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SIVcol Nef counteracts SERINC5 by promoting its proteasomal degradation but does not efficiently enhance HIV-1 replication in human CD4+ T cells and lymphoid tissue.

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SIVcol Nef counteracts SERINC5 by promoting its proteasomal degradation but does not efficiently enhance HIV-1 replication in human CD4+ T cells and lymphoid tissue.

PLoS Pathog. 2018 Aug 20;14(8):e1007269

Authors: Kmiec D, Akbil B, Ananth S, Hotter D, Sparrer K, Stürzel CM, Trautz B, Ayouba A, Peeters M, Yao Z, Stagljar I, Passos V, Zillinger T, Goffinet C, Sauter D, Fackler OT, Kirchhoff F

Abstract
SERINC5 is a host restriction factor that impairs infectivity of HIV-1 and other primate lentiviruses and is counteracted by the viral accessory protein Nef. However, the importance of SERINC5 antagonism for viral replication and cytopathicity remained unclear. Here, we show that the Nef protein of the highly divergent SIVcol lineage infecting mantled guerezas (Colobus guereza) is a potent antagonist of SERINC5, although it lacks the CD4, CD3 and CD28 down-modulation activities exerted by other primate lentiviral Nefs. In addition, SIVcol Nefs decrease CXCR4 cell surface expression, suppress TCR-induced actin remodeling, and counteract Colobus but not human tetherin. Unlike HIV-1 Nef proteins, SIVcol Nef induces efficient proteasomal degradation of SERINC5 and counteracts orthologs from highly divergent vertebrate species, such as Xenopus frogs and zebrafish. A single Y86F mutation disrupts SERINC5 and tetherin antagonism but not CXCR4 down-modulation by SIVcol Nef, while mutation of a C-proximal di-leucine motif has the opposite effect. Unexpectedly, the Y86F change in SIVcol Nef had little if any effect on viral replication and CD4+ T cell depletion in preactivated human CD4+ T cells and in ex vivo infected lymphoid tissue. However, SIVcol Nef increased virion infectivity up to 10-fold and moderately increased viral replication in resting peripheral blood mononuclear cells (PBMCs) that were first infected with HIV-1 and activated three or six days later. In conclusion, SIVcol Nef lacks several activities that are conserved in other primate lentiviruses and utilizes a distinct proteasome-dependent mechanism to counteract SERINC5. Our finding that evolutionarily distinct SIVcol Nefs show potent anti-SERINC5 activity supports a relevant role of SERINC5 antagonism for viral fitness in vivo. Our results further suggest this Nef function is particularly important for virion infectivity under conditions of limited CD4+ T cell activation.

PMID: 30125328 [PubMed - as supplied by publisher]



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The Banality of Anal: Safer Sexual Erotics in the Gay Men's Health Crisis' Safer Sex Comix and Ex Aequo's Alex et la vie d'après.

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The Banality of Anal: Safer Sexual Erotics in the Gay Men's Health Crisis' Safer Sex Comix and Ex Aequo's Alex et la vie d'après.

J Med Humanit. 2018 Aug 17;:

Authors: Greenblatt J

Abstract
Analyzing two harm reduction comics campaigns-one early in the AIDS crisis (the Gay Men's Health Crisis' [GMHC] 1980s Safer Sex Comix) and one more recent (Fabrice Neaud and Thierry Robberecht's 2008 Alex et la vie d'après), I explore tensions between queer safer sexual erotics and national discourses of sexual norms/deviation raised by Cindy Patton and William Haver at the height of AIDS discourse theory in 1996, approximately halfway between the comics. Using these theorists' reflections on the history of AIDS activism/representation as a hinge, I explore the manifestation/transformation a decade later of the ethical, educational, and erotic issues they raise. Both foreground the ways that HIV, safer sex, and/or eroticism pose difficulties for systems of linguistic and visual representation. Combining text and image, comics-a common harm reduction medium-epitomize this representational issue. While the GMHC addresses an immediate need for information about safer sex, Alex attempts to tackle the unrepresentability/unthinkability of safer and/or seropositive sex(uality). Safer Sex Comix, while largely prioritizing directness above formal experimentation, employ strategies of transgressing the borders of the comics panel to emphasize a plethora of lower-risk sexual acts. The most visually inventive moments in Alex represent Alex's feelings of unintelligbility post-diagnosis, but the comic restricts its representation of sex only to anal intercourse, and it proves unable to visualize alternative formulations of the erotic, turning to more normative narratives and images as earlier, visually explicit unsafe sexual encounters are replaced with more a/illusive representations post-conversion, literalizing the unrepresentability of seropositive erotic life.

PMID: 30120671 [PubMed - as supplied by publisher]



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Extrachromosomal circular elements targeted by CRISPR-Cas in Dehalococcoides mccartyi are linked to mobilization of reductive dehalogenase genes.

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Extrachromosomal circular elements targeted by CRISPR-Cas in Dehalococcoides mccartyi are linked to mobilization of reductive dehalogenase genes.

ISME J. 2018 Aug 13;:

Authors: Molenda O, Tang S, Lomheim L, Gautam VK, Lemak S, Yakunin AF, Maxwell KL, Edwards EA

Abstract
Dehalococcoides mccartyi are obligate organohalide-respiring bacteria that play an important detoxifying role in the environment. They have small genomes (~1.4 Mb) with a core region interrupted by two high plasticity regions (HPRs) containing dozens of genes encoding reductive dehalogenases involved in organohalide respiration. The genomes of eight new strains of D. mccartyi were closed from metagenomic data from a related set of enrichment cultures, bringing the total number of genomes to 24. Two of the newly sequenced strains and three previously sequenced strains contain CRISPR-Cas systems. These D. mccartyi CRISPR-Cas systems were found to primarily target prophages and genomic islands. The genomic islands were identified either as integrated into D. mccartyi genomes or as circular extrachromosomal elements. We observed active circularization of the integrated genomic island containing vcrABC operon encoding the dehalogenase (VcrA) responsible for the transformation of vinyl chloride to non-toxic ethene. We interrogated archived DNA from established enrichment cultures and found that the CRISPR array acquired three new spacers in 11 years. These data provide a glimpse into dynamic processes operating on the genomes distinct to D. mccartyi strains found in enrichment cultures and provide the first insights into possible mechanisms of lateral DNA exchange in D. mccartyi.

PMID: 30104577 [PubMed - as supplied by publisher]



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Stem cell bioengineering: building from stem cell biology.

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Stem cell bioengineering: building from stem cell biology.

Nat Rev Genet. 2018 Aug 08;:

Authors: Tewary M, Shakiba N, Zandstra PW

Abstract
New fundamental discoveries in stem cell biology have yielded potentially transformative regenerative therapeutics. However, widespread implementation of stem-cell-derived therapeutics remains sporadic. Barriers that impede the development of these therapeutics can be linked to our incomplete understanding of how the regulatory networks that encode stem cell fate govern the development of the complex tissues and organs that are ultimately required for restorative function. Bioengineering tools, strategies and design principles represent core components of the stem cell bioengineering toolbox. Applied to the different layers of complexity present in stem-cell-derived systems - from gene regulatory networks in single stem cells to the systemic interactions of stem-cell-derived organs and tissues - stem cell bioengineering can address existing challenges and advance regenerative medicine and cellular therapies.

PMID: 30089805 [PubMed - as supplied by publisher]



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Multiplexed assays of variant effects contribute to a growing genotype-phenotype atlas.

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Multiplexed assays of variant effects contribute to a growing genotype-phenotype atlas.

Hum Genet. 2018 Aug 02;:

Authors: Weile J, Roth FP

Abstract
Given the constantly improving cost and speed of genome sequencing, it is reasonable to expect that personal genomes will soon be known for many millions of humans. This stands in stark contrast with our limited ability to interpret the sequence variants which we find. Although it is, perhaps, easiest to interpret variants in coding regions, knowledge of functional impact is unknown for the vast majority of missense variants. While many computational approaches can predict the impact of coding variants, they are given a little weight in the current guidelines for interpreting clinical variants. Laboratory assays produce comparatively more trustworthy results, but until recently did not scale to the space of all possible mutations. The development of deep mutational scanning and other multiplexed assays of variant effect has now brought feasibility of this endeavour within view. Here, we review progress in this field over the last decade, break down the different approaches into their components, and compare methodological differences.

PMID: 30073413 [PubMed - as supplied by publisher]



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Acute Effects of Drugs on Caenorhabditis elegans Movement Reveal Complex Responses and Plasticity.

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Acute Effects of Drugs on Caenorhabditis elegans Movement Reveal Complex Responses and Plasticity.

G3 (Bethesda). 2018 Jul 30;:

Authors: Spensley M, Del Borrello S, Pajkic D, Fraser AG

Abstract
Many drugs act very rapidly; they can turn on or off their targets within minutes in a whole animal. What are the acute effects of drug treatment and how does an animal respond to these? We developed a simple assay to measure the acute effects of drugs on C. elegans movement and examined the effects of a range of compounds including neuroactive drugs, toxins, environmental stresses and novel compounds on worm movement over a time period of 3 hours. We find that many treatments show complex acute responses, where a phase of rapid paralysis is followed by one or more recovery phases. The recoveries are not the result of some generic stress response but are specific to the drug e.g. recovery from paralysis due to a neuroactive drug requires neurotransmitter pathways whereas recovery from a metabolic inhibitor requires metabolic changes. Finally, we also find that acute responses can vary greatly across development and that there is extensive and complex natural variation in acute responses. In summary, acute responses are sensitive probes of the ability of biological networks to respond to drug treatment and these responses can reveal the action of unexplored pathways.

PMID: 30061375 [PubMed - as supplied by publisher]



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mTOR complex 1 controls the nuclear localization and function of glycogen synthase kinase 3β.

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mTOR complex 1 controls the nuclear localization and function of glycogen synthase kinase 3β.

J Biol Chem. 2018 Jul 30;:

Authors: Bautista SJ, Boras I, Vissa A, Mecica N, Yip CM, Kim PK, Antonescu CN

Abstract
Glycogen synthase kinase 3β (GSK3β) phosphorylates and thereby regulates a wide range of protein substrates involved in diverse cellular functions. Some GSK3β substrates, such as c-myc and snail, are nuclear transcription factors, suggesting the possibility that GSK3β function is controlled through its nuclear localization. Here, using ARPE-19 and MDA-MB-231 human cell lines, we found that inhibition of mTOR complex 1 (mTORC1) leads to partial redistribution of GSK3β from the cytosol to the nucleus and to a GSK3β-dependent reduction of the levels of both c-myc and snail. mTORC1 is known to be controlled by metabolic cues, such as by AMP-activated protein kinase (AMPK) or amino acid abundance, and we observed here that AMPK activation or amino acid deprivation promotes GSK3β nuclear localization in an mTORC1-dependent manner. GSK3β was detected on several distinct endomembrane compartments, including lysosomes. Consistently, disruption of late endosomes/lysosomes through perturbation of RAB7, member RAS oncogene family 7 (Rab7) resulted in loss of GSK3β from lysosomes and in enhanced GSK3β nuclear localization as well as GSK3β-dependent reduction of c-myc levels. These findings indicate that the nuclear localization and function of GSK3β is suppressed by mTORC1 and suggest a link between metabolic conditions sensed by mTORC1 and GSK3β-dependent regulation of transcriptional networks controlling cellular biomass production.

PMID: 30061153 [PubMed - as supplied by publisher]



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Skin-derived precursor cells undergo substrate-dependent galvanotaxis that can be modified by neighbouring cells.

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Skin-derived precursor cells undergo substrate-dependent galvanotaxis that can be modified by neighbouring cells.

Stem Cell Res. 2018 Jul 19;31:95-101

Authors: Iwasa SN, Popovic MR, Morshead CM

Abstract
Many cell types respond to electric fields (EFs) through cell migration, a process termed galvanotaxis. The galvanotactic response is critical for development and wound healing. Here we investigate whether skin-derived precursor cells (SKPs), which have the potential to differentiate into mesodermal and peripheral neural cell types, undergo directed migration in the presence of an EF. We found that EF application promotes SKP migration towards the anode. The migratory response is substrate-dependent as SKPs undergo directed migration on laminin and Matrigel, but not collagen. The majority of SKPs express the undifferentiated cell markers nestin, fibronectin and Sox2, after both EF application and in sister cultures with no EF application, suggesting that EFs do not promote cell differentiation. Co-cultures of SKPs and brain-derived neural precursor cells (NPCs), a population of cells that undergo rapid, cathode-directed migration, reveal that in the presence of NPCs an increased percentage of SKPs undergo galvanotaxis, providing evidence that cells can provide cues to modify the galvanotactic response. We propose that a better understanding of SKP migration in the presence of EFs may provide insight into improved strategies for wound repair.

PMID: 30059907 [PubMed - as supplied by publisher]



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Integrating genetic and protein-protein interaction networks maps a functional wiring diagram of a cell.

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Integrating genetic and protein-protein interaction networks maps a functional wiring diagram of a cell.

Curr Opin Microbiol. 2018 Jul 27;45:170-179

Authors: VanderSluis B, Costanzo M, Billmann M, Ward HN, Myers CL, Andrews BJ, Boone C

Abstract
Systematic experimental approaches have led to construction of comprehensive genetic and protein-protein interaction networks for the budding yeast, Saccharomyces cerevisiae. Genetic interactions capture functional relationships between genes using phenotypic readouts, while protein-protein interactions identify physical connections between gene products. These complementary, and largely non-overlapping, networks provide a global view of the functional architecture of a cell, revealing general organizing principles, many of which appear to be evolutionarily conserved. Here, we focus on insights derived from the integration of large-scale genetic and protein-protein interaction networks, highlighting principles that apply to both unicellular and more complex systems, including human cells. Network integration reveals fundamental connections involving key functional modules of eukaryotic cells, defining a core network of cellular function, which could be elaborated to explore cell-type specificity in metazoans.

PMID: 30059827 [PubMed - as supplied by publisher]



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Melatonin receptors limit dopamine reuptake by regulating dopamine transporter cell-surface exposure.

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Melatonin receptors limit dopamine reuptake by regulating dopamine transporter cell-surface exposure.

Cell Mol Life Sci. 2018 Jul 24;:

Authors: Benleulmi-Chaachoua A, Hegron A, Le Boulch M, Karamitri A, Wierzbicka M, Wong V, Stagljar I, Delagrange P, Ahmad R, Jockers R

Abstract
Melatonin, a neuro-hormone released by the pineal gland, has multiple effects in the central nervous system including the regulation of dopamine (DA) levels, but how melatonin accomplishes this task is not clear. Here, we show that melatonin MT1 and MT2 receptors co-immunoprecipitate with the DA transporter (DAT) in mouse striatal synaptosomes. Increased DA re-uptake and decreased amphetamine-induced locomotor activity were observed in the striatum of mice with targeted deletion of MT1 or MT2 receptors. In vitro experiments confirmed the interactions and recapitulated the inhibitory effect of melatonin receptors on DA re-uptake. Melatonin receptors retained DAT in the endoplasmic reticulum in its immature non-glycosylated form. In conclusion, we reveal one of the first molecular complexes between G protein-coupled receptors (MT1 and MT2) and transporters (DAT) in which melatonin receptors regulate the availability of DAT at the plasma membrane, thus limiting the striatal DA re-uptake capacity in mice.

PMID: 30043140 [PubMed - as supplied by publisher]



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