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Found 34783 matches. Displaying 191-200
Kume K, Cantwell H, Burrell A, Nurse P
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Nuclear membrane protein Lem2 regulates nuclear size through membrane flow

NATURE COMMUNICATIONS 2019 APR 23; 10(?):? Article 1871
The size of the membrane-bound nucleus scales with cell size in a wide range of cell types but the mechanisms determining overall nuclear size remain largely unknown. Here we investigate the role of fission yeast inner nuclear membrane proteins in determining nuclear size, and propose that the Lap2-Emerin-Manl domain protein Lem2 acts as a barrier to membrane flow between the nucleus and other parts of the cellular membrane system. Lem2 deletion increases membrane flow into and out of the nuclear envelope in response to changes in membrane synthesis and nucleocytoplasmic transport, altering nuclear size. The endoplasmic reticulum protein Lnp1 acts as a secondary barrier to membrane flow, functionally compensating for lack of Lem2. We propose that this is part of the mechanism that maintains nuclear size proportional to cellular membrane content and thus to cell size. Similar regulatory principles may apply to other organelles in the eukaryotic subcellular membrane network.
Indiani C, Sauve K, Raz A, Abdelhady W, Xiong YQ, Cassino C, Elayer AS, Schuch R
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The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-Resistant Staphylococcus aureus Bacteriolysis

Bacteriophage-derived lysins are cell-wall-hydrolytic enzymes that represent a potential new class of antibacterial therapeutics in development to address burgeoning antimicrobial resistance. CF-301, the lead compound in this class, is in clinical development as an adjunctive treatment to potentially improve clinical cure rates of Staphylococcus aureus bacteremia and infective endocarditis (IE) when used in addition to antibiotics. In order to profile the activity of CF-301 in a clinically relevant milieu, we assessed its in vitro activity in human blood versus in a conventional testing medium (cation-adjusted Mueller-Hinton broth [caMHB]). CF-301 exhibited substantially greater potency (32 to >= 100-fold) in human blood versus caMHB in three standard microbiologic testing formats (e.g., broth dilution MICs, checkerboard synergy, and time-kill assays). We demonstrated that CF-301 acted synergistically with two key human blood factors, human serum lysozyme (HuLYZ) and human serum albumin (HSA), which normally have no nascent antistaphylococcal activity, against a prototypic methicillin-resistant S. aureus (MRSA) strain (MW2). Similar in vitro enhancement of CF-301 activity was also observed in rabbit, horse, and dog (but not rat or mouse) blood. Two well-established MRSA IE models in rabbit and rat were used to validate these findings in vivo by demonstrating comparable synergistic efficacy with standard-of-care anti-MRSA antibiotics at >= 100-fold lower lysin doses in the rabbit than in the rat model. The unique properties of CF-301 that enable bactericidal potentiation of antimicrobial activity via activation of "latent" host factors in human blood may have important therapeutic implications for durable improvements in clinical outcomes of serious antibiotic-resistant staphylococcal infections.
Alsahafi N, Bakouche N, Kazemi M, Richard J, Ding SL, Bhattacharyya S, Das D, Anand SP, Prevost J, Tolbert WD, Lu H, Medjahed H, Gendron-Lepage G, Delgado GGO, Kirk S, Melillo B, Mothes W, Sodroski J, Smith AB, Kaufmann DE, Wu XL, Pazgier M, Rouiller I, Finzi A, Munro JB
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An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity

CELL HOST & MICROBE 2019 APR 10; 25(4):578-587.e5
The HIV-1 envelope glycoprotein (Env) (gp120-gp41)(3) is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant. CD4 binding induces an intermediate state (State 2), followed by an open conformation (State 3) that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes. We investigate conformational changes in Env that induce ADCC in the presence of a smallmolecule CD4-mimetic compound (CD4mc). We uncover an asymmetric Env conformation (State 2A) recognized by antibodies targeting the conserved gp120 inner domain and mediating ADCC. Sera from HIV+ individuals contain these antibodies, which can stabilize Env State 2A in combination with CD4mc. Additionally, triggering State 2A on HIV-infected primary CD4(+) T cells exposes epitopes that induce ADCC. Strategies that induce this Env conformation may represent approaches to fight HIV-1 infection.
Li R, Hadi S, Guttman-Yassky E
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Current and emerging biologic and small molecule therapies for atopic dermatitis

Introduction: Atopic dermatitis (AD) is the most common inflammatory skin disease, yet until recently there were no safe systemic therapies approved for the long-term management of AD in adult patients. A deeper understanding of disease pathogenesis and identification of molecular and cellular changes has resulted in a rapidly evolving pipeline of therapeutics that holds promise for safer long-term control. Areas covered: In this review, we highlight the growing arsenal of biologic and small molecule antagonists that target pathways implicated in AD pathogenesis. Evidence that AD is driven by multiple immune axes extending beyond the Th2 polarization has resulted in therapies targeting additional pathways, including the Th22, Th17/IL-23, and JAK-STAT pathways. Pruritus, a hallmark of AD, has been linked to multiple mechanisms and various therapeutics have emerged in response to alternative hypotheses. Expert opinion: Despite the assumption that AD has a common disease mechanism, recent studies indicate that the disorder is characterized by several phenotypes and therapy may need to be tailored to the unique immune traits of specific phenotypes. Targeted therapy should complement and expand our molecular map of AD across the various phenotypic iterations and help push AD pharmacotherapy into a new era of personalized medicine.
Shimada M, Chen WY, Nakadai T, Onikubo T, Guermah M, Rhodes D, Roeder RG
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Gene-Specific H1 Eviction through a Transcriptional Activator -> p300 -> NAP1 -> H1 Pathway

MOLECULAR CELL 2019 APR 18; 74(2):268-283.e5
Linker histone H1 has been correlated with transcriptional inhibition, but the mechanistic basis of the inhibition and its reversal during gene activation has remained enigmatic. We report that H1-compacted chromatin, reconstituted in vitro, blocks transcription by abrogating core histone modifications by p300 but not activator and p300 binding. Transcription from H1-bound chromatin is elicited by the H1 chaperone NAP1, which is recruited in a genespecific manner through direct interactions with activator-bound p300 that facilitate core histone acetylation (by p300) and concomitant eviction of H1 and H2A-H2B. An analysis in B cells confirms the strong dependency on NAP1-mediated H1 eviction for induction of the silent CD40 gene and further demonstrates that H1 eviction, seeded by activator-p300-NAP1-H1 interactions, is propagated over a CCCTC-binding factor (CTCF)-demarcated region through a distinct mechanism that also involves NAP1. Our results confirm direct transcriptional inhibition by H1 and establish a gene-specific H1 eviction mechanism through an activator -> p300 -> NAP1 -> H1 pathway.
Galea S, Vaughan R
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Tradeoffs Between Equity and Efficiency at the Heart of Population Health Science: A Public Health of Consequence, April 2019

Caskey M
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Delivery of anti-HIV bNAbs by viral vectors

LANCET HIV 2019 APR; 6(4):E207-E208
Lopez-Cruz A, Sordillo A, Pokala N, Liu Q, McGrath PT, Bargmann CI
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Parallel Multimodal Circuits Control an Innate Foraging Behavior

NEURON 2019 APR 17; 102(2):407-419.e8
Foraging strategies emerge from genetically encoded programs that are similar across animal species. Here, we examine circuits that control a conserved foraging state, local search behavior after food removal, in Caenorhabditis elegans. We show that local search is triggered by two parallel groups of chemosensory and mechanosensory glutamater-gic neurons that detect food-related cues. Each group of sensory neurons suppresses distinct integrating neurons through a G protein-coupled metabotropic glutamate receptor, MGL-1, to release local search. The chemosensory and mechanosensory modules are separate and redundant; glutamate release from either module can drive the full behavior. A transition from local search to global search over several minutes after food removal is associated with two changes in circuit function. First, the spontaneous activity of sensory neurons falls. Second, the motor pattern generator for local search becomes less responsive to sensory input. This multimodal, distributed short-term food memory provides robust control of an innate behavior.
Paris K, Haddad E, Borte M, Brodszki N, Derfalvi B, Marodi L, Hussain I, Darter A, Engl W, Leibl H, McCoy B, Yel L
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Tolerability of subcutaneous immunoglobulin 20%, Ig20Gly, in pediatric patients with primary immunodeficiencies

IMMUNOTHERAPY 2019 APR; 11(5):397-406
Aim: To assess Ig20Gly tolerability in pediatric patients with primary immunodeficiencies. Patients & methods: Infusion parameters and tolerability were analyzed in pediatric patients (aged 2-5 years [n=6], 6-11 years [n=22] and 12-17 years [n=22]) receiving Ig20Gly in two Phase II/III trials. Results: Of 2624 Ig20Gly infusions, >99% did not require any rate reduction, interruption or discontinuation due to adverse events (AEs). Median maximum infusion rates and volumes/site were higher in patients 12-17 years of age (30ml/h/site; 30ml/site) versus 6-11 years (20ml/h/site; 15ml/site) and 2-5 years (18ml/h/site; 14ml/site). Rates of causally related systemic and local AEs (0.009 and 0.063 AEs/infusion) were low. Conclusion: Ig20Gly infused at relatively high rates and volumes was well tolerated in children.
Rickman K, Smogorzewska A
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Advances in understanding DNA processing and protection at stalled replication forks

JOURNAL OF CELL BIOLOGY 2019 APR; 218(4):1096-1107
The replisome, the molecular machine dedicated to copying DNA, encounters a variety of obstacles during S phase. Without a proper response to this replication stress, the genome becomes unstable, leading to disease, including cancer. The immediate response is localized to the stalled replisome and includes protection of the nascent DNA. A number of recent studies have provided insight into the factors recruited to and responsible for protecting stalled replication forks. In response to replication stress, the SNF2 family of DNA translocases has emerged as being responsible for remodeling replication forks in vivo. The protection of stalled replication forks requires the cooperation of RAD51, BRCA1, BRCA2, and many other DNA damage response proteins. In the absence of these fork protection factors, fork remodeling renders them vulnerable to degradation by nucleases and helicases, ultimately compromising genome integrity. In this review, we focus on the recent progress in understanding the protection, processing, and remodeling of stalled replication forks in mammalian cells.