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Found 36144 matches. Displaying 41-50
Tan XC, Banerjee P, Shi L, Xiao GY, Rodriguez BL, Grzeskowiak CL, Liu X, Yu J, Gibbons DL, Russell WK, Creighton CJ, Kurie JM
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p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi

SCIENCE ADVANCES 2021 JUN; 7(25):? Article eabf4885
Cancer cells exhibit hyperactive secretory states that maintain cancer cell viability and remodel the tumor microenvironment. However, the oncogenic signals that heighten secretion remain unclear. Here, we show that p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi. p53 loss up-regulates the expression of a Golgi scaffolding protein, progestin and adipoQ receptor 11 (PAQR11), which recruits an adenosine diphosphate ribosylation factor 1-containing protein complex that loads cargos into secretory vesicles. PAQR11-dependent secretion of a protease, PLAU, prevents anoikis and initiates autocrine activation of a PLAU receptor/signal transducer and activator of transcription-3-dependent pathway that up-regulates PAQR11 expression, thereby completing a feedforward loop that amplifies prometastatic effector protein secretion. Pharmacologic inhibition of PLAU receptor impairs the growth and metastasis of p53-deficient cancers. Blockade of PAQR11-dependent secretion inhibits immunosuppressive processes in the tumor microenvironment. Thus, Golgi reprogramming by p53 loss is a key driver of hypersecretion in cancer.
Narla S, Azzam M, Townsend S, Vellaichamy G, Marzano AV, Alavi A, Lowes MA, Hamzavi IH
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Identifying key components and therapeutic targets of the immune system in hidradenitis suppurativa with an emphasis on neutrophils

Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent and debilitating skin disease of the hair follicle unit that typically develops after puberty. The disorder is characterized by comedones, painful inflammatory nodules, abscesses, dermal tunnels and scarring, with a predilection for intertriginous areas of the body (axillae, inguinal and anogenital regions). Recruitment of neutrophils to HS lesion sites may play an essential role in the development of the painful inflammatory nodules and abscesses that characterize the disease. This is a review of the major mediators involved in the recruitment of neutrophils to sites of active inflammation, including bacterial components (endotoxins, exotoxins, capsule fragments, etc.), the complement pathway anaphylatoxins C3a and C5a, tumour necrosis factor-alpha, interleukin (IL)-17, IL-8 (CXCL8), IL-36, IL-1, lipocalin-2, leukotriene B4, platelet-activating factor, kallikreins, matrix metalloproteinases, and myeloperoxidase inhibitors. Pharmacological manipulation of the various pathways involved in the process of neutrophil recruitment and activation could allow for successful control and stabilization of HS lesions and the remission of active, severe flares.
Clark AT, Brivanlou A, Fu JP, Kato K, Mathews D, Niakan KK, Rivron N, Saitou M, Surani A, Tang FC, Rossant J
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Human embryo research, stem cell-derived embryo models and in vitro gametogenesis: Considerations leading to the revised ISSCR guidelines

STEM CELL REPORTS 2021 JUN 8; 16(6):1416-1424
The ISSCR Guidelines for Stem Cell Research and Clinical Translation were last revised in 2016. Since then, rapid progress has been made in research areas related to in vitro culture of human embryos, creation of stem cell-based embryo models, and in vitro gametogenesis. Therefore, a working group of international experts was convened to review the oversight process and provide an update to the guidelines. This report captures the discussion and summarizes the major recommendations made by this working group, with a specific emphasis on updating the categories of review and engagement with the specialized scientific and ethical oversight process.
Pedersen MW, De Sanctis B, Saremi NF, Sikora M, Puckett EE, Gu ZQ, Moon KL, Kapp JD, Vinner L, Vardanyan Z, Ardelean CF, Arroyo-Cabrales J, Cahill JA, Heintzman PD, Zazula G, MacPhee RDE, Shapiro B, Durbin R, Willerslev E
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Environmental genomics of Late Pleistocene black bears and giant short-faced bears

CURRENT BIOLOGY 2021 JUN 21; 31(12):2728-2736.e8
Analysis of ancient environmental DNA(eDNA) has revolutionized our ability to describe biological communities in space and time,(1-3) by allowing for parallel sequencing of DNA from all trophic levels.(4-8) However, because environmental samples contain sparse and fragmented data from multiple individuals, and often contain closely related species,(9) the field of ancient eDNA has so far been limited to organellar genomes in its contribution to population and phylogenetic studies.(5,6,10,11) This is in contrast to data from fossils(12,13) where full-genome studies are routine, despite these being rare and their destruction for sequencing undesirable.(14-16) Here, we report the retrieval of three low-coverage (0.033) environmental genomes from American black bear (Ursus americanus) and a 0.043 environmental genome of the extinct giant short-faced bear (Arctodus simus) from cave sediment samples from northern Mexico dated to 16-14 thousand calibrated years before present (cal kyr BP), which we contextualize with a new high-coverage (263) and two lower-coverage giant short-faced bear genomes obtained from fossils recovered from Yukon Territory, Canada, which date to similar to 22-50 cal kyr BP. We show that the Late Pleistocene black bear population in Mexico is ancestrally related to the present-day Eastern American black bear population, and that the extinct giant short-faced bears present in Mexico were deeply divergent from the earlier Beringian population. Our findings demonstrate the ability to separately analyze genomic-scale DNA sequences of closely related species co-preserved in environmental samples, which brings the use of ancient eDNA into the era of population genomics and phylogenetics.
Chandra V, Gal A, Kronauer DJC
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Colony expansions underlie the evolution of army ant mass raiding

The mass raids of army ants are an iconic collective phenomenon, in which many thousands of ants spontaneously leave their nest to hunt for food, mostly other arthropods. While the structure and ecology of these raids have been relatively well studied, how army ants evolved such complex cooperative behavior is not understood. Here, we show that army ant mass raiding has evolved from a different form of cooperative hunting called group raiding, in which a scout directs a small group of ants to a specific target through chemical communication. We describe the structure of group raids in the clonal raider ant, a close relative of army ants in the subfamily Dorylinae. We find evidence that the coarse structure of group raids and mass raids is highly conserved and that all doryline ants likely follow similar behavioral rules for raiding. We also find that the evolution of army ant mass raiding occurred concurrently with expansions in colony size. By experimentally increasing colony size in the clonal raider ant, we show that mass raiding gradually emerges from group raiding without altering individual behavioral rules. This suggests that increasing colony size can explain the evolution of army ant mass raids and supports the idea that complex social behaviors may evolve via mechanisms that need not alter the behavioral interaction rules that immediately underlie the collective behavior of interest.
Lawal OU, Barata M, Fraqueza MJ, Worning P, Bartels MD, Goncalves L, Paixao P, Goncalves E, Toscano C, Empel J, Urbas M, Domiinguez MA, Westh H, de Lencastre H, Miragaia M
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Staphylococcus saprophyticus From Clinical and Environmental Origins Have Distinct Biofilm Composition

FRONTIERS IN MICROBIOLOGY 2021 JUN 7; 12(?):? Article 663768
Biofilm formation has been shown to be critical to the success of uropathogens. Although Staphylococcus saprophyticus is a common cause of urinary tract infections, its biofilm production capacity, composition, genetic basis, and origin are poorly understood. We investigated biofilm formation in a large and diverse collection of S. saprophyticus (n = 422). Biofilm matrix composition was assessed in representative strains (n = 63) belonging to two main S. saprophyticus lineages (G and S) recovered from human infection, colonization, and food-related environment using biofilm detachment approach. To identify factors that could be associated with biofilm formation and structure variation, we used a pangenome-wide association study approach. Almost all the isolates (91%; n = 384/422) produced biofilm. Among the 63 representative strains, we identified eight biofilm matrix phenotypes, but the most common were composed of protein or protein-extracellular DNA (eDNA)-polysaccharides (38%, 24/63 each). Biofilms containing protein-eDNA-polysaccharides were linked to lineage G and environmental isolates, whereas protein-based biofilms were produced by lineage S and infection isolates (p < 0.05). Putative biofilm-associated genes, namely, aas, atl, ebpS, uafA, sasF, sasD, sdrH, splE, sdrE, sdrC, sraP, and ica genes, were found with different frequencies (3-100%), but there was no correlation between their presence and biofilm production or matrix types. Notably, icaC_1 was ubiquitous in the collection, while icaR was lineage G-associated, and only four strains carried a complete ica gene cluster (icaADBCR) except one that was without icaR. We provided evidence, using a comparative genomic approach, that the complete icaADBCR cluster was acquired multiple times by S. saprophyticus and originated from other coagulase-negative staphylococci. Overall, the composition of S. saprophyticus biofilms was distinct in environmental and clinical isolates, suggesting that modulation of biofilm structure could be a key step in the pathogenicity of these bacteria. Moreover, biofilm production in S. saprophyticus is ica-independent, and the complete icaADBCR was acquired from other staphylococci.
Koning R, Bastard P, Casanova JL, Brouwer MC, van de Beek D
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Autoantibodies against type I interferons are associated with multi-organ failure in COVID-19 patients

Gilligan CJ, Cohen SP, Fischetti VA, Hirsch JA, Czaplewski LG
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Chronic low back pain, bacterial infection and treatment with antibiotics

SPINE JOURNAL 2021 JUN; 21(6):903-914
The contribution of bacterial infection to chronic low back pain and its treatment with antibiotics have generated considerable controversy in literature. If efficacious, antibiotics have the potential to transform the treatment of chronic low back pain in a significant subset of patients. Some microbiology studies of disc tissue from patients with CLBP have shown that bacteria are present, most likely due to infection, while others conclude they are absent or if found, it is due to surgical contamination. Clinical studies testing the efficacy of oral antibiotics to treat CLBP have either shown that the treatment is efficacious leading to significantly reduced pain and disability or that their effect is modest and not clinically significant. Critical review of the literature on CLBP, bacterial infection and treatment with antibiotics identified five well-designed and executed microbiology studies characterizing bacteria in disc samples that demonstrate that bacteria do infect herniated disc tissue, but that the bacterial burden is low and may be below the limits of detection in some studies. Two randomized, controlled clinical trials evaluating oral antibiotics in patients with CLBP indicate that for certain subsets of patients, the reduction in pain and disability achieved with antibiotic therapy may be significant. In patients for whom other therapies have failed, and who might otherwise progress to disc replacement or fusion surgery, antibiotic therapy may well be an attractive option to reduce the individual suffering associated with this debilitating condition. Additional clinical research is recommended to refine the selection of patients with CLBP caused or complicated by bacterial infection and most likely to respond to antibiotics, to optimize antibiotic therapy to maximize patient benefit, to minimize and manage side effects, and to address legitimate concerns about antibiotic stewardship. (C) 2021 The Author(s). Published by Elsevier Inc.
Durkin SM, Chakraborty M, Abrieux A, Lewald KM, Gadau A, Svetec N, Peng JH, Kopyto M, Langer CB, Chiu JC, Emerson JJ, Zhao L
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Behavioral and Genomic Sensory Adaptations Underlying the Pest Activity of Drosophila suzukii

Studying how novel phenotypes originate and evolve is fundamental to the field of evolutionary biology as it allows us to understand how organismal diversity is generated and maintained. However, determining the basis of novel phenotypes is challenging as it involves orchestrated changes at multiple biological levels. Here, we aim to overcome this challenge by using a comparative species framework combining behavioral, gene expression, and genomic analyses to understand the evolutionary novel egg-laying substrate-choice behavior of the invasive pest species Drosophila suzukii. First, we used egg-laying behavioral assays to understand the evolution of ripe fruit oviposition preference in D. suzukii compared with closely related species D. subpulchrella and D. biarmipes as well as D. melanogaster. We show that D. subpulchrella and D. biarmipes lay eggs on both ripe and rotten fruits, suggesting that the transition to ripe fruit preference was gradual. Second, using two-choice oviposition assays, we studied how D. suzukii, D. subpulchrella, D. biarmipes, and D. melanogaster differentially process key sensory cues distinguishing ripe from rotten fruit during egg-laying. We found that D. suzukii's preference for ripe fruit is in part mediated through a species-specific preference for stiff substrates. Last, we sequenced and annotated a high-quality genome for D. subpulchrella. Using comparative genomic approaches, we identified candidate genes involved in D. suzukii's ability to seek out and target ripe fruits. Our results provide detail to the stepwise evolution of pest activity in D. suzukii, indicating important cues used by this species when finding a host, and the molecular mechanisms potentially underlying their adaptation to a new ecological niche.
Hogg SJ, Motorna O, Cluse LA, Johanson TM, Coughlan HD, Raviram R, Myers RM, Costacurta M, Todorovski I, Pijpers L, Bjelosevic S, Williams T, Huskins SN, Kearney CJ, Devlin JR, Fan Z, Jabbari JS, Martin BP, Fareh M, Kelly MJ, Dupere-Richer D, Sandow JJ, Feran B, Knight D, Khong T, Spencer A, Harrison SJ, Gregory G, Wickramasinghe VO, Webb AI, Taberlay PC, Bromberg KD, Lai A, Papenfuss AT, Smyth GK, Allan RS, Licht JD, Landau DA, Abdel-Wahab O, Shortt J, Vervoort SJ, Johnstone RW
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Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition

MOLECULAR CELL 2021 MAY 20; 81(10):2183-2200.e13
To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP in hematological malignancies. We found that catalytic P300/CBP inhibition dynamically perturbs steady-state acetylation kinetics and suppresses oncogenic transcriptional networks in the absence of changes to chromatin accessibility. CRISPR-Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principal antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300/CBP inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anticancer regimen.