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PLoS Biology

Emily Dangelmaier, Sarah B Lazar, Ashish Lal
p53 regulates the expression of hundreds of genes. Recent surprising observations indicate that no single protein-coding gene controls the tumor suppressor effects of p53. This raises the possibility that a subset of these genes, regulated by a p53-induced long noncoding RNA (lncRNA), could control p53's tumor suppressor function. We propose molecular mechanisms through which lncRNAs could regulate this subset of genes and hypothesize an exciting, direct role of lncRNAs in p53's genome stability maintenance function...
February 13, 2019: PLoS Biology
Maria E Yurgel, Priyanka Kakad, Meet Zandawala, Dick R Nässel, Tanja A Godenschwege, Alex C Keene
Dysregulation of sleep and feeding has widespread health consequences. Despite extensive epidemiological evidence for interactions between sleep and metabolic function, little is known about the neural or molecular basis underlying the integration of these processes. D. melanogaster potently suppress sleep in response to starvation, and powerful genetic tools allow for mechanistic investigation of sleep-metabolism interactions. We have previously identified neurons expressing the neuropeptide leucokinin (Lk) as being required for starvation-mediated changes in sleep...
February 13, 2019: PLoS Biology
Karine Narbonne-Reveau, Cédric Maurange
In many organisms, the regenerative capacity of tissues progressively decreases as development progresses. However, the developmental mechanisms that restrict regenerative potential remain unclear. In Drosophila, wing imaginal discs become unable to regenerate upon damage during the third larval stage (L3). Here, we show that production of ecdysone after larvae reach their critical weight (CW) terminates the window of regenerative potential by acting on a bistable loop composed of 2 antagonistic Broad-complex/Tramtrack/Bric-à-brac Zinc-finger (ZBTB) genes: chinmo and broad (br)...
February 11, 2019: PLoS Biology
Chris Ellison, Doris Bachtrog
The repeatability or predictability of evolution is a central question in evolutionary biology and most often addressed in experimental evolution studies. Here, we infer how genetically heterogeneous natural systems acquire the same molecular changes to address how genomic background affects adaptation in natural populations. In particular, we take advantage of independently formed neo-sex chromosomes in Drosophila species that have evolved dosage compensation by co-opting the dosage-compensation male-specific lethal (MSL) complex to study the mutational paths that have led to the acquisition of hundreds of novel binding sites for the MSL complex in different species...
February 11, 2019: PLoS Biology
Lihong Zhan, Grietje Krabbe, Fei Du, Ian Jones, Meredith C Reichert, Maria Telpoukhovskaia, Lay Kodama, Chao Wang, Seo-Hyun Cho, Faten Sayed, Yaqiao Li, David Le, Yungui Zhou, Yin Shen, Brian West, Li Gan
Microglia are resident immune cells that play critical roles in maintaining the normal physiology of the central nervous system (CNS). Remarkably, microglia have an intrinsic capacity to repopulate themselves after acute ablation. However, the underlying mechanisms that drive such restoration remain elusive. Here, we characterized microglial repopulation both spatially and temporally following removal via treatment with the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622. We show that microglia were replenished via self-renewal, with no contribution from nonmicroglial lineages, including Nestin+ progenitors and the circulating myeloid population...
February 8, 2019: PLoS Biology
Fernanda A Sala, Gareth S A Wright, Svetlana V Antonyuk, Richard C Garratt, S Samar Hasnain
Superoxide dismutase-1 (SOD1) maturation comprises a string of posttranslational modifications which transform the nascent peptide into a stable and active enzyme. The successive folding, metal ion binding, and disulphide acquisition steps in this pathway can be catalysed through a direct interaction with the copper chaperone for SOD1 (CCS). This process confers enzymatic activity and reduces access to noncanonical, aggregation-prone states. Here, we present the functional mechanisms of human copper chaperone for SOD1 (hCCS)-catalysed SOD1 activation based on crystal structures of reaction precursors, intermediates, and products...
February 8, 2019: PLoS Biology
Vitaly Ryu, Christoph Buettner
The sympathetic nervous system (SNS) controls key aspects of adipose tissue (AT) function through the release of norepinephrine (NE) and beta adrenergic signaling. Sympathetic tone is determined by NE release but also by the rate of extracellular NE clearance that historically has been believed to occur solely through solute carrier family 6 member 2 (SLC6A2) expressed on sympathetic neurons. Song and colleagues show that adipocytes can also clear NE through organic cation transporter 3 (Oct3). This contributes to our understanding of how adrenergic signaling is controlled in AT and also emphasizes the need to develop better methods to assess adrenergic signaling in vivo...
February 7, 2019: PLoS Biology
Leonid A Gavrilov, Natalia S Gavrilova
Knowledge of true mortality trajectory at extreme old ages is important for biologists who test their theories of aging with demographic data. Studies using both simulation and direct age validation found that longevity records for ages 105 years and older are often incorrect and may lead to spurious mortality deceleration and mortality plateau. After age 105 years, longevity claims should be considered as extraordinary claims that require extraordinary evidence. Traditional methods of data cleaning and data quality control are just not sufficient...
February 7, 2019: PLoS Biology
Alexa Sadier, Monika Twarogowska, Klara Steklikova, Luke Hayden, Anne Lambert, Pascal Schneider, Vincent Laudet, Maria Hovorakova, Vincent Calvez, Sophie Pantalacci
When patterns are set during embryogenesis, it is expected that they are straightly established rather than subsequently modified. The patterning of the three mouse molars is, however, far from straight, likely as a result of mouse evolutionary history. The first-formed tooth signaling centers, called MS and R2, disappear before driving tooth formation and are thought to be vestiges of the premolars found in mouse ancestors. Moreover, the mature signaling center of the first molar (M1) is formed from the fusion of two signaling centers (R2 and early M1)...
February 7, 2019: PLoS Biology
Yong Tang, Thomas R Meister, Marta Walczak, Michael J Pulkoski-Gross, Sanjay B Hari, Robert T Sauer, Katherine Amberg-Johnson, Ellen Yeh
Endosymbiosis has driven major molecular and cellular innovations. Plasmodium spp. parasites that cause malaria contain an essential, non-photosynthetic plastid-the apicoplast-which originated from a secondary (eukaryote-eukaryote) endosymbiosis. To discover organellar pathways with evolutionary and biomedical significance, we performed a mutagenesis screen for essential genes required for apicoplast biogenesis in Plasmodium falciparum. Apicoplast(-) mutants were isolated using a chemical rescue that permits conditional disruption of the apicoplast and a new fluorescent reporter for organelle loss...
February 6, 2019: PLoS Biology
Nicolas Sarute, Nouhou Ibrahim, Bani Medegan Fagla, Madakasira Lavanya, Christian Cuevas, Spyridon Stavrou, Guliz Otkiran-Clare, Henna Tyynismaa, Jorge Henao-Mejia, Susan R Ross
Tripartite motif (TRIM) proteins belong to a large family with many roles in host biology, including restricting virus infection. Here, we found that TRIM2, which has been implicated in cases of Charcot-Marie-Tooth disease (CMTD) in humans, acts by blocking hemorrhagic fever New World arenavirus (NWA) entry into cells. We show that Trim2-knockout mice, as well as primary fibroblasts from a CMTD patient with mutations in TRIM2, are more highly infected by the NWAs Junín and Tacaribe virus than wild-type mice or cells are...
February 6, 2019: PLoS Biology
Hongge Li, Yingyu Mao, Michael Bouaziz, Honglian Yu, Xiuxia Qu, Fen Wang, Gen-Sheng Feng, Carrie Shawber, Xin Zhang
How multiple receptor tyrosine kinases coordinate cell fate determination is yet to be elucidated. We show here that the receptor for platelet-derived growth factor (PDGF) signaling recruits the p85 subunit of Phosphoinositide 3-kinase (PI3K) to regulate mammalian lens development. Activation of PI3K signaling not only prevents B-cell lymphoma 2 (BCL2)-Associated X (Bax)- and BCL2 Antagonist/Killer (Bak)-mediated apoptosis but also promotes Notch signaling to prevent premature cell differentiation. Reducing PI3K activity destabilizes the Notch intracellular domain, while the constitutive activation of Notch reverses the PI3K deficiency phenotype...
February 4, 2019: PLoS Biology
Neda Barghi, Raymond Tobler, Viola Nolte, Ana Marija Jakšić, François Mallard, Kathrin Anna Otte, Marlies Dolezal, Thomas Taus, Robert Kofler, Christian Schlötterer
The genetic architecture of adaptive traits is of key importance to predict evolutionary responses. Most adaptive traits are polygenic-i.e., result from selection on a large number of genetic loci-but most molecularly characterized traits have a simple genetic basis. This discrepancy is best explained by the difficulty in detecting small allele frequency changes (AFCs) across many contributing loci. To resolve this, we use laboratory natural selection to detect signatures for selective sweeps and polygenic adaptation...
February 4, 2019: PLoS Biology
Nicole M Vega
Understanding how microbes adapt to their host is an enduring problem in microbiome ecology, and understanding the microbial traits that allow colonization of the host and increase adaptation to the host environment is of particular interest. In this study, Robinson and colleagues use experimental evolution to demonstrate adaptation of a commensal bacterium to its zebrafish host and describe the changes in phenotype that emerge during this evolutionary process. These results provide insight into the evolutionary problem of host adaptation and demonstrate the utility of simple models for understanding host-microbiome dynamics...
February 4, 2019: PLoS Biology
Hannah L Turner, Jesper Pallesen, Shanshan Lang, Sandhya Bangaru, Sarah Urata, Sheng Li, Christopher A Cottrell, Charles A Bowman, James E Crowe, Ian A Wilson, Andrew B Ward
Seasonal influenza virus infections can cause significant morbidity and mortality, but the threat from the emergence of a new pandemic influenza strain might have potentially even more devastating consequences. As such, there is intense interest in isolating and characterizing potent neutralizing antibodies that target the hemagglutinin (HA) viral surface glycoprotein. Here, we use cryo-electron microscopy (cryoEM) to decipher the mechanism of action of a potent HA head-directed monoclonal antibody (mAb) bound to an influenza H7 HA...
February 4, 2019: PLoS Biology
Lior Ofer, Mason N Dean, Paul Zaslansky, Shiri Kult, Yulia Shwartz, Janna Zaretsky, Shelley Griess-Fishheimer, Efrat Monsonego-Ornan, Elazar Zelzer, Ron Shahar
Osteocytes, cells forming an elaborate network within the bones of most vertebrate taxa, are thought to be the master regulators of bone modeling, a process of coordinated, local bone-tissue deposition and removal that keeps bone strains at safe levels throughout life. Neoteleost fish, however, lack osteocytes and yet are known to be capable of bone modeling, although no osteocyte-independent modeling regulatory mechanism has so far been described. Here, we characterize a novel, to our knowledge, bone-modeling regulatory mechanism in a fish species (medaka), showing that although lacking osteocytes (i...
February 1, 2019: PLoS Biology
Elise Cau, Brice Ronsin, Laurianne Bessière, Patrick Blader
Neural progenitors produce neurons whose identities can vary as a function of the time that specification occurs. Here, we describe the heterochronic specification of two photoreceptor (PhR) subtypes in the zebrafish pineal gland. We find that accelerating PhR specification by impairing Notch signaling favors the early fate at the expense of the later fate. Using in vivo lineage tracing, we show that most pineal PhRs are born from a fate-restricted progenitor. Furthermore, sister cells derived from the division of PhR-restricted progenitors activate the bone morphogenetic protein (BMP) signaling pathway at different times after division, and this heterochrony requires Notch activity...
January 31, 2019: PLoS Biology
Máté Manczinger, Gábor Boross, Lajos Kemény, Viktor Müller, Tobias L Lenz, Balázs Papp, Csaba Pál
Central players of the adaptive immune system are the groups of proteins encoded in the major histocompatibility complex (MHC), which shape the immune response against pathogens and tolerance to self-peptides. The corresponding genomic region is of particular interest, as it harbors more disease associations than any other region in the human genome, including associations with infectious diseases, autoimmune disorders, cancers, and neuropsychiatric diseases. Certain MHC molecules can bind to a much wider range of epitopes than others, but the functional implication of such an elevated epitope-binding repertoire has remained largely unclear...
January 31, 2019: PLoS Biology
Susanna R Bidgood
The eradication of smallpox is one of the greatest medical successes in history. Vaccinia virus was made famous by being the virus used in the live vaccine that enabled this feat. Nearly 40 years on from that success, this prototypical poxvirus continues to empower the exploration of fundamental biology and the potential to develop therapeutics against some of the major causes of death and disease in the modern world.
January 30, 2019: PLoS Biology
Jana Helsen, Jens Frickel, Rob Jelier, Kevin J Verstrepen
The regulatory processes in cells are typically organized into complex genetic networks. However, it is still unclear how this network structure modulates the evolution of cellular regulation. One would expect that mutations in central and highly connected modules of a network (so-called hubs) would often result in a breakdown and therefore be an evolutionary dead end. However, a new study by Koubkova-Yu and colleagues finds that in some circumstances, altering a hub can offer a quick evolutionary advantage...
January 30, 2019: PLoS Biology
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