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Article

Accounting for the Influence of Inflammation on Retinol Binding Protein in a Population Survey of Liberian Preschool-Aged Children

by Leila Margaret Larson; O. Addo; Fanny Sandalinas; Katherine Faigao; Roland Kupka; Rafael Flores-Ayala; Parminder Suchdev

2015

Subjects
  • Health Sciences, Nutrition
  • File Download
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Vitamin A deficiency (VAD) is an important contributor to child morbidity and mortality. The prevalence of VAD, measured by retinol-binding protein (RBP) or retinol, is overestimated in populations with a high prevalence of inflammation. We aimed to quantify and adjust for the effect of inflammation on VAD prevalence in a nationally representative survey of Liberian children 6 to 35months of age. We compared five approaches to adjust RBP for inflammation and estimate VAD prevalence (defined as RBP<0.7μmol/L): (1) ignoring inflammation; (2) excluding individuals with inflammation (C-reactive protein (CRP) >5mg/L or alpha1-acid glycoprotein (AGP) >1g/)L; (3) multiplying each individual's RBP by an internal correction factor; (4) by an external correction factor; and (5) using regression (corrected RBP=exp(InRBP - β1(lnCRPobs-lnCRPref) - β2(lnAGPobs-lnAGPref)). Corrected RBP was based on a regression model where reference lnCRP and lnAGP were set to the maximum of the lowest decile. The unadjusted prevalence of VAD was 24.7%. Children with elevated CRP and/or AGP had significantly lower RBP concentrations than their apparently healthy peers (geometric mean RBP 0.79μmol/L (95% CI: 0.76, 0.82) vs. 0.95μmol/L (95% CI: 0.92, 0.97), P<0.001). Using approaches 2-5 resulted in a prevalence of VAD of 11.6%, 14.3%, 13.5% and 7.3%, respectively. Depending on the approach, the VAD prevalence is reduced 10-17 percentage points when inflammation is taken into account. Further quantification of the influence of inflammation on biomarkers of vitamin A status from other national surveys is needed to compare and recommend the preferred adjustment approach across populations.

Article

Cryo-EM structure of TRPC5 at 2.8-angstrom resolution reveals unique and conserved structural elements essential for channel function

by Jingjing Duan; Jian Li; Gui-Lan Chen; Yan Ge; Jieyu Liu; Kechen Xie; Xiaogang Peng; Wei Zhou; Jianing Zhong; Yixing Zhang; Jie Xu; Changhu Xue; Bo Liang; Lan Zhu; Wei Liu; Cheng Zhang; Xiao-Li Tian; Jianbin Wang; David E. Clapham; Bo Zeng; Zongli Li; Jin Zhang

2019

Subjects
  • Biology, Molecular
  • Chemistry, Pharmaceutical
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The transient receptor potential canonical subfamily member 5 (TRPC5), one of seven mammalian TRPC members, is a nonselective calcium-permeant cation channel. TRPC5 is of considerable interest as a drug target in the treatment of progressive kidney disease, depression, and anxiety. Here, we present the 2.8-Å resolution cryo–electron microscopy (cryo-EM) structure of the mouse TRPC5 (mTRPC5) homotetramer. Comparison of the TRPC5 structure to previously determined structures of other TRPC and TRP channels reveals differences in the extracellular pore domain and in the length of the S3 helix. The disulfide bond at the extracellular side of the pore and a preceding small loop are essential elements for its proper function. This high-resolution structure of mTRPC5, combined with electrophysiology and mutagenesis, provides insight into the lipid modulation and gating mechanisms of the TRPC family of ion channels.

Article

Pseudomonas aeruginosa Induced Host Epithelial Cell Mitochondrial Dysfunction

by Nicholas Maurice; Brahmchetna Bedi; Zhihong Yuan; Joanna Goldberg; Michael Koval; C. Michael Hart; Ruxana Sadikot

2019

Subjects
  • Biology, Microbiology
  • Health Sciences, Medicine and Surgery
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The pathogenicity of P. aeruginosa is dependent on quorum sensing (QS), an inter-bacterial communication system that can also modulate host biology. The innate immune function of the lung mucosal barrier is dependent on proper mitochondrial function. The purpose of this study was to define the mechanism by which bacterial factors modulate host lung epithelial cell mitochondrial function and to investigate novel therapies that ameliorate this effect. 3-oxo-C12-HSL disrupts mitochondrial morphology, attenuates mitochondrial bioenergetics, and induces mitochondrial DNA oxidative injury. Mechanistically, we show that 3-oxo-C12-HSL attenuates expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, antioxidant defense, and cellular respiration, and its downstream effectors in both BEAS-2B and primary lung epithelial cells. Overexpression of PGC-1α attenuates the inhibition in cellular respiration caused by 3-oxo-C12-HSL. Pharmacologic activation of PGC-1α restores barrier integrity in cells treated with 3-oxo-C12-HSL. These data demonstrate that the P. aeruginosa QS molecule, 3-oxo-C12-HSL, alters mitochondrial pathways critical for lung mucosal immunity. Genetic and pharmacologic strategies that activate the PGC-1α pathway enhance host epithelial cell mitochondrial function and improve the epithelial innate response to P. aeruginosa. Therapies that rescue PGC-1α function may provide a complementary approach in the treatment of P. aeruginosa infection.

Conference

The evolution of infectious agents in relation to sex in animals and humans: brief discussions of some individual organisms

by David L. Reed; Russell W. Currier; Shelley F. Walton; Melissa Conrad; Steven A. Sullivan; Jane M. Carlton; Timothy Read; Alberto Severini; Shaun Tyler; R. Eberle; Welkin E. Johnson; Guido Silvestri; Ian N. Clarke; Teresa Lagergard; Sheila A. Lukehart; Magnus Unemo; William Shafer; R. Palmer Beasley; Tomas Bergstrom; Peter Norberg; Andrew J. Davison; Paul M. Sharp; Beatrice H. Hahn; Jonas Blomberg

2011-01-01

Subjects
  • Health Sciences, Public Health
  • Biology, Virology
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Abstract:Close

The following series of concise summaries addresses the evolution of infectious agents in relation to sex in animals and humans from the perspective of three specific questions: (1) what have we learned about the likely origin and phylogeny, up to the establishment of the infectious agent in the genital econiche, including the relative frequency of its sexual transmission; (2) what further research is needed to provide additional knowledge on some of these evolutionary aspects; and (3) what evolutionary considerations might aid in providing novel approaches to the more practical clinical and public health issues facing us currently and in the future?

Article

Role of CCL3L1-CCR5 Genotypes in the Epidemic Spread of HIV-1 and Evaluation of Vaccine Efficacy

by Hemant Kulkarni; Vincent Marconi; Brian K. Agan; Carole McArthur; George Crawford; Robert A. Clark; Matthew J. Dolan; Sunil K. Ahuja

2008

Subjects
  • Biology, Genetics
  • Health Sciences, Epidemiology
  • Biology, Virology
  • File Download
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Abstract:Close

Background: Polymorphisms in CCR5, the major coreceptor for HIV, and CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine, are determinants of HIV-AIDS susceptibility. Here, we mathematically modeled the potential impact of these genetic factors on the epidemic spread of HIV, as well as on its prevention. Methods and Results: Ro, the basic reproductive number, is a fundamental concept in explaining the emergence and persistence of epidemics. By modeling sexual transmission among HIV+/HIV- partner pairs, we find that Ro estimates, and concordantly, the temporal and spatial patterns of HIV outgrowth are highly dependent on the infecting partners' CCL3L1-CCR5 genotype. Ro was least and highest when the infected partner possessed protective and detrimental CCL3L1-CCR5 genotypes, respectively. The modeling data indicate that in populations such as Pygmies with a high CCL3L1 gene dose and protective CCR5 genotypes, the spread of HIV might be minimal. Additionally, Pc, the critical vaccination proportion, an estimate of the fraction of the population that must be vaccinated successfully to eradicate an epidemic was < 1 only when the infected partner had a protective CCL3L1-CCR5 genotype. Since in practice Pc cannot be > 1, to prevent epidemic spread, population groups defined by specific CCL3L1-CCR5 genotypes might require repeated vaccination, or as our models suggest, a vaccine with an efficacy of > 70%. Further, failure to account for CCL3L1-CCR5-based genetic risk might confound estimates of vaccine efficacy. For example, in a modeled trial of 500 subjects, misallocation of CCL3L1-CCR5 genotype of only 25 (5%) subjects between placebo and vaccine arms results in a relative error of ∼12% from the true vaccine efficacy. Conclusions: CCL3L1-CCR5 genotypes may impact on the dynamics of the HIV epidemic and, consequently, the observed heterogeneous global distribution of HIV infection. As Ro is lowest when the infecting partner has beneficial CCL3L1-CCR5 genotypes, we infer that therapeutic vaccines directed towards reducing the infectivity of the host may play a role in halting epidemic spread. Further, CCL3L1-CCR5 genotype may provide critical guidance for optimizing the design and evaluation of HIV-1 vaccine trials and prevention programs.

Article

Initial genome sequencing and analysis of multiple myeloma

by Michael A. Chapman; Michael S. Lawrence; Jonathan J. Keats; Kristian Cibulskis; Carrie Sougnez; Anna C. Schinzel; Christina L. Harview; Jean-Philippe Brunet; Gregory J. Ahmann; Mazhar Adli; Kenneth C. Anderson; Kristin G. Ardlie; Daniel Auclair; Angela Baker; P. Leif Bergsagel; Bradley E. Bernstein; Yotam Drier; Rafael Fonseca; Craig Hofmeister; Sagar Lonial

2011

Subjects
  • Health Sciences, Oncology
  • Biology, Genetics
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Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-Î °B signalling was indicated by mutations in 11 members of the NF-Î °B pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.

Article

Linked CSF reduction of phosphorylated tau and IL-8 in HIV associated neurocognitive disorder

by Tugba Ozturk; Alexander Kollhoff; Albert Anderson; J. Christina Howell; David Loring; Drenna Waldrop-Valverde; Donald Franklin; Scott Letendre; William Tyor; William Hu

2019

Subjects
  • Health Sciences, Public Health
  • Health Sciences, Immunology
  • Biology, Neuroscience
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Abstract:Close

HIV-associated neurocognitive disorder (HAND) is a common condition in both developed and developing nations, but its cause is largely unknown. Previous research has inconsistently linked Alzheimer’s disease (AD), viral burden, and inflammation to the onset of HAND in HIV-infected individuals. Here we simultaneously measured cerebrospinal fluid (CSF) levels of established amyloid and tau biomarkers for AD, viral copy numbers, and six key cytokines in 41 HIV-infected individuals off combination anti-retroviral therapy (14 with HAND) who underwent detailed clinical and neuropsychological characterization, and compared their CSF patterns with those from young healthy subjects, older healthy subjects with normal cognition, and older people with AD. HAND was associated with the lowest CSF levels of phosphorylated tau (p-Tau181) after accounting for age and race. We also found very high CSF levels of the pro-inflammatory interferon gamma-induced protein 10 (IP-10/CXCL10) in HIV regardless of cognition, but elevated CSF interleukin 8 (IL-8/CXCL8) only in HIV-NC but not HAND. Eleven HIV-infected subjects underwent repeat CSF collection six months later and showed strongly correlated longitudinal changes in p-Tau181 and IL-8 levels (R = 0.841). These data suggest reduced IL-8 relative to IP-10 and reduced p-Tau181 to characterize HAND.

Article

Depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy

by Grace Pavlath; Brenda Janice Sanchez; Anne-Marie K. Tremblay; Jean-Philippe Leduc-Gaudet; Derek T. Hall; Erzsebet Kovacs; Jennifer F. Ma; Souad Mubaid; Patricia L. Hallauer; Brittany L. Phillips; Katherine E. Vest; Anita Corbett; Dimitris L. Kontoyiannis; Sabah N. A. Hussain; Kenneth E. M. Hastings; Sergio Di Marco; Imed-Eddine Gallouzi

2019

Subjects
  • Biology, General
  • Chemistry, Biochemistry
  • File Download
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The master posttranscriptional regulator HuR promotes muscle fiber formation in cultured muscle cells. However, its impact on muscle physiology and function in vivo is still unclear. Here, we show that muscle-specific HuR knockout (muHuR-KO) mice have high exercise endurance that is associated with enhanced oxygen consumption and carbon dioxide production. muHuR-KO mice exhibit a significant increase in the proportion of oxidative type I fibers in several skeletal muscles. HuR mediates these effects by collaborating with the mRNA decay factor KSRP to destabilize the PGC-1α mRNA. The type I fiber-enriched phenotype of muHuR-KO mice protects against cancer cachexia-induced muscle loss. Therefore, our study uncovers that under normal conditions HuR modulates muscle fiber type specification by promoting the formation of glycolytic type II fibers. We also provide a proof-of-principle that HuR expression can be targeted therapeutically in skeletal muscles to combat cancer-induced muscle wasting.

Article

Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery

by Jonathan R. Honegger; Dana Tedesco; Jennifer A. Kohout; Mona R. Prasad; Aryn A. Price; Tera Lindquist; Samantha Ohmer; Melissa Moore-Clingenpeel; Arash Grakoui; Christopher M. Walker

2016

Subjects
  • Health Sciences, Immunology
  • Biology, Microbiology
  • Health Sciences, Obstetrics and Gynecology
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Chronic hepatitis C virus (HCV) infection is characterized by exhaustion of virus-specific T-cells and stable viremia. Pregnancy is an exception. Viremia gradually climbs during gestation but sometimes declines sharply in the months following delivery. Here, we demonstrated that postpartum HCV control was associated with enhanced virus-specific T-cell immunity. Women with viral load declines of at least 1 log10 between the third trimester and 3-mo postpartum exhibited HCV-specific T-cell responses of greater breadth (P = 0.0052) and magnitude (P = 0.026) at 3-mo postpartum than women who failed to control viremia. Moreover, viral dynamics were consistent in women after consecutive pregnancies, suggesting genetic underpinnings. We therefore searched for genetic associations with human leukocyte antigen (HLA) alleles and IFN-λ3 gene (IFNL3) polymorphisms that influence HCV infection outcome. Postpartum viral control was associated with the IFNL3 rs12979860 genotype CC (P = 0.045 at 6 mo) that predicts a positive response to IFN-based therapy. Suppression of virus replication after pregnancy was also strongly influenced by the HLA class II DPB1 locus. HLA-DPB1 alleles are classified by high and low patterns of expression. Carriage of at least one high-expression HLA-DPB1 allele predicted resurgent virus-specific T-cell immunity and viral control at 3-mo postpartum (P = 0.0002). When considered together in multivariable analysis, IFNL3 and HLA-DPB1 independently affected viral control at 3- and 6-mo postpartum. Together, these findings support a model where spontaneous control of HCV such as sometimes follows pregnancy is governed by genetic polymorphisms that affect type III IFN signaling and virus-specific cellular immune responses.

Article

Immunoengineering nerve repair

by Nassir Mokarram; Kyle Dymanus; Akhil Srinivasan; Johnathan G. Lyon; John Tipton; Jason Chu; Arthur English; Ravi Bellamkonda

2017

Subjects
  • Health Sciences, Immunology
  • Biology, Neuroscience
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Injuries to the peripheral nervous system are major sources of disability and often result in painful neuropathies or the impairment of muscle movement and/or normal sensations. For gaps smaller than 10 mm in rodents, nearly normal functional recovery can be achieved; for longer gaps, however, there are challenges that have remained insurmountable. The current clinical gold standard used to bridge long, nonhealing nerve gaps, the autologous nerve graft (autograft), has several drawbacks. Despite best efforts, engineering an alternative "nerve bridge" for peripheral nerve repair remains elusive; hence, there is a compelling need to design new approaches that match or exceed the performance of autografts across critically sized nerve gaps. Here an immunomodulatory approach to stimulating nerve repair in a nerve-guidance scaffold was used to explore the regenerative effect of reparative monocyte recruitment. Early modulation of the immune environment at the injury site via fractalkine delivery resulted in a dramatic increase in regeneration as evident from histological and electrophysiological analyses. This study suggests that biasing the infiltrating inflammatory/immune cellular milieu after injury toward a proregenerative population creates a permissive environment for repair. This approach is a shift from the current modes of clinical and laboratory methods for nerve repair, which potentially opens an alternative paradigm to stimulate endogenous peripheral nerve repair.
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