number maps from 2457 unrelated individuals, and uncovered copy-number variation of paralogous genes. We identify nine genes where none of the analyzed samples have a copy number of two, 92 genes where the majority of samples have a copy number other than two, and describe rare copy number variation effecting multiple genes at the APOBEC3 locus., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
- Published
- 2020
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43. Efficacy of human-simulated bronchopulmonary exposures of cefepime, zidebactam and the combination (WCK 5222) against MDR Pseudomonas aeruginosa in a neutropenic murine pneumonia model.
- Author
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Kidd JM, Abdelraouf K, and Nicolau DP
- Subjects
- Animals, Anti-Bacterial Agents pharmacokinetics, Azabicyclo Compounds pharmacokinetics, Cefepime pharmacokinetics, Cephalosporins pharmacokinetics, Cyclooctanes pharmacokinetics, Disease Models, Animal, Drug Therapy, Combination, Female, Healthy Volunteers, Humans, Lung drug effects, Lung microbiology, Mice, Microbial Sensitivity Tests, Neutropenia, Piperidines pharmacokinetics, Pneumonia, Bacterial drug therapy, Pseudomonas Infections microbiology, Pseudomonas aeruginosa drug effects, Specific Pathogen-Free Organisms, Anti-Bacterial Agents therapeutic use, Azabicyclo Compounds therapeutic use, Cefepime therapeutic use, Cephalosporins therapeutic use, Cyclooctanes therapeutic use, Drug Resistance, Multiple, Bacterial, Piperidines therapeutic use, Pseudomonas Infections drug therapy
- Abstract
Objectives: WCK 5222 combines cefepime with zidebactam, a β-lactam enhancer that binds PBP2 and inhibits class A and C β-lactamases. The efficacy of human-simulated bronchopulmonary exposures of WCK 5222 against MDR Pseudomonas aeruginosa was investigated in a neutropenic murine pneumonia model., Methods: Nineteen MDR isolates of P. aeruginosa (cefepime MICs ≥64 mg/L) were studied. MICs of zidebactam and WCK 5222 ranged from 4 to 512 mg/L and from 4 to 32 mg/L, respectively. Dosing regimens of cefepime and zidebactam alone and in combination that achieved epithelial lining fluid (ELF) exposures in mice approximating human ELF exposures after doses of 2 g of cefepime/1 g of zidebactam every 8 h (1 h infusion) were utilized; controls were vehicle-dosed. Lungs were intranasally inoculated with 107-108 cfu/mL bacterial suspensions. Mice were dosed subcutaneously 2 h after inoculation for 24 h, then lungs were harvested., Results: In vitro MIC was predictive of in vivo response to WCK 5222 treatment. Mean±SD changes in bacterial density at 24 h compared with 0 h controls (6.72±0.50 log10 cfu/lungs) for 13 isolates with WCK 5222 MICs ≤16 mg/L were 1.17±1.00, -0.99±1.45 and -2.21±0.79 log10 cfu/lungs for cefepime, zidebactam and WCK 5222, respectively. Against these isolates, zidebactam yielded >1 log10 cfu/lungs reductions in 8/13, while activity was enhanced with WCK 5222, producing >2 log10 cfu/lungs reductions in 10/13 and >1 log10 cfu/lungs reductions in 12/13. Among isolates with WCK 5222 MICs of 32 mg/L, five out of six showed a bacteriostatic response., Conclusions: Human-simulated bronchopulmonary exposure of WCK 5222 is effective against MDR P. aeruginosa at MIC ≤16 mg/L in a murine pneumonia model. These data support the clinical development of WCK 5222 for pseudomonal lung infections., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2020
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44. Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation.
- Author
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Kidd JM, Sakon CM, Oleksiuk LM, Cies JJ, Pettit RS, Nicolau DP, and Kuti JL
- Subjects
- Adult, Algorithms, Female, Humans, Male, Methicillin-Resistant Staphylococcus aureus drug effects, Methicillin-Resistant Staphylococcus aureus pathogenicity, Microbial Sensitivity Tests, Middle Aged, Monte Carlo Method, Prospective Studies, Staphylococcal Infections drug therapy, Staphylococcal Infections microbiology, Aminoglycosides pharmacokinetics, Aminoglycosides therapeutic use, Anti-Bacterial Agents pharmacokinetics, Anti-Bacterial Agents therapeutic use, Cystic Fibrosis drug therapy, Cystic Fibrosis microbiology, Lipoglycopeptides pharmacokinetics, Lipoglycopeptides therapeutic use
- Abstract
Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus , which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients ( n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment ( V
c ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight ( Vθ ) normalized by the median observed value ( Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ , 4.92 ± 0.76 liters · kg-1 ; CLNR , 0.59 ± 0.30 liters · h-1 ; CLθ , 5.97 × 10-3 ± 1.24 × 10-3 ; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h-1 The free area under the concentration-time curve ( f AUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a f AUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter-1 ) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.)., (Copyright © 2019 American Society for Microbiology.)- Published
- 2019
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45. Efficacy of Humanized Cefiderocol Exposure Is Unaltered by Host Iron Overload in the Thigh Infection Model.
- Author
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Kidd JM, Abdelraouf K, and Nicolau DP
- Subjects
- Acinetobacter baumannii drug effects, Acinetobacter baumannii pathogenicity, Animals, Cephalosporins pharmacology, Drug Resistance, Multiple, Bacterial, Female, Gram-Negative Bacteria drug effects, Humans, Iron metabolism, Iron Overload, Meropenem pharmacology, Mice, Microbial Sensitivity Tests, Pseudomonas aeruginosa drug effects, Pseudomonas aeruginosa metabolism, Siderophores chemistry, Cefiderocol, Anti-Bacterial Agents pharmacology, Cephalosporins therapeutic use, Gram-Negative Bacteria pathogenicity, Thigh microbiology
- Abstract
Cefiderocol is a siderophore-cephalosporin conjugate with greater in vitro potency under iron-depleted conditions. During infection, iron is scarce in host tissue; however, it is not known whether iron overload in the host, such as in cases of hereditary hemochromatosis, alters the efficacy of cefiderocol. We compared cefiderocol efficacy between iron-overloaded and standard murine thigh infection models. Female CD-1 mice rendered neutropenic received 2 weeks of iron dextran at 100 mg/kg of body weight/day intraperitoneally (iron-overloaded model) or no injections (standard model). Mice were inoculated (10
7 CFU/ml) with Enterobacterales , Acinetobacter baumannii , and Pseudomonas aeruginosa with previously determined cefiderocol MICs from 0.25 to 64 mg/liter. Human-simulated regimens of cefiderocol or meropenem (2 g every 8 h [q8h], 3-h infusion) were administered for 24 h (31 strains) or 72 h (15 strains; cefiderocol only). Procedures were simultaneously performed in standard and iron-overloaded models. Mean bacterial burdens (log10 CFU/thigh) at baseline were 5.75 ± 0.47 versus 5.81 ± 0.51 in standard versus iron-overloaded models, respectively. At 24 h, mean burdens in standard versus iron-overloaded models decreased by -0.8 ± 1.9 versus -1.2 ± 2.0 ( P = 0.25) in meropenem-treated mice and by -1.5 ± 1.4 versus -1.6 ± 1.5 ( P = 0.54) in cefiderocol-treated mice. At 72 h, mean burdens in cefiderocol-treated mice decreased by -2.5 ± 1.5 versus -2.5 ± 1.4. No overall differences in efficacy between the models were observed for meropenem or cefiderocol. Human-simulated exposure of cefiderocol is equally efficacious in iron-overloaded and normal hosts. The potential clinical use of cefiderocol to treat Gram-negative infections in patients with iron overload is supported., (Copyright © 2019 American Society for Microbiology.)- Published
- 2019
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46. Development of Neutropenic Murine Models of Iron Overload and Depletion To Study the Efficacy of Siderophore-Antibiotic Conjugates.
- Author
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Kidd JM, Abdelraouf K, and Nicolau DP
- Subjects
- Animals, Cephalosporins chemistry, Cephalosporins therapeutic use, Deferoxamine chemistry, Deferoxamine therapeutic use, Disease Models, Animal, Female, Iron, Meropenem chemistry, Meropenem therapeutic use, Mice, Microbial Sensitivity Tests, Cefiderocol, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents therapeutic use, Iron Overload drug therapy, Iron Overload metabolism, Siderophores chemistry
- Abstract
Siderophore-antibiotic conjugates have increased in vitro activity in low-iron environments where bacteria express siderophores and associated transporters. The host immune hypoferremic response reduces iron availability to bacteria; however, patients with iron overload or deficiency may have altered ability to restrict iron, which may affect the efficacy of siderophore-antibiotic conjugates. In vivo models of infection with iron overload and deficiency are needed to perform this assessment. The standard neutropenic murine thigh infection model was supplemented with iron-altering treatments: iron dextran at 100 mg/kg of body weight daily for 14 days to load iron or deferoxamine at 100 mg/kg daily plus a low-iron diet for up to 30 days to deplete iron. Human-simulated regimens of cefiderocol and meropenem were administered in both models to assess any impact of iron alteration on plasma pharmacokinetics. Median iron in overloaded mice was significantly higher than that of controls in plasma (1,657 versus 336 μg/dl; P < 0.001), liver (2,133 versus 11 μg/g; P < 0.001), and spleen (473 versus 144 μg/g; P < 0.001). At 30 days, depleted mice had significantly lower iron than controls in liver (2.4 versus 6.5 μg/g; P < 0.001) and spleen (72 versus 133 μg/g; P = 0.029) but not plasma (351 versus 324 μg/dl; P = 0.95). Cefiderocol and meropenem plasma concentrations were similar in iron overloaded and control mice but varied in iron-depleted mice. The iron-overloaded murine thigh infection model was established, and human-simulated regimens of cefiderocol and meropenem were validated therein. While deferoxamine successfully reduced liver and splenic iron, this depleting treatment altered the pharmacokinetics of both antimicrobials., (Copyright © 2019 American Society for Microbiology.)
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- 2019
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47. A Neofunctionalized X-Linked Ampliconic Gene Family Is Essential for Male Fertility and Equal Sex Ratio in Mice.
- Author
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Kruger AN, Brogley MA, Huizinga JL, Kidd JM, de Rooij DG, Hu YC, and Mueller JL
- Subjects
- Animals, Female, Gene Dosage, Gene Expression, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Fertility genetics, Genes, X-Linked genetics, Multigene Family genetics, Sex Chromosomes genetics, Sex Ratio
- Abstract
The mammalian sex chromosomes harbor an abundance of newly acquired ampliconic genes, although their functions require elucidation [1-9]. Here, we demonstrate that the X-linked Slx and Slxl1 ampliconic gene families represent mouse-specific neofunctionalized copies of a meiotic synaptonemal complex protein, Sycp3. In contrast to the meiotic role of Sycp3, CRISPR-loxP-mediated multi-megabase deletions of the Slx (5 Mb) and Slxl1 (2.3Mb) ampliconic regions result in post-meiotic defects, abnormal sperm, and male infertility. Males carrying Slxl1 deletions sire more male offspring, whereas males carrying Slx and Slxl1 duplications sire more female offspring, which directly correlates with Slxl1 gene dosage and gene expression levels. SLX and SLXL1 proteins interact with spindlin protein family members (SPIN1 and SSTY1/2) and males carrying Slxl1 deletions downregulate a sex chromatin modifier, Scml2, leading us to speculate that Slx and Slxl1 function in chromatin regulation. Our study demonstrates how newly acquired X-linked genes can rapidly evolve new and essential functions and how gene amplification can increase sex chromosome transmission., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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48. Stable integrant-specific differences in bimodal HIV-1 expression patterns revealed by high-throughput analysis.
- Author
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Read DF, Atindaana E, Pyaram K, Yang F, Emery S, Cheong A, Nakama KR, Burnett C, Larragoite ET, Battivelli E, Verdin E, Planelles V, Chang CH, Telesnitsky A, and Kidd JM
- Subjects
- CD4-Positive T-Lymphocytes metabolism, HIV Infections genetics, High-Throughput Screening Assays, Humans, Jurkat Cells, Transduction, Genetic, CD4-Positive T-Lymphocytes virology, HIV Infections virology, HIV-1 physiology, Proviruses genetics, Virus Integration genetics, Virus Replication
- Abstract
HIV-1 gene expression is regulated by host and viral factors that interact with viral motifs and is influenced by proviral integration sites. Here, expression variation among integrants was followed for hundreds of individual proviral clones within polyclonal populations throughout successive rounds of virus and cultured cell replication, with limited findings using CD4+ cells from donor blood consistent with observations in immortalized cells. Tracking clonal behavior by proviral "zip codes" indicated that mutational inactivation during reverse transcription was rare, while clonal expansion and proviral expression states varied widely. By sorting for provirus expression using a GFP reporter in the nef open reading frame, distinct clone-specific variation in on/off proportions were observed that spanned three orders of magnitude. Tracking GFP phenotypes over time revealed that as cells divided, their progeny alternated between HIV transcriptional activity and non-activity. Despite these phenotypic oscillations, the overall GFP+ population within each clone was remarkably stable, with clones maintaining clone-specific equilibrium mixtures of GFP+ and GFP- cells. Integration sites were analyzed for correlations between genomic features and the epigenetic phenomena described here. Integrants inserted in the sense orientation of genes were more frequently found to be GFP negative than those in the antisense orientation, and clones with high GFP+ proportions were more distal to repressive H3K9me3 peaks than low GFP+ clones. Clones with low frequencies of GFP positivity appeared to expand more rapidly than clones for which most cells were GFP+, even though the tested proviruses were Vpr-. Thus, much of the increase in the GFP- population in these polyclonal pools over time reflected differential clonal expansion. Together, these results underscore the temporal and quantitative variability in HIV-1 gene expression among proviral clones that are conferred in the absence of metabolic or cell-type dependent variability, and shed light on cell-intrinsic layers of regulation that affect HIV-1 population dynamics., Competing Interests: The authors have declared that no competing interests exist.
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- 2019
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49. Comparative In Vivo Antibacterial Activity of Human-Simulated Exposures of Cefiderocol and Ceftazidime against Stenotrophomonas maltophilia in the Murine Thigh Model.
- Author
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Chen IH, Kidd JM, Abdelraouf K, and Nicolau DP
- Abstract
Cefiderocol is a novel siderophore cephalosporin that utilizes bacterial ferric iron transports to cross the outer membrane. Cefiderocol shows high stability against all classes of β-lactamases, rendering it extremely potent against carbapenem- and multidrug-resistant Gram-negative organisms. Using a neutropenic murine thigh model, we compared the efficacies of human-simulated exposures of cefiderocol (2 g Q8H 3 h infusion) and ceftazidime (2 g Q8H 2 h infusion) against Stenotrophomonas maltophilia , an emerging opportunistic Gram-negative organism associated with serious and often fatal nosocomial infections. Twenty-four S. maltophilia isolates were studied, including isolates resistant to ceftazidime, trimethoprim-sulfate, and/or levofloxacin. The thighs were inoculated with bacterial suspensions of 10
8 CFU/mL and the human-simulated regimens were administered over 24 h. Efficacy was measured as the change in log10 CFU/thigh at 24 h compared with 0 h controls. Cefiderocol human-simulated exposure demonstrated potent bacterial killing; mean bacterial reduction at 24 h was -2.67 ± 0.68 log10 CFU/thigh with ≥ 2 log-reduction achieved in 21 isolates (87.5%) and ≥ 1 log-reduction achieved in the remaining three isolates (12.5%). In comparison, ceftazidime human-simulated exposure produced mean bacterial reduction of -1.38 ± 1.49 log10 CFU/thigh among 10 ceftazidime-susceptible isolates and mean bacterial growth of 0.64 ± 0.79 log10 CFU/thigh among 14 ceftazidime-non-susceptible isolates. While ceftazidime showed modest efficacy against most susceptible isolates, humanized cefiderocol exposures resulted in remarkable in vivo activity against all S. maltophilia isolates examined, inclusive of ceftazidime-non-susceptible isolates. The potent in vitro and in vivo activity of cefiderocol supports the development of this novel compound for managing S. maltophilia infections., (Copyright © 2019 American Society for Microbiology.)- Published
- 2019
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50. In vitro activity of ampicillin and ceftriaxone against ampicillin-susceptible Enterococcus faecium.
- Author
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Lorenzo MP, Kidd JM, Jenkins SG, Nicolau DP, and Housman ST
- Subjects
- Drug Synergism, Enterococcus faecalis drug effects, Enterococcus faecalis isolation & purification, Enterococcus faecium isolation & purification, France, Gram-Positive Bacterial Infections microbiology, Humans, Microbial Sensitivity Tests, Microbial Viability drug effects, Time Factors, United States, Ampicillin pharmacology, Anti-Bacterial Agents pharmacology, Ceftriaxone pharmacology, Enterococcus faecium drug effects
- Abstract
Objectives: To assess activity of the combination of ceftriaxone and ampicillin against clinical isolates of ampicillin-susceptible Enterococcus faecium., Methods: Ampicillin-susceptible E. faecium (n = 29) and Enterococcus faecalis (n = 10) collected from locations in the USA and France were used for this analysis. Susceptibility testing was performed by gradient diffusion strip (GDS) and broth microdilution (BMD). Synergy with the combination of ceftriaxone and ampicillin was assessed in all isolates using GDS crossing and double disc diffusion methods. Selected isolates (nine E. faecium and three E. faecalis) were assessed for synergy in time-kill studies using ampicillin alone and in combination with ceftriaxone., Results: In isolates of E. faecium, the median (range) ampicillin MIC by BMD was 0.5 (0.25-4) mg/L and by GDS it was 2 (1-8) mg/L. In E. faecalis, the median (range) ampicillin MIC by BMD was 0.5 (0.5-1) mg/L and by GDS it was 2 (0.75-3) mg/L. A total of 24/29 (82.8%) isolates of E. faecium displayed synergy by GDS and 22/29 (75.9%) by double disc diffusion. Seven of 10 (70%) isolates of E. faecalis displayed synergy by GDS and 4/10 (40%) by double disc diffusion. Time-kill studies found synergy in 3/9 (33.3%) E. faecium and 3/3 (100%) E. faecalis., Conclusions: In contrast to the demonstrated synergy in time-kill models of ceftriaxone and ampicillin for E. faecalis, this combination does not appear to provide uniform synergy in E. faecium. Antagonism was not observed. Clinical correlation is necessary and caution should be used when considering ampicillin and ceftriaxone for the treatment of infections caused by ampicillin-susceptible E. faecium., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
- Full Text
- View/download PDF
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