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Found 34428 matches. Displaying 61-70
Guttman-Yassky E, Bissonnette R, Ungar B, Suarez-Farinas M, Ardeleanu M, Esaki H, Suprun M, Estrada Y, Xu H, Peng XY, Silverberg JI, Menter A, Krueger JG, Zhang R, Chaudhry U, Swanson B, Graham NMH, Pirozzi G, Yancopoulos GD, Hamilton JDD
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Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

Background: Dupilumab is an IL-4 receptor a mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2-driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1: 1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4-16). Mean improvements in a meta-analysis-derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and -10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P <.001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and T(H)17/T(H)22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P =.001; week 16, P =.0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergenspecific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor a blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.
Hatzi K, Geng HM, Doane AS, Meydan C, LaRiviere R, Cardenas M, Duy C, Shen H, Vidal MNC, Baslan T, Mohammad HP, Kruger RG, Shaknovich R, Haberman AM, Inghirami G, Lowe SW, Melnick AM
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Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis

NATURE IMMUNOLOGY 2019 JAN; 20(1):86-96
Germinal center (GC) B cells feature repression of many gene enhancers to establish their characteristic transcriptome. Here we show that conditional deletion of Lsd1 in GCs significantly impaired GC formation, associated with failure to repress immune synapse genes linked to GC exit, which are also direct targets of the transcriptional repressor BCL6. We found that BCL6 directly binds LSD1 and recruits it primarily to intergenic and intronic enhancers. Conditional deletion of Lsd1 suppressed GC hyperplasia caused by constitutive expression of BCL6 and significantly delayed BCL6-driven lymphomagenesis. Administration of catalytic inhibitors of LSD1 had little effect on GC formation or GC-derived lymphoma cells. Using a CRISPR-Cas9 domain screen, we found instead that the LSD1 Tower domain was critical for dependence on LSD1 in GC-derived B cells. These results indicate an essential role for LSD1 in the humoral immune response, where it modulates enhancer function by forming repression complexes with BCL6.
Csanady L, Vergani P, Gadsby DC
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The cystic fibrosis transmembrane conductance regulator (CFTR) belongs to the ATP binding cassette (ABC) transporter superfamily but functions as an anion channel crucial for salt and water transport across epithelial cells. CFTR dysfunction, because of mutations, causes cystic fibrosis (CF). The anion-selective pore of the CFTR protein is formed by its two transmembrane domains (TMDs) and regulated by its cytosolic domains: two nucleotide binding domains (NBDs) and a regulatory (R) domain. Channel activation requires phosphorylation of the R domain by cAMP-dependent protein kinase (PKA), and pore opening and closing (gating) of phosphorylated channels is driven by ATP binding and hydrolysis at the NBDs. This review summarizes available information on structure and mechanism of the CFTR protein, with a particular focus on atomic-level insight gained from recent cryo-electron microscopic structures and on the molecular mechanisms of channel gating and its regulation. The pharmacological mechanisms of small molecules targeting CFTR's ion channel function, aimed at treating patients suffering from CF and other diseases, are briefly discussed.
Martinez-Barricarte R, Markle JG, Ma CS, Deenick EK, Ramirez-Alejo N, Mele F, Latorre D, Mandaviani SA, Aytekin C, Mansouri D, Bryant VL, Jabot-Hanin F, Deswarte C, Nieto-Patlan A, Surace L, Kerner G, Itan Y, Jovic S, Avery DT, Wong N, Rao G, Patin E, Okada S, Bigio B, Boisson B, Rapaport F, Seeleuthner Y, Schmidt M, Ikinciogullari A, Dogu F, Tanir G, Tabarsi P, Bloursaz MR, Josephs JK, Heer A, Kong XF, Migaud M, Lazarov T, Geissmann F, Fleckenstein B, Arlehamn CL, Sette A, Puel A, Emile JF, van de Vosse E, Quintana-Murci L, Di Santo JP, Abel L, Boisson-Dupuis S, Bustamante J, Tangye SG, Sallusto F, Casanova JL
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Human IFN-gamma immunity to mycobacteria is governed by both IL-12 and IL-23

SCIENCE IMMUNOLOGY 2018 DEC; 3(30):? Article eaau6759
Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12R beta 1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-gamma immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12R beta 2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that alpha beta T, gamma delta T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-gamma in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-gamma in response to IL-23. We also show that the development of IFN-gamma-producing CD4(+) T cells, including, in particular, mycobacterium-specific T(H)1* cells (CD45RA(-)CCR6(+)), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12R beta 2 or IL-23R deficiency, relative to IL-12R beta 1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12R beta 2-deficient than IL-12R beta 1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-gamma, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-gamma-dependent immunity to mycobacteria, both individually and much more so cooperatively.
Nirody JA, Jinn J, Libby T, Lee TJ, Jusufi A, Hu DL, Full RJ
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Geckos Race Across the Water's Surface Using Multiple Mechanisms

CURRENT BIOLOGY 2018 DEC 17; 28(24):4046-4051.e2
Acrobatic geckos can sprint at high speeds over challenging terrain [1], scamper up the smoothest surfaces [2], rapidly swing underneath leaves [3], and right themselves in midair by swinging only their tails [4, 5]. From our field observations, we can add racing on the water's surface to the gecko's list of agile feats. Locomotion at the air-water interface evolved in over a thousand species, including insects, fish, reptiles, and mammals [6]. To support their weight, some larger-legged vertebrates use forces generated by vigorous slapping of the fluid's surface followed by a stroke of their appendage [7-12], whereas smaller animals, like arthropods, rely on surface tension to walk on water [6, 13]. Intermediate-sized geckos (Hemidactylus platyurus) fall squarely between these two regimes. Here, we report the unique ability of geckos to exceed the speed limits of conventional surface swimming. Several mechanisms likely contribute in this intermediate regime. In contrast to bipedal basilisk lizards [7-10], geckos used a stereotypic trotting gait with all four limbs, creating air cavities during slapping to raise their head and anterior trunk above water. Adding surfactant to the water decreased velocity by half, confirming surface tension's role. The superhydrophobic skin could reduce drag during semi-planing. Geckos laterally undulated their bodies, including their submerged posterior trunk and tail, generating thrust for forward propulsion, much like water dragons [14] and alligators [15]. Geckos again remind us of the advantages of multi-functional morphologies providing the opportunity for multiple mechanisms for motion.
Sajkmar TP, Huber T
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Ancient Family of Retinal Proteins Brought to Light "Sight-Unseen"

BIOCHEMISTRY 2018 DEC 11; 57(49):6735-6737
Boisson-Dupuis S, Ramirez-Alejo N, Li Z, Patin E, Rao G, Kerner G, Lim CK, Krementsov DN, Hernandez N, Ma CS, Zhang Q, Markle J, Martinez-Barricarte R, Payne K, Fisch R, Deswarte C, Halpern J, Bouaziz M, Mulwa J, Sivanesan D, Lazarov T, Naves R, Garcia P, Itan Y, Boisson B, Checchi A, Jabot-Hanin F, Cobat A, Guennoun A, Jackson CC, Pekcan S, Caliskaner Z, Inostroza J, Costa-Carvalho BT, de Albuquerque JAT, Garcia-Ortiz H, Orozco L, Ozcelik T, Abid A, Rhorfi IA, Souhi H, Amrani HN, Zegmout A, Geissmann F, Michnick SW, Muller-Fleckenstein I, Fleckenstein B, Puel A, Ciancanelli MJ, Marr N, Abolhassani H, Balcells ME, Condino-Neto A, Strickler A, Abarca K, Teuscher C, Ochs HD, Reisli I, Sayar EH, El-Baghdadi J, Bustamante J, Hammarstrom L, Tangye SG, Pellegrini S, Quintana-Murci L, Abel L, Casanova JL
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Tuberculosis and impaired IL-23-dependent IFN-gamma immunity in humans homozygous for a common TYK2 missense variant

SCIENCE IMMUNOLOGY 2018 DEC; 3(30):? Article eaau8714
Inherited IL-12R beta 1 and TYK2 deficiencies impair both IL-12- and IL-23 -dependent IFN-gamma immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (P = 8.37 x 10(-8); odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-alpha, IL-10, or even IL-12, which, like IL-23, induces IFN-gamma via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of TYK2 selectively disrupts the induction of IFN-gamma by IL-23 and is a common monogenic etiology of tuberculosis.
Touhara KK, MacKinnon R
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Molecular basis of signaling specificity between GIRK channels and GPCRs

ELIFE 2018 DEC 10; 7(?):? Article e42908
Stimulated muscarinic acetylcholine receptors (M2Rs) release G beta gamma subunits, which slow heart rate by activating a G protein-gated K+ channel (GIRK). Stimulated beta 2 adrenergic receptors (beta 2ARs) also release G beta gamma subunits, but GIRK is not activated. This study addresses the mechanism underlying this specificity of GIRK activation by M2Rs. K+ currents and bioluminescence resonance energy transfer between labelled G proteins and GIRK show that M2Rs catalyze G beta gamma subunit release at higher rates than beta 2ARs, generating higher G beta gamma concentrations that activate GIRK and regulate other targets of G beta gamma. The higher rate of G beta gamma release is attributable to a faster G protein coupled receptor - G protein trimer association rate in M2R compared to beta 2AR. Thus, a rate difference in a single kinetic step accounts for specificity.
Xue BK, Leibler S
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Benefits of phenotypic plasticity for population growth in varying environments

Phenotypic plasticity refers to the capacity of the same organisms to exhibit different characteristics under varied environmental conditions. A plastic developmental program allows organisms to sense environmental cues in early stages of life and express phenotypes that are better fitted to environments encountered later in life. This is often considered an adaptive strategy for living in varying environments as long as the plastic response is sufficiently fast, is accurate, and is not too costly. However, despite direct costs of maintaining plasticity and producing phenotypes, a fundamental constraint on the benefit of phenotypic plasticity comes from the predictability of the future environment based on the environmental cues received during development. Here, we analyze a model of plastic development and derive the limits within which this strategy can promote population growth. An explicit expression for the long-term growth rate of a developmentally plastic population is found, which can be decomposed into several easily interpretable terms, representing the benefits and the limitations of phenotypic plasticity as an adaptation strategy. This growth rate decomposition has a remarkably similar form to the expressions previously obtained for the bet-hedging strategy, in which a population randomly diversifies into coexisting subgroups with different phenotypes, implying that those evolutionary strategies may be unified under a common general framework.
Black EM, Giunta S
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Repetitive Fragile Sites: Centromere Satellite DNA as a Source of Genome Instability in Human Diseases

GENES 2018 DEC; 9(12):? Article 615
Maintenance of an intact genome is essential for cellular and organismal homeostasis. The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division. Human centromeres are composed of large tandem arrays of repetitive alpha-satellite DNA, which are often sites of aberrant rearrangements that may lead to chromosome fusions and genetic abnormalities. While the centromere has an essential role in chromosome segregation during mitosis, the long and repetitive nature of the highly identical repeats has greatly hindered in-depth genetic studies, and complete annotation of all human centromeres is still lacking. Here, we review our current understanding of human centromere genetics and epigenetics as well as recent investigations into the role of centromere DNA in disease, with a special focus on cancer, aging, and human immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. We also highlight the causes and consequences of genomic instability at these large repetitive arrays and describe the possible sources of centromere fragility. The novel connection between alpha-satellite DNA instability and human pathological conditions emphasizes the importance of obtaining a truly complete human genome assembly and accelerating our understanding of centromere repeats' role in physiology and beyond.