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Search Results: 1 - 10 of 684929 matches for " Sandra A. S. Johnson equal contributor "
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Maf1 Is a Novel Target of PTEN and PI3K Signaling That Negatively Regulates Oncogenesis and Lipid Metabolism
Beth M. Palian equal contributor,Aarti D. Rohira equal contributor,Sandra A. S. Johnson equal contributor,Lina He,Ni Zheng,Louis Dubeau,Bangyan L. Stiles,Deborah L. Johnson
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004789
Abstract: Maf1 was initially identified as a transcriptional repressor of RNA pol III-transcribed genes, yet little is known about its other potential target genes or its biological function. Here, we show that Maf1 is a key downstream target of PTEN that drives both its tumor suppressor and metabolic functions. Maf1 expression is diminished with loss of PTEN in both mouse models and human cancers. Consistent with its role as a tumor suppressor, Maf1 reduces anchorage-independent growth and tumor formation in mice. PTEN-mediated changes in Maf1 expression are mediated by PTEN acting on PI3K/AKT/FoxO1 signaling, revealing a new pathway that regulates RNA pol III-dependent genes. This regulatory event is biologically relevant as diet-induced PI3K activation reduces Maf1 expression in mouse liver. We further identify lipogenic enzymes as a new class of Maf1-regulated genes whereby Maf1 occupancy at the FASN promoter opposes SREBP1c-mediated transcription activation. Consistent with these findings, Maf1 inhibits intracellular lipid accumulation and increasing Maf1 expression in mouse liver abrogates diet-mediated induction of lipogenic enzymes and triglycerides. Together, these results establish a new biological role for Maf1 as a downstream effector of PTEN/PI3K signaling and reveal that Maf1 is a key element by which this pathway co-regulates lipid metabolism and oncogenesis.
CPAF: A Chlamydial Protease in Search of an Authentic Substrate
Allan L. Chen equal contributor,Kirsten A. Johnson equal contributor,Jennifer K. Lee equal contributor,Christine Sütterlin ,Ming Tan
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002842
Abstract: Bacteria in the genus Chlamydia are major human pathogens that cause an intracellular infection. A chlamydial protease, CPAF, has been proposed as an important virulence factor that cleaves or degrades at least 16 host proteins, thereby altering multiple cellular processes. We examined 11 published CPAF substrates and found that there was no detectable proteolysis when CPAF activity was inhibited during cell processing. We show that the reported proteolysis of these putative CPAF substrates was due to enzymatic activity in cell lysates rather than in intact cells. Nevertheless, Chlamydia-infected cells displayed Chlamydia-host interactions, such as Golgi reorganization, apoptosis resistance, and host cytoskeletal remodeling, that have been attributed to CPAF-dependent proteolysis of host proteins. Our findings suggest that other mechanisms may be responsible for these Chlamydia-host interactions, and raise concerns about all published CPAF substrates and the proposed roles of CPAF in chlamydial pathogenesis.
Pervasive Sign Epistasis between Conjugative Plasmids and Drug-Resistance Chromosomal Mutations
Rui F. Silva equal contributor,Sílvia C. M. Mendon?a equal contributor,Luís M. Carvalho,Ana M. Reis,Isabel Gordo,Sandra Trindade,Francisco Dionisio
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002181
Abstract: Multidrug-resistant bacteria arise mostly by the accumulation of plasmids and chromosomal mutations. Typically, these resistant determinants are costly to the bacterial cell. Yet, recently, it has been found that, in Escherichia coli bacterial cells, a mutation conferring resistance to an antibiotic can be advantageous to the bacterial cell if another antibiotic-resistance mutation is already present, a phenomenon called sign epistasis. Here we study the interaction between antibiotic-resistance chromosomal mutations and conjugative (i.e., self-transmissible) plasmids and find many cases of sign epistasis (40%)—including one of reciprocal sign epistasis where the strain carrying both resistance determinants is fitter than the two strains carrying only one of the determinants. This implies that the acquisition of an additional resistance plasmid or of a resistance mutation often increases the fitness of a bacterial strain already resistant to antibiotics. We further show that there is an overall antagonistic interaction between mutations and plasmids (52%). These results further complicate expectations of resistance reversal by interdiction of antibiotic use.
Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry
Amidou N'Diaye equal contributor,Gary K. Chen equal contributor,Cameron D. Palmer equal contributor,Bing Ge,Bamidele Tayo,Rasika A. Mathias,Jingzhong Ding,Michael A. Nalls,Adebowale Adeyemo,Véronique Adoue,Christine B. Ambrosone,Larry Atwood,Elisa V. Bandera,Lewis C. Becker,Sonja I. Berndt,Leslie Bernstein,William J. Blot,Eric Boerwinkle,Angela Britton,Graham Casey,Stephen J. Chanock,Ellen Demerath,Sandra L. Deming,W. Ryan Diver,Caroline Fox,Tamara B. Harris,Dena G. Hernandez,Jennifer J. Hu,Sue A. Ingles,Esther M. John,Craig Johnson,Brendan Keating,Rick A. Kittles,Laurence N. Kolonel,Stephen B. Kritchevsky,Loic Le Marchand,Kurt Lohman,Jiankang Liu,Robert C. Millikan,Adam Murphy,Solomon Musani,Christine Neslund-Dudas,Kari E. North,Sarah Nyante,Adesola Ogunniyi,Elaine A. Ostrander,George Papanicolaou,Sanjay Patel,Curtis A. Pettaway,Michael F. Press,Susan Redline,Jorge L. Rodriguez-Gil,Charles Rotimi,Benjamin A. Rybicki,Babatunde Salako,Pamela J. Schreiner,Lisa B. Signorello,Andrew B. Singleton,Janet L. Stanford,Alex H. Stram,Daniel O. Stram,Sara S. Strom,Bhoom Suktitipat,Michael J. Thun,John S. Witte,Lisa R. Yanek,Regina G. Ziegler,Wei Zheng,Xiaofeng Zhu,Joseph M. Zmuda,Alan B. Zonderman,Michele K. Evans,Yongmei Liu,Diane M. Becker,Richard S. Cooper,Tomi Pastinen,Brian E. Henderson,Joel N. Hirschhorn ,Guillaume Lettre ,Christopher A. Haiman
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002298
Abstract: Adult height is a classic polygenic trait of high heritability (h2 ~0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ~10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10?12 and 2p14-rs4315565, P = 1.2×10?8). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10?4 for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits.
Recurrent Chromosome 16p13.1 Duplications Are a Risk Factor for Aortic Dissections
Shao-Qing Kuang equal contributor,Dong-Chuan Guo equal contributor,Siddharth K. Prakash equal contributor,Merry-Lynn N. McDonald,Ralph J. Johnson,Min Wang,Ellen S. Regalado,Ludivine Russell,Jiu-Mei Cao,Callie Kwartler,Kurt Fraivillig,Joseph S. Coselli,Hazim J. Safi,Anthony L. Estrera,Suzanne M. Leal,Scott A. LeMaire,John W. Belmont,Dianna M. Milewicz ,GenTAC Investigators
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002118
Abstract: Chromosomal deletions or reciprocal duplications of the 16p13.1 region have been implicated in a variety of neuropsychiatric disorders such as autism, schizophrenia, epilepsies, and attention-deficit hyperactivity disorder (ADHD). In this study, we investigated the association of recurrent genomic copy number variants (CNVs) with thoracic aortic aneurysms and dissections (TAAD). By using SNP arrays to screen and comparative genomic hybridization microarrays to validate, we identified 16p13.1 duplications in 8 out of 765 patients of European descent with adult-onset TAAD compared with 4 of 4,569 controls matched for ethnicity (P = 5.0×10?5, OR = 12.2). The findings were replicated in an independent cohort of 467 patients of European descent with TAAD (P = 0.005, OR = 14.7). Patients with 16p13.1 duplications were more likely to harbor a second rare CNV (P = 0.012) and to present with aortic dissections (P = 0.010) than patients without duplications. Duplications of 16p13.1 were identified in 2 of 130 patients with familial TAAD, but the duplications did not segregate with TAAD in the families. MYH11, a gene known to predispose to TAAD, lies in the duplicated region of 16p13.1, and increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. These data suggest chromosome 16p13.1 duplications confer a risk for TAAD in addition to the established risk for neuropsychiatric disorders. It also indicates that recurrent CNVs may predispose to disorders involving more than one organ system, an observation critical to the understanding of the role of recurrent CNVs in human disease and a finding that may be common to other recurrent CNVs involving multiple genes.
miR-182 and miR-10a Are Key Regulators of Treg Specialisation and Stability during Schistosome and Leishmania-associated Inflammation
Samir Kelada equal contributor,Praveen Sethupathy equal contributor,Isobel S. Okoye equal contributor,Eleni Kistasis,Stephanie Czieso,Sandra D. White,David Chou,Craig Martens,Stacy M. Ricklefs,Kimmo Virtaneva,Dan E. Sturdevant,Stephen F. Porcella,Yasmine Belkaid,Thomas A. Wynn,Mark S. Wilson
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003451
Abstract: A diverse suite of effector immune responses provide protection against various pathogens. However, the array of effector responses must be immunologically regulated to limit pathogen- and immune-associated damage. CD4+Foxp3+ regulatory T cells (Treg) calibrate immune responses; however, how Treg cells adapt to control different effector responses is unclear. To investigate the molecular mechanism of Treg diversity we used whole genome expression profiling and next generation small RNA sequencing of Treg cells isolated from type-1 or type-2 inflamed tissue following Leishmania major or Schistosoma mansoni infection, respectively. In-silico analyses identified two miRNA “regulatory hubs” miR-10a and miR-182 as critical miRNAs in Th1- or Th2-associated Treg cells, respectively. Functionally and mechanistically, in-vitro and in-vivo systems identified that an IL-12/IFNγ axis regulated miR-10a and its putative transcription factor, Creb. Importantly, reduced miR-10a in Th1-associated Treg cells was critical for Treg function and controlled a suite of genes preventing IFNγ production. In contrast, IL-4 regulated miR-182 and cMaf in Th2-associed Treg cells, which mitigated IL-2 secretion, in part through repression of IL2-promoting genes. Together, this study indicates that CD4+Foxp3+ cells can be shaped by local environmental factors, which orchestrate distinct miRNA pathways preserving Treg stability and suppressor function.
Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum
Daria Van Tyne equal contributor,Daniel J. Park equal contributor,Stephen F. Schaffner equal contributor,Daniel E. Neafsey equal contributor,Elaine Angelino equal contributor,Joseph F. Cortese,Kayla G. Barnes,David M. Rosen,Amanda K. Lukens,Rachel F. Daniels,Danny A. Milner Jr.,Charles A. Johnson,Ilya Shlyakhter,Sharon R. Grossman,Justin S. Becker,Daniel Yamins,Elinor K. Karlsson,Daouda Ndiaye,Ousmane Sarr,Souleymane Mboup,Christian Happi,Nicholas A. Furlotte,Eleazar Eskin,Hyun Min Kang,Daniel L. Hartl,Bruce W. Birren,Roger C. Wiegand,Eric S. Lander,Dyann F. Wirth ?,Sarah K. Volkman ?,Pardis C. Sabeti ?
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1001383
Abstract: The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (~1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.
A Simple Genetic Architecture Underlies Morphological Variation in Dogs
Adam R. Boyko equal contributor,Pascale Quignon equal contributor,Lin Li equal contributor,Jeffrey J. Schoenebeck,Jeremiah D. Degenhardt,Kirk E. Lohmueller,Keyan Zhao,Abra Brisbin,Heidi G. Parker,Bridgett M. vonHoldt,Michele Cargill,Adam Auton,Andy Reynolds,Abdel G. Elkahloun,Marta Castelhano,Dana S. Mosher,Nathan B. Sutter,Gary S. Johnson,John Novembre,Melissa J. Hubisz,Adam Siepel,Robert K. Wayne,Carlos D. Bustamante ? ,Elaine A. Ostrander ?
PLOS Biology , 2010, DOI: 10.1371/journal.pbio.1000451
Abstract: Domestic dogs exhibit tremendous phenotypic diversity, including a greater variation in body size than any other terrestrial mammal. Here, we generate a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African shelter dogs across 60,968 single-nucleotide polymorphisms (SNPs). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. The complex traits include average breed body size and external body dimensions and cranial, dental, and long bone shape and size with and without allometric scaling. In contrast to the results from association mapping of quantitative traits in humans and domesticated plants, we find that across dog breeds, a small number of quantitative trait loci (≤3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species.
Metabolic Reprogramming during Purine Stress in the Protozoan Pathogen Leishmania donovani
Jessica L. Martin equal contributor,Phillip A. Yates equal contributor,Radika Soysa,Joshua F. Alfaro,Feng Yang,Kristin E. Burnum-Johnson,Vladislav A. Petyuk,Karl K. Weitz,David G. Camp II,Richard D. Smith,Phillip A. Wilmarth,Larry L. David,Gowthaman Ramasamy,Peter J. Myler,Nicola S. Carter
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1003938
Abstract: The ability of Leishmania to survive in their insect or mammalian host is dependent upon an ability to sense and adapt to changes in the microenvironment. However, little is known about the molecular mechanisms underlying the parasite response to environmental changes, such as nutrient availability. To elucidate nutrient stress response pathways in Leishmania donovani, we have used purine starvation as the paradigm. The salvage of purines from the host milieu is obligatory for parasite replication; nevertheless, purine-starved parasites can persist in culture without supplementary purine for over three months, indicating that the response to purine starvation is robust and engenders parasite survival under conditions of extreme scarcity. To understand metabolic reprogramming during purine starvation we have employed global approaches. Whole proteome comparisons between purine-starved and purine-replete parasites over a 6–48 h span have revealed a temporal and coordinated response to purine starvation. Purine transporters and enzymes involved in acquisition at the cell surface are upregulated within a few hours of purine removal from the media, while other key purine salvage components are upregulated later in the time-course and more modestly. After 48 h, the proteome of purine-starved parasites is extensively remodeled and adaptations to purine stress appear tailored to deal with both purine deprivation and general stress. To probe the molecular mechanisms affecting proteome remodeling in response to purine starvation, comparative RNA-seq analyses, qRT-PCR, and luciferase reporter assays were performed on purine-starved versus purine-replete parasites. While the regulation of a minority of proteins tracked with changes at the mRNA level, for many regulated proteins it appears that proteome remodeling during purine stress occurs primarily via translational and/or post-translational mechanisms.
Human Neutrophil Clearance of Bacterial Pathogens Triggers Anti-Microbial γδ T Cell Responses in Early Infection
Martin S. Davey equal contributor,Chan-Yu Lin equal contributor,Gareth W. Roberts,Sinéad Heuston,Amanda C. Brown,James A. Chess,Mark A. Toleman,Cormac G. M. Gahan,Colin Hill,Tanya Parish,John D. Williams,Simon J. Davies,David W. Johnson,Nicholas Topley,Bernhard Moser,Matthias Eberl
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002040
Abstract: Human blood Vγ9/Vδ2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vγ9/Vδ2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vγ9/Vδ2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vγ9/Vδ2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-α dependent proliferation of Vγ9/Vδ2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting γδ T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vγ9/Vδ2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The γδ T cell-driven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of γδ T cells and TNF-α and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive γδ T cells in early infection and suggest novel diagnostic and therapeutic approaches.
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