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eLife
Journal Prestige (SJR): 7.121
Citation Impact (citeScore): 7
Number of Followers: 98  

  This is an Open Access Journal Open Access journal
ISSN (Online) 2050-084X
Published by eLife Sciences Publications Homepage  [1 journal]
  • Multistep loading of a DNA sliding clamp onto DNA by replication factor C

    • Authors: remusd@mskcc.org (Charanya Kumar, remusd@mskcc.org (Dirk Remus, remusd@mskcc.org (Juan C Castaneda, remusd@mskcc.org (Marina Schrecker, remusd@mskcc.org (Richard K Hite, remusd@mskcc.org (Sujan Devbhandari
      Abstract: The DNA sliding clamp proliferating cell nuclear antigen (PCNA) is an essential co-factor for many eukaryotic DNA metabolic enzymes. PCNA is loaded around DNA by the ATP-dependent clamp loader replication factor C (RFC), which acts at single-stranded (ss)/double-stranded DNA (dsDNA) junctions harboring a recessed 3’ end (3’ ss/dsDNA junctions) and at DNA nicks. To illuminate the loading mechanism we have investigated the structure of RFC:PCNA bound to ATPγS and 3’ ss/dsDNA junctions or nicked DNA using cryogenic electron microscopy. Unexpectedly, we observe open and closed PCNA conformations in the RFC:PCNA:DNA complex, revealing that PCNA can adopt an open, planar conformation that allows direct insertion of dsDNA, and raising the question of whether PCNA ring closure is mechanistically coupled to ATP hydrolysis. By resolving multiple DNA-bound states of RFC:PCNA we observe that partial melting facilitates lateral insertion into the central channel formed by RFC:PCNA. We also resolve the Rfc1 N-terminal domain and demonstrate that its single BRCT domain participates in coordinating DNA prior to insertion into the central RFC channel, which promotes PCNA loading on the lagging strand of replication forks in vitro. Combined, our data suggest a comprehensive and fundamentally revised model for the RFC-catalyzed loading of PCNA onto DNA.
      PubDate: 2022-08-08T00:00:00Z
      DOI: 10.7554/eLife.78253
       
  • Estimation and worldwide monitoring of the effective reproductive number
           of SARS-CoV-2

    • Authors: jana.huisman@env.ethz.ch (Daniel C Angst, jana.huisman@env.ethz.ch (Jana Sanne Huisman, jana.huisman@env.ethz.ch (Jérémie Scire, jana.huisman@env.ethz.ch (Jinzhou Li, jana.huisman@env.ethz.ch (Marloes H Maathuis, jana.huisman@env.ethz.ch (Richard A Neher, jana.huisman@env.ethz.ch (Sebastian Bonhoeffer, jana.huisman@env.ethz.ch (Tanja Stadler
      Abstract: The effective reproductive number Re is a key indicator of the growth of an epidemic. Since the start of the SARS-CoV-2 pandemic, many methods and online dashboards have sprung up to monitor this number through time. However, these methods are not always thoroughly tested, correctly placed in time, or are overly confident during high incidence periods. Here, we present a method for timely estimation of Re, applied to COVID-19 epidemic data from 170 countries. We thoroughly evaluate the method on simulated data, and present an intuitive web interface for interactive data exploration. We show that, in early 2020, in the majority of countries the estimated Re dropped below 1 only after the introduction of major non-pharmaceutical interventions. For Europe the implementation of non-pharmaceutical interventions was broadly associated with reductions in the estimated Re. Globally though, relaxing non-pharmaceutical interventions had more varied effects on subsequent Re estimates. Our framework is useful to inform governments and the general public on the status of epidemics in their country, and is used as the official source of Re estimates for SARS-CoV-2 in Switzerland. It further allows detailed comparison between countries and in relation to covariates such as implemented public health policies, mobility, behaviour, or weather data.
      PubDate: 2022-08-08T00:00:00Z
      DOI: 10.7554/eLife.71345
       
  • Nomograms of human hippocampal volume shifted by polygenic scores

    • Authors: Rmapmja@ucl.ac.uk (Andre Altmann, Rmapmja@ucl.ac.uk (Jonathan M Schott, Rmapmja@ucl.ac.uk (Leon Aksman, Rmapmja@ucl.ac.uk (Mohammed Janahi, Rmapmja@ucl.ac.uk (Younes Mokrab
      Abstract: Nomograms are important clinical tools applied widely in both developing and aging populations. They are generally constructed as normative models identifying cases as outliers to a distribution of healthy controls. Currently used normative models do not account for genetic heterogeneity. Hippocampal Volume (HV) is a key endophenotype for many brain disorders. Here, we examine the impact of genetic adjustment on HV nomograms and the translational ability to detect dementia patients. Using imaging data from 35,686 healthy subjects aged 44 to 82 from the UK BioBank (UKB), we built HV nomograms using gaussian process regression (GPR), which - compared to a previous method - extended the application age by 20 years, including dementia critical age ranges. Using HV Polygenic Scores (HV-PGS), we built genetically adjusted nomograms from participants stratified into the top and bottom 30% of HV-PGS. This shifted the nomograms in the expected directions by ~100 mm3 (2.3% of the average HV), which equates to 3 years of normal aging for a person aged ~65. Clinical impact of genetically adjusted nomograms was investigated by comparing 818 subjects from the AD neuroimaging (ADNI) database diagnosed as either cognitively normal (CN), having mild cognitive impairment (MCI) or Alzheimer’s disease patients (AD). While no significant change in the survival analysis was found for MCI-to-AD conversion, an average of 68% relative decrease was found in intra-diagnostic-group variance, highlighting the importance of genetic adjustment in untangling phenotypic heterogeneity.
      PubDate: 2022-08-08T00:00:00Z
      DOI: 10.7554/eLife.78232
       
  • Adiposity may confound the association between vitamin D and disease risk
           – a lifecourse Mendelian randomization study

    • Authors: Tom.G.Richardson@bristol.ac.uk (George Davey Smith, Tom.G.Richardson@bristol.ac.uk (Grace M Power, Tom.G.Richardson@bristol.ac.uk (Tom G Richardson
      PubDate: 2022-08-08T00:00:00Z
      DOI: 10.7554/eLife.79798
       
  • A pulse-chasable reporter processing assay for mammalian autophagic flux
           with HaloTag

    • Authors: hayashi-yamamoto@nms.ac.jp (Hayashi Yamamoto, hayashi-yamamoto@nms.ac.jp (Noboru Mizushima, hayashi-yamamoto@nms.ac.jp (Willa Wen-You Yim
      Abstract: Monitoring autophagic flux is necessary for most autophagy studies. The autophagic flux assays currently available for mammalian cells are generally complicated and do not yield highly quantitative results. Yeast autophagic flux is routinely monitored with the GFP-based processing assay, whereby the amount of GFP proteolytically released from GFP-containing reporters (e.g., GFP-Atg8), detected by immunoblotting, reflects autophagic flux. However, this simple and effective assay is typically inapplicable to mammalian cells because GFP is efficiently degraded in lysosomes while the more proteolytically resistant RFP accumulates in lysosomes under basal conditions. Here, we report a HaloTag (Halo)-based reporter processing assay to monitor mammalian autophagic flux. We found that Halo is sensitive to lysosomal proteolysis but becomes resistant upon ligand binding. When delivered into lysosomes by autophagy, pulse-labeled Halo-based reporters (e.g., Halo-LC3 and Halo-GFP) are proteolytically processed to generate Haloligand when delivered into lysosomes by autophagy. Hence, the amount of free Haloligand detected by immunoblotting or in-gel fluorescence imaging reflects autophagic flux. We demonstrate the applications of this assay by monitoring the autophagy pathways, macroautophagy, selective autophagy, and even bulk nonselective autophagy. With the Halo-based processing assay, mammalian autophagic flux and lysosome-mediated degradation can be monitored easily and precisely.
      PubDate: 2022-08-08T00:00:00Z
      DOI: 10.7554/eLife.78923
       
  • The VINE complex is an endosomal VPS9-domain GEF and SNX-BAR coat

    • Authors: conibear@cmmt.ubc.ca (Elizabeth Conibear, conibear@cmmt.ubc.ca (Mia S Frier, conibear@cmmt.ubc.ca (Michael Davey, conibear@cmmt.ubc.ca (Ponthakorn Wongsangaroonsri, conibear@cmmt.ubc.ca (Shawn P Shortill
      Abstract: Membrane trafficking pathways perform important roles in establishing and maintaining the endosomal network. Retrograde protein sorting from the endosome is promoted by conserved SNX-BAR-containing coat complexes including retromer which enrich cargo at tubular microdomains and generate transport carriers. In metazoans, retromer cooperates with VARP, a conserved VPS9-domain GEF, to direct an endosomal recycling pathway. The function of the yeast VARP homolog Vrl1 has been overlooked due to an inactivating mutation found in commonly studied strains. Here, we demonstrate that Vrl1 has features of a SNX-BAR coat protein and forms an obligate complex with Vin1, the paralog of the retromer SNX-BAR protein Vps5. Unique features in the Vin1 N-terminus allow Vrl1 to distinguish it from Vps5, thereby forming a complex that we have named VINE. The VINE complex occupies endosomal tubules and redistributes a conserved mannose 6-phosphate receptor-like protein from endosomes. We also find that membrane recruitment by Vin1 is essential for Vrl1 GEF activity, suggesting that VINE is a multifunctional coat complex that regulates trafficking and signaling events at the endosome.
      PubDate: 2022-08-08T00:00:00Z
      DOI: 10.7554/eLife.77035
       
  • Science Forum: How failure to falsify in high-volume science contributes
           to the replication crisis

    • Authors: fhillary@psu.edu (Frank G Hillary, fhillary@psu.edu (Sarah M Rajtmajer, fhillary@psu.edu (Timothy M Errington
      Abstract: The number of scientific papers published every year continues to increase, but scientific knowledge is not progressing at the same rate. Here we argue that a greater emphasis on falsification - the direct testing of strong hypotheses - would lead to faster progress by allowing well-specified hypotheses to be eliminated. We describe an example from neuroscience where there has been little work to directly test two prominent but incompatible hypotheses related to traumatic brain injury. Based on this example, we discuss how building strong hypotheses and then setting out to falsify them can bring greater precision to the clinical neurosciences, and argue that this approach could be beneficial to all areas of science.
      PubDate: 2022-08-08T00:00:00Z
      DOI: 10.7554/eLife.78830
       
  • Polysome-CAGE of TCL1-driven chronic lymphocytic leukemia revealed
           multiple N-terminally altered epigenetic regulators and a translation
           stress signature

    • Authors: rivka.dikstein@weizmann.ac.il (Ariel Ogran, rivka.dikstein@weizmann.ac.il (Idit Shachar, rivka.dikstein@weizmann.ac.il (Keren David, rivka.dikstein@weizmann.ac.il (Rivka Dikstein, rivka.dikstein@weizmann.ac.il (Shirly Becker-Herman, rivka.dikstein@weizmann.ac.il (Tal Havkin-Solomon
      Abstract: The transformation of normal to malignant cells is accompanied by substantial changes in gene expression programs through diverse mechanisms. Here, we examined the changes in the landscape of transcription start sites and alternative promoter (AP) usage and their impact on the translatome in TCL1-driven chronic lymphocytic leukemia (CLL). Our findings revealed a marked elevation of APs in CLL B cells from Eµ-Tcl1 transgenic mice, which are particularly enriched with intra-genic promoters that generate N-terminally truncated or modified proteins. Intra-genic promoter activation is mediated by (1) loss of function of ‘closed chromatin’ epigenetic regulators due to the generation of inactive N-terminally modified isoforms or reduced expression; (2) upregulation of transcription factors, including c-Myc, targeting the intra-genic promoters and their associated enhancers. Exogenous expression of Tcl1 in MEFs is sufficient to induce intra-genic promoters of epigenetic regulators and promote c-Myc expression. We further found a dramatic translation downregulation of transcripts bearing CNY cap-proximal trinucleotides, reminiscent of cells undergoing metabolic stress. These findings uncovered the role of Tcl1 oncogenic function in altering promoter usage and mRNA translation in leukemogenesis.
      PubDate: 2022-08-08T00:00:00Z
      DOI: 10.7554/eLife.77714
       
  • Allosteric stabilization of calcium and phosphoinositide dual binding
           engages several synaptotagmins in fast exocytosis

    • Authors: awalter@sund.ku.dk (Alexander M Walter, awalter@sund.ku.dk (Jakob Balslev Sørensen, awalter@sund.ku.dk (Janus RL Kobbersmed, awalter@sund.ku.dk (Manon MM Berns, awalter@sund.ku.dk (Susanne Ditlevsen
      Abstract: Synaptic communication relies on the fusion of synaptic vesicles with the plasma membrane, which leads to neurotransmitter release. This exocytosis is triggered by brief and local elevations of intracellular Ca2+ with remarkably high sensitivity. How this is molecularly achieved is unknown. While synaptotagmins confer the Ca2+ sensitivity of neurotransmitter exocytosis, biochemical measurements reported Ca2+ affinities too low to account for synaptic function. However, synaptotagmin's Ca2+ affinity increases upon binding the plasma membrane phospholipid PI(4,5)P2 and, vice versa, Ca2+-binding increases synaptotagmin's PI(4,5)P2 affinity, indicating a stabilization of the Ca2+/PI(4,5)P2 dual-bound syt. Here we devise a molecular exocytosis model based on this positive allosteric stabilization and the assumptions that (1.) synaptotagmin Ca2+/PI(4,5)P2 dual binding lowers the energy barrier for vesicle fusion and that (2.) the effect of multiple synaptotagmins on the energy barrier is additive. The model, which relies on biochemically measured Ca2+/PI(4,5)P2 affinities and protein copy numbers, reproduced the steep Ca2+ dependency of neurotransmitter release. Our results indicate that each synaptotagmin dual binding Ca2+/PI(4,5)P2 lowers the energy barrier for vesicle fusion by ~5 kBT and that allosteric stabilization of this state enables the synchronized engagement of several (typically three) synaptotagmins for fast exocytosis. Furthermore, we show that mutations altering synaptotagmin’s allosteric properties may show dominant-negative effects, even though synaptotagmins act independently on the energy barrier, and that dynamic changes of local PI(4,5)P2 (e.g. upon vesicle movement) dramatically impact synaptic responses. We conclude that allosterically stabilized Ca2+/PI(4,5)P2 dual binding enables synaptotagmins to exert their coordinated function in neurotransmission.
      PubDate: 2022-08-05T00:00:00Z
      DOI: 10.7554/eLife.74810
       
  • A computational account of why more valuable goals seem to require more
           effortful actions

    • Authors: emmanuelle.bioud@gmail.com (Corentin Tasu, emmanuelle.bioud@gmail.com (Emmanuelle Bioud, emmanuelle.bioud@gmail.com (Mathias Pessiglione
      Abstract: To decide whether a course of action is worth pursuing, individuals typically weigh its expected costs and benefits. Optimal decision-making relies upon accurate effort cost anticipation, which is generally assumed to be performed independently from goal valuation. In two experiments (n = 46), we challenged this independence principle of standard decision theory. We presented participants with a series of treadmill routes randomly associated to monetary rewards and collected both ‘accept’ versus ‘decline’ decisions and subjective estimates of energetic cost. Behavioural results show that higher monetary prospects led participants to provide higher cost estimates, although reward was independent from effort in our design. Among candidate cognitive explanations, they support a model in which prospective cost assessment is biased by the output of an automatic computation adjusting effort expenditure to goal value. This decision bias might lead people to abandon the pursuit of valuable goals that are in fact not so costly to achieve.
      PubDate: 2022-08-05T00:00:00Z
      DOI: 10.7554/eLife.61712
       
  • trim-21 promotes proteasomal degradation of CED-1 for apoptotic cell
           clearance in C. elegans

    • Authors: xiaohui20022008@163.com (Huiru Jing, xiaohui20022008@163.com (Hui Xiao, xiaohui20022008@163.com (Lei Yuan, xiaohui20022008@163.com (Peiyao Li, xiaohui20022008@163.com (Qian Zheng
      Abstract: The phagocytic receptor CED-1 mediates apoptotic cell recognition by phagocytic cells, enabling cell corpse clearance in Caenorhabditis elegans. Whether appropriate levels of CED-1 are maintained for executing the engulfment function remains unknown. Here, we identified the C. elegans E3 ubiquitin ligase tripartite motif containing-21 (TRIM-21) as a component of the CED-1 pathway for apoptotic cell clearance. When the NPXY motif of CED-1 was bound to the adaptor protein CED-6 or the YXXL motif of CED-1 was phosphorylated by tyrosine kinase SRC-1 and subsequently bound to the adaptor protein NCK-1 containing the SH2 domain, TRIM-21 functioned in conjunction with UBC-21 to catalyze K48-linked poly-ubiquitination on CED-1, targeting it for proteasomal degradation. In the absence of TRIM-21, CED-1 accumulated post-translationally and drove cell corpse degradation defects, as evidenced by direct binding to VHA-10. These findings reveal a unique mechanism for the maintenance of appropriate levels of CED-1 to regulate apoptotic cell clearance.
      PubDate: 2022-08-05T00:00:00Z
      DOI: 10.7554/eLife.76436
       
  • Stereotyped behavioral maturation and rhythmic quiescence in
           C.elegans embryos

    • Authors: ardiel@molbio.mgh.harvard.edu (Andrew Lauziere, ardiel@molbio.mgh.harvard.edu (Brandon J Harvey, ardiel@molbio.mgh.harvard.edu (Evan L Ardiel, ardiel@molbio.mgh.harvard.edu (Hari Shroff, ardiel@molbio.mgh.harvard.edu (Joshua M Kaplan, ardiel@molbio.mgh.harvard.edu (Ryan Patrick Christensen, ardiel@molbio.mgh.harvard.edu (Stephen Nurrish, ardiel@molbio.mgh.harvard.edu (Stephen Xu
      Abstract: Systematic analysis of rich behavioral recordings is being used to uncover how circuits encode complex behaviors. Here we apply this approach to embryos. What are the first embryonic behaviors and how do they evolve as early neurodevelopment ensues' To address these questions, we present a systematic description of behavioral maturation for Caenorhabditis elegans embryos. Posture libraries were built using a genetically encoded motion capture suit imaged with light-sheet microscopy and annotated using custom tracking software. Analysis of cell trajectories, postures, and behavioral motifs revealed a stereotyped developmental progression. Early movement is dominated by flipping between dorsal and ventral coiling, which gradually slows into a period of reduced motility. Late-stage embryos exhibit sinusoidal waves of dorsoventral bends, prolonged bouts of directed motion, and a rhythmic pattern of pausing, which we designate slow wave twitch (SWT). Synaptic transmission is required for late-stage motion but not for early flipping nor the intervening inactive phase. A high-throughput behavioral assay and calcium imaging revealed that SWT is elicited by the rhythmic activity of a quiescence-promoting neuron (RIS). Similar periodic quiescent states are seen prenatally in diverse animals and may play an important role in promoting normal developmental outcomes.
      PubDate: 2022-08-05T00:00:00Z
      DOI: 10.7554/eLife.76836
       
  • Septin7 is indispensable for proper skeletal muscle architecture and
           function

    • Authors: csl@edu.unideb.hu (Andrea Telek, csl@edu.unideb.hu (Beatrix Dienes, csl@edu.unideb.hu (Gréta Kis, csl@edu.unideb.hu (György Trencsenyi, csl@edu.unideb.hu (János Fodor, csl@edu.unideb.hu (László Csernoch, csl@edu.unideb.hu (László Szabó, csl@edu.unideb.hu (Miklós Antal, csl@edu.unideb.hu (Mónika Gönczi, csl@edu.unideb.hu (Nóra Dobrosi, csl@edu.unideb.hu (Norbert Balogh, csl@edu.unideb.hu (Péter Szentesi, csl@edu.unideb.hu (Zsolt Ráduly
      Abstract: Today septins are considered as the fourth component of the cytoskeleton, with the Septin7 isoform playing a critical role in the formation of higher-order structures. While its importance has already been confirmed in several intracellular processes of different organs, very little is known about its role in skeletal muscle. Here, using Septin7 conditional knockdown (KD) mouse model, the C2C12 cell line, and enzymatically isolated adult muscle fibers, the organization and localization of septin filaments are revealed, and an ontogenesis-dependent expression of Septin7 is demonstrated. KD mice displayed a characteristic hunchback phenotype with skeletal deformities, reduction in in vivo and in vitro force generation, and disorganized mitochondrial networks. Furthermore, knockout of Septin7 in C2C12 cells resulted in complete loss of cell division while KD cells provided evidence that Septin7 is essential for proper myotube differentiation. These and the transient increase in Septin7 expression following muscle injury suggest that it may be involved in muscle regeneration and development.
      PubDate: 2022-08-05T00:00:00Z
      DOI: 10.7554/eLife.75863
       
  • Poor eyesight reveals a new vision gene

    • Authors: nro@stowers.org (Jaya Krishnan, nro@stowers.org (Nicolas Rohner, nro@stowers.org (Tathagata Biswas
      Abstract: Comparing the genomes of mammals which evolved to have poor vision identifies an important gene for eyesight.
      PubDate: 2022-08-05T00:00:00Z
      DOI: 10.7554/eLife.81520
       
  • An auto-inhibited state of protein kinase G and implications for selective
           activation

    • Authors: kevin.mackenzie@bcm.edu (Banumathi Sankaran, kevin.mackenzie@bcm.edu (Bryan VanSchouwen, kevin.mackenzie@bcm.edu (Choel W Kim, kevin.mackenzie@bcm.edu (Darren E Casteel, kevin.mackenzie@bcm.edu (Fritz W Herberg, kevin.mackenzie@bcm.edu (Giuseppe Melacini, kevin.mackenzie@bcm.edu (Gundeep Kaur, kevin.mackenzie@bcm.edu (Jeong Joo Kim, kevin.mackenzie@bcm.edu (Kevin R MacKenzie, kevin.mackenzie@bcm.edu (Liying Qin, kevin.mackenzie@bcm.edu (Madoka Akimoto, kevin.mackenzie@bcm.edu (Philipp Henning, kevin.mackenzie@bcm.edu (Rajesh Sharma
      Abstract: Cyclic GMP-dependent protein kinases (PKGs) are key mediators of the nitric oxide/cGMP signaling pathway that regulates biological functions as diverse as smooth muscle contraction, cardiac function, and axon guidance. Understanding how cGMP differentially triggers mammalian PKG isoforms could lead to new therapeutics that inhibit or activate PKGs, complementing drugs that target nitric oxide synthases and cyclic nucleotide phosphodiesterases in this signaling axis. Alternate splicing of PRKG1 transcripts confers distinct leucine zippers, linkers, and auto-inhibitory pseudo-substrate sequences to PKG Iα and Iβ that result in isoform-specific activation properties, but the mechanism of enzyme auto-inhibition and its alleviation by cGMP is not well understood. Here we present a crystal structure of PKG Iβ in which the auto-inhibitory sequence and the cyclic nucleotide binding domains are bound to the catalytic domain, providing a snapshot of the auto-inhibited state. Specific contacts between the PKG Iβ auto-inhibitory sequence and the enzyme active site help explain isoform-specific activation constants and the effects of phosphorylation in the linker. We also present a crystal structure of a PKG I cyclic nucleotide binding domain with an activating mutation linked to Thoracic Aortic Aneurysms and Dissections. Similarity of this structure to wild type cGMP-bound domains and differences with the auto-inhibited enzyme provide a mechanistic basis for constitutive activation. We show that PKG Iβ auto-inhibition is mediated by contacts within each monomer of the native full-length dimeric protein, and using the available structural and biochemical data we develop a model for the regulation and cooperative activation of PKGs.
      PubDate: 2022-08-05T00:00:00Z
      DOI: 10.7554/eLife.79530
       
  • The evolution of a counter-defense mechanism in a virus constrains its
           host range

    • Authors: laub@mit.edu (Chantal K Guegler, laub@mit.edu (Michael T Laub, laub@mit.edu (Sriram Srikant
      Abstract: Bacteria use diverse immunity mechanisms to defend themselves against their viral predators, bacteriophages. In turn, phages can acquire counter-defense systems, but it remains unclear how such mechanisms arise and what factors constrain viral evolution. Here, we experimentally evolved T4 phage to overcome a phage-defensive toxin-antitoxin system, toxIN, in E. coli. Through recombination, T4 rapidly acquires segmental amplifications of a previously uncharacterized gene, now named tifA, encoding an inhibitor of the toxin, ToxN. These amplifications subsequently drive large deletions elsewhere in T4's genome to maintain a genome size compatible with capsid packaging. The deleted regions include accessory genes that help T4 overcome defense systems in alternative hosts. Thus, our results reveal a trade-off in viral evolution; the emergence of one counter-defense mechanism can lead to loss of other such mechanisms, thereby constraining host range. We propose that the accessory genomes of viruses reflect the integrated evolutionary history of the hosts they infected.
      PubDate: 2022-08-04T00:00:00Z
      DOI: 10.7554/eLife.79549
       
  • Coupling to short linear motifs creates versatile PME-1 activities in PP2A
           holoenzyme demethylation and inhibition

    • Authors: xing@oncology.wisc.edu (Anastasia Phoebe Bravos, xing@oncology.wisc.edu (Cheng-Guo Wu, xing@oncology.wisc.edu (Irina V Novikova, xing@oncology.wisc.edu (Michael Rowse, xing@oncology.wisc.edu (Stefan Strack, xing@oncology.wisc.edu (Vijaya Kumar Balakrishnan, xing@oncology.wisc.edu (Vikash K Yadav, xing@oncology.wisc.edu (Yitong Li, xing@oncology.wisc.edu (YIva Ivarsson, xing@oncology.wisc.edu (Yongna Xing
      Abstract: Protein phosphatase 2A (PP2A) holoenzymes target broad substrates by recognizing short motifs via regulatory subunits. PP2A methylesterase 1 (PME-1) is a cancer-promoting enzyme and undergoes methylesterase activation upon binding to the PP2A core enzyme. Here we showed that PME-1 readily demethylates different families of PP2A holoenzymes and blocks substrate recognition in vitro. The high-resolution cryo-EM structure of a PP2A-B56 holoenzyme-PME-1 complex reveals that PME-1 disordered regions, including a substrate-mimicking motif, tether to the B56 regulatory subunit at remote sites. They occupy the holoenzyme substrate-binding groove and allow large structural shifts in both holoenzyme and PME-1 to enable multi-partite contacts at structured cores to activate the methylesterase. B56-interface mutations selectively block PME-1 activity toward PP2A-B56 holoenzymes and affect the methylation of a fraction of total cellular PP2A. The B56-interface mutations allow us to uncover B56-specific PME-1 functions in p53 signaling. Our studies reveal multiple mechanisms of PME-1 in suppressing holoenzyme functions and versatile PME-1 activities derived from coupling substrate-mimicking motifs to dynamic structured cores.
      PubDate: 2022-08-04T00:00:00Z
      DOI: 10.7554/eLife.79736
       
  • Expansion and contraction of resource allocation in sensory bottlenecks

    • Authors: h.saal@sheffield.ac.uk (Alejandro Jiménez Rodríguez, h.saal@sheffield.ac.uk (Hannes P Saal, h.saal@sheffield.ac.uk (Laura R Edmondson
      Abstract: Topographic sensory representations often do not scale proportionally to the size of their input regions, with some expanded and others contracted. In vision, the foveal representation is magnified cortically, as are the fingertips in touch. What principles drive this allocation, and how should receptor density, e.g. the high innervation of the fovea or the fingertips, and stimulus statistics, e.g. the higher contact frequencies on the fingertips, contribute' Building on work in efficient coding, we address this problem using linear models that optimally decorrelate the sensory signals. We introduce a sensory bottleneck to impose constraints on resource allocation and derive the optimal neural allocation. We find that bottleneck width is a crucial factor in resource allocation, inducing either expansion or contraction. Both receptor density and stimulus statistics affect allocation and jointly determine convergence for wider bottlenecks. Furthermore, we show a close match between the predicted and empirical cortical allocations in a well-studied model system, the star-nosed mole. Overall, our results suggest that the strength of cortical magnification depends on resource limits.
      PubDate: 2022-08-04T00:00:00Z
      DOI: 10.7554/eLife.70777
       
  • Modular, cascade-like transcriptional program of regeneration in
           Stentor

    • Authors: wallace.marshall@ucsf.edu (Ambika Nadkarni, wallace.marshall@ucsf.edu (Athena Lin, wallace.marshall@ucsf.edu (Connie Yan, wallace.marshall@ucsf.edu (Pranidhi Sood, wallace.marshall@ucsf.edu (Rebecca McGillivary, wallace.marshall@ucsf.edu (Sindy KY Tang, wallace.marshall@ucsf.edu (Tatyana Makushok, wallace.marshall@ucsf.edu (Ulises Diaz, wallace.marshall@ucsf.edu (Wallace F Marshall
      Abstract: The giant ciliate Stentor coeruleus is a classical model system for studying regeneration and morphogenesis at the level of a single cell. The anterior of the cell is marked by an array of cilia, known as the oral apparatus, which can be induced to shed and regenerate in a series of reproducible morphological steps, previously shown to require transcription. If a cell is cut in half, each half will regenerate an intact cell, including a new oral apparatus in the posterior half. We used RNAseq to assay the dynamic changes in Stentor's transcriptome during regeneration, after both oral apparatus shedding and bisection, allowing us to identify distinct temporal waves of gene expression including kinases, RNA binding proteins, centriole biogenesis factors, and orthologs of human ciliopathy genes implicated in Meckel and Joubert syndromes. By comparing transcriptional profiles of different regeneration events in the same species, we were able to identify distinct modules of gene expression corresponding to oral apparatus regeneration, posterior holdfast regeneration, and recovery after wounding. By measuring gene expression in cells in which translation is blocked, we show that the sequential waves of gene expression involve a cascade mechanism in which later waves of expression are triggered by translation products of early-expressed genes. Among the early-expressed genes, we identified an E2F transcription factor and the conserved RNA binding protein Pumilio as potential regulators of regeneration based on the expression pattern of their predicted target genes. RNAi mediated knockdown experiments indicate that Pumilio is required for regenerating oral structures of the correct size. We show that E2F is involved in the completion of regeneration but is dispensable for earlier steps. This work allows us to classify regeneration genes into groups based on their potential role for regeneration in distinct cell regeneration paradigms, and provides insight into how a single cell can coordinate complex morphogenetic pathways to regenerate missing structures.
      PubDate: 2022-08-04T00:00:00Z
      DOI: 10.7554/eLife.80778
       
  • Structural motifs for subtype-specific pH-sensitive gating of vertebrate
           otopetrin proton channels

    • Authors: liman@usc.edu (Andrew B Ward, liman@usc.edu (Batuujin Burendei, liman@usc.edu (Bochuan Teng, liman@usc.edu (Emily R Liman, liman@usc.edu (Joshua P Kaplan, liman@usc.edu (Yu-Hsiang Tu, liman@usc.edu (Zachary Krieger, liman@usc.edu (Ziyu Liang
      Abstract: Otopetrin (OTOP) channels are proton-selective ion channels conserved among vertebrates and invertebrates, with no structural similarity to other ion channels. There are three vertebrate OTOP channels (OTOP1, OTOP2, and OTOP3), of which one (OTOP1) functions as a sour taste receptor. Whether extracellular protons gate OTOP channels, in addition to permeating them, was not known. Here, we compare the functional properties of the three murine OTOP channels using patch-clamp recording and cytosolic pH microfluorimetry. We find that OTOP1 and OTOP3 are both steeply activated by extracellular protons, with thresholds of pHo <6.0 and 5.5, respectively, and kinetics that are pH-dependent. In contrast, OTOP2 channels are broadly active over a large pH range (pH 5 pH 10) and carry outward currents in response to extracellular alkalinization (>pH 9.0). Strikingly, we could change the pH-sensitive gating of OTOP2 and OTOP3 channels by swapping extracellular linkers that connect transmembrane domains. Swaps of extracellular linkers in the N domain, comprising transmembrane domains 1–6, tended to change the relative conductance at alkaline pH of chimeric channels, while swaps within the C domain, containing transmembrane domains 7–12, tended to change the rates of OTOP3 current activation. We conclude that members of the OTOP channel family are proton-gated (acid-sensitive) proton channels and that the gating apparatus is distributed across multiple extracellular regions within both the N and C domains of the channels. In addition to the taste system, OTOP channels are expressed in the vertebrate vestibular and digestive systems. The distinct gating properties we describe may allow them to subserve varying cell-type specific functions in these and other biological systems.
      PubDate: 2022-08-03T00:00:00Z
      DOI: 10.7554/eLife.77946
       
  • Multiple UBX proteins reduce the ubiquitin threshold of the mammalian
           p97-UFD1-NPL4 unfoldase

    • Authors: kpmlabib@dundee.ac.uk (Cristian Polo Rivera, kpmlabib@dundee.ac.uk (Karim Labib, kpmlabib@dundee.ac.uk (Ryo Fujisawa
      Abstract: The p97 / Cdc48 ATPase and its ubiquitin receptors Ufd1-Npl4 are essential to unfold ubiquitylated proteins in many areas of eukaryotic cell biology. In yeast, Cdc48-Ufd1-Npl4 is controlled by a quality control mechanism, whereby substrates must be conjugated to at least five ubiquitins. Here we show that mammalian p97-UFD1-NPL4 is governed by a complex interplay between additional p97 cofactors and the number of conjugated ubiquitins. Using reconstituted assays for the disassembly of ubiquitylated CMG (Cdc45-MCM-GINS) helicase by human p97-UFD1-NPL4, we show that the unfoldase has a high ubiquitin threshold for substrate unfolding, which can be reduced by the UBX proteins UBXN7, FAF1 or FAF2. Our data indicate that the UBX proteins function by binding to p97-UFD1-NPL4 and stabilising productive interactions between UFD1-NPL4 and K48-linked chains of at least five ubiquitins. Stimulation by UBXN7 is dependent upon known ubiquitin binding motifs, whereas FAF1 and FAF2 use a previously uncharacterised coiled-coil domain to reduce the ubiquitin threshold of p97-UFD1-NPL4. We show that deleting the Ubnx7 and Faf1 genes impairs CMG disassembly during S-phase and mitosis and sensitises cells to reduced ubiquitin ligase activity. These findings indicate that multiple UBX proteins are important for the efficient unfolding of ubiquitylated proteins by p97-UFD1-NPL4 in mammalian cells.
      PubDate: 2022-08-03T00:00:00Z
      DOI: 10.7554/eLife.76763
       
  • Maintaining naivety of T cells

    • Authors: Ken.Duffy@mu.ie (Ken Duffy
      Abstract: Mathematical models encoding biological hypotheses reveal new insight into the dynamics of naive immune cells in mice from birth to old age.
      PubDate: 2022-08-03T00:00:00Z
      DOI: 10.7554/eLife.81077
       
  • Maternal H3K36 and H3K27 HMTs protect germline development via regulation
           of the transcription factor LIN-15B

    • Authors: sstrome@ucsc.edu (Chad Steven Cockrum, sstrome@ucsc.edu (Susan Strome
      Abstract: Maternally synthesized products play critical roles in the development of offspring. A premier example is the Caenorhabditis elegans H3K36 methyltransferase MES-4, which is essential for germline survival and development in offspring. How maternal MES-4 protects the germline is not well understood, but its role in H3K36 methylation hinted that it may regulate gene expression in primordial germ cells (PGCs). We tested this hypothesis by profiling transcripts from nascent germlines (PGCs and their descendants) dissected from wild-type and mes-4 mutant (lacking maternal and zygotic MES-4) larvae. mes-4 nascent germlines displayed downregulation of some germline genes, upregulation of some somatic genes, and dramatic upregulation of hundreds of genes on the X chromosome. We demonstrated that upregulation of one or more genes on the X is the cause of germline death by generating and analyzing mes-4 mutants that inherited different endowments of X chromosome(s). Intriguingly, removal of the THAP transcription factor LIN-15B from mes-4 mutants reduced X misexpression and prevented germline death. lin-15B is X-linked and misexpressed in mes-4 PGCs, identifying it as a critical target for MES-4 repression. The above findings extend to the H3K27 methyltransferase MES-2/3/6, the C. elegans version of polycomb repressive complex 2. We propose that maternal MES-4 and PRC2 cooperate to protect germline survival by preventing synthesis of germline-toxic products encoded by genes on the X chromosome, including the key transcription factor LIN-15B.
      PubDate: 2022-08-03T00:00:00Z
      DOI: 10.7554/eLife.77951
       
  • Full spectrum flow cytometry reveals mesenchymal heterogeneity in first
           trimester placentae and phenotypic convergence in culture, providing
           insight into the origins of placental mesenchymal stromal cells

    • Authors: a.boss@auckland.ac.nz (Anna ES Brooks, a.boss@auckland.ac.nz (Anna Leabourn Boss, a.boss@auckland.ac.nz (Jo L James, a.boss@auckland.ac.nz (Larry W Chamley, a.boss@auckland.ac.nz (Tanvi Damani, a.boss@auckland.ac.nz (Tayla J Wickman
      Abstract: Single-cell technologies (RNA-sequencing, flow cytometry) are critical tools to reveal how cell heterogeneity impacts developmental pathways. The placenta is a fetal exchange organ, containing a heterogeneous mix of mesenchymal cells (fibroblasts, myofibroblasts, perivascular, and progenitor cells) . Placental mesenchymal stromal cells (pMSC) are also routinely isolated, for therapeutic and research purposes. However, our understanding of the diverse phenotypes of placental mesenchymal lineages, and their relationships remain unclear. We designed a 23-colour flow cytometry panel to assess mesenchymal heterogeneity in first-trimester human placentae. . Four distinct mesenchymal subsets were identified; CD73+CD90+ mesenchymal cells, CD146+CD271+ perivascular cells, podoplanin+CD36+ stromal cells, and CD26+CD90+ myofibroblasts. CD73+CD90+ and podoplanin+CD36+ cells expressed markers consistent with cultured pMSCs, and were explored further. Despite their distinct ex-vivo phenotype, in culture CD73+CD90+ cells and podoplanin+CD36+ cells underwent phenotypic convergence, losing CD271 or CD36 expression respectively, and homogenously exhibiting a basic MSC phenotype (CD73+CD90+CD31-CD144-CD45-). However, some markers (CD26, CD146) were not impacted, or differentially impacted by culture in different populations. Comparisons of cultured phenotypes to pMSCs further suggested cultured pMSCs originate from podoplanin+CD36+ cells. This highlights the importance of detailed cell phenotyping to optimise therapeutic capacity, and ensure use of relevant cells in functional assays.
      PubDate: 2022-08-03T00:00:00Z
      DOI: 10.7554/eLife.76622
       
  • Hematopoietic plasticity mapped in Drosophila and other insects

    • Authors: dan.hultmark@ucmp.umu.se (Dan Hultmark, dan.hultmark@ucmp.umu.se (István Andó
      Abstract: Hemocytes, similar to vertebrate blood cells, play important roles in insect development and immunity, but it is not well understood how they perform their tasks. New technology, in particular single-cell transcriptomic analysis in combination with Drosophila genetics, may now change this picture. This review aims to make sense of recently published data, focusing on Drosophila melanogaster and comparing to data from other drosophilids, the malaria mosquito, Anopheles gambiae, and the silkworm, Bombyx mori. Basically, the new data support the presence of a few major classes of hemocytes: (1) a highly heterogenous and plastic class of professional phagocytes with many functions, called plasmatocytes in Drosophila and granular cells in other insects. (2) A conserved class of cells that control melanin deposition around parasites and wounds, called crystal cells in D. melanogaster, and oenocytoids in other insects. (3) A new class of cells, the primocytes, so far only identified in D. melanogaster. They are related to cells of the so-called posterior signaling center of the larval hematopoietic organ, which controls the hematopoiesis of other hemocytes. (4) Different kinds of specialized cells, like the lamellocytes in D. melanogaster, for the encapsulation of parasites. These cells undergo rapid evolution, and the homology relationships between such cells in different insects are uncertain. Lists of genes expressed in the different hemocyte classes now provide a solid ground for further investigation of function.
      PubDate: 2022-08-03T00:00:00Z
      DOI: 10.7554/eLife.78906
       
  • Robust and Efficient Assessment of Potency (REAP) as a quantitative tool
           for dose-response curve estimation

    • Authors: shouhao.zhou@psu.edu (Chan Shen, shouhao.zhou@psu.edu (Hong-Gang Wang, shouhao.zhou@psu.edu (J Jack Lee, shouhao.zhou@psu.edu (Michael Wang, shouhao.zhou@psu.edu (Nikolay V Dokholyan, shouhao.zhou@psu.edu (Shouhao Zhou, shouhao.zhou@psu.edu (Vernon M Chinchilli, shouhao.zhou@psu.edu (Xinyi Liu, shouhao.zhou@psu.edu (Xinying Fang
      Abstract: The median-effect equation has been widely used to describe the dose-response relationship and identify compounds that activate or inhibit specific disease targets in contemporary drug discovery. However, the experimental data often contain extreme responses, which may significantly impair the estimation accuracy and impede valid quantitative assessment in the standard estimation procedure. To improve the quantitative estimation of the dose-response relationship, we introduce a novel approach based on robust beta regression. Substantive simulation studies under various scenarios demonstrate solid evidence that the proposed approach consistently provides robust estimation for the median-effect equation, particularly when there are extreme outcome observations. Moreover, simulation studies illustrate that the proposed approach also provides a narrower confidence interval, suggesting a higher power in statistical testing. Finally, to efficiently and conveniently perform common lab data analyses, we develop a freely accessible web-based analytic tool to facilitate the quantitative implementation of the proposed approach for the scientific community.
      PubDate: 2022-08-03T00:00:00Z
      DOI: 10.7554/eLife.78634
       
  • Genomic evidence for global ocean plankton biogeography shaped by
           large-scale current systems

    • Authors: vargas@sb-roscoff.fr (Antonio Fernàndez-Guerra, vargas@sb-roscoff.fr (Cédric Berney, vargas@sb-roscoff.fr (Céline Dimier, vargas@sb-roscoff.fr (Chris Bowler, vargas@sb-roscoff.fr (Claire Lemaitre, vargas@sb-roscoff.fr (Colomban de Vargas, vargas@sb-roscoff.fr (Damien Eveillard, vargas@sb-roscoff.fr (Daniele Iudicone, vargas@sb-roscoff.fr (Daniel J Richter, vargas@sb-roscoff.fr (Eric Karsenti, vargas@sb-roscoff.fr (Eric Mahieu, vargas@sb-roscoff.fr (Eric Pelletier, vargas@sb-roscoff.fr (Fabien Lombard, vargas@sb-roscoff.fr (Frederick Gavory, vargas@sb-roscoff.fr (Gabriel Reygondeau, vargas@sb-roscoff.fr (Gaëtan Benoit, vargas@sb-roscoff.fr (Ian Probert, vargas@sb-roscoff.fr (Jade Leconte, vargas@sb-roscoff.fr (Jean-Marc Aury, vargas@sb-roscoff.fr (Jennifer R Brum, vargas@sb-roscoff.fr (Julie Poulain, vargas@sb-roscoff.fr (Karine Labadie, vargas@sb-roscoff.fr (Lee Karp-Boss, vargas@sb-roscoff.fr (Lionel Guidi, vargas@sb-roscoff.fr (Mahendra Mariadassou, vargas@sb-roscoff.fr (Marc Picheral, vargas@sb-roscoff.fr (Matthew B Sullivan, vargas@sb-roscoff.fr (Maurizio Ribera d'Alcalà, vargas@sb-roscoff.fr (Nicolas Henry, vargas@sb-roscoff.fr (Nicolas Maillet, vargas@sb-roscoff.fr (Olivier Jaillon, vargas@sb-roscoff.fr (Ophélie Da Silva, vargas@sb-roscoff.fr (Patrick Wincker, vargas@sb-roscoff.fr (Paul Frémont, vargas@sb-roscoff.fr (Peer Bork, vargas@sb-roscoff.fr (Pierre Peterlongo, vargas@sb-roscoff.fr (Romain Narci, vargas@sb-roscoff.fr (Romain Watteaux, vargas@sb-roscoff.fr (Samir Suweis, vargas@sb-roscoff.fr (Sarah Romac, vargas@sb-roscoff.fr (Sarah Searson, vargas@sb-roscoff.fr (Shinichi Sunagawa, vargas@sb-roscoff.fr (Simon Roux, vargas@sb-roscoff.fr (Stefanie Kandels, vargas@sb-roscoff.fr (Stéphane Pesant, vargas@sb-roscoff.fr (Thomas Vannier, vargas@sb-roscoff.fr (Tom O Delmont
      Abstract: Biogeographical studies have traditionally focused on readily visible organisms, but recent technological advances are enabling analyses of the large-scale distribution of microscopic organisms, whose biogeographical patterns have long been debated. Here we assessed the global structure of plankton geography and its relation to the biological, chemical, and physical context of the ocean (the ‘seascape’) by analyzing metagenomes of plankton communities sampled across oceans during the Tara Oceans expedition, in light of environmental data and ocean current transport. Using a consistent approach across organismal sizes that provides unprecedented resolution to measure changes in genomic composition between communities, we report a pan-ocean, size-dependent plankton biogeography overlying regional heterogeneity. We found robust evidence for a basin-scale impact of transport by ocean currents on plankton biogeography, and on a characteristic timescale of community dynamics going beyond simple seasonality or life history transitions of plankton.
      PubDate: 2022-08-03T00:00:00Z
      DOI: 10.7554/eLife.78129
       
  • Estimating the potential to prevent locally acquired HIV infections in a
           UNAIDS Fast-Track City, Amsterdam

    • Authors: a.blenkinsop@imperial.ac.uk (Alexandra Blenkinsop, a.blenkinsop@imperial.ac.uk (Ard van Sighem, a.blenkinsop@imperial.ac.uk (Christophe Fraser, a.blenkinsop@imperial.ac.uk (Daniela Bezemer, a.blenkinsop@imperial.ac.uk (Eline Op de Coul, a.blenkinsop@imperial.ac.uk (Godelieve J de Bree, a.blenkinsop@imperial.ac.uk (Maria Prins, a.blenkinsop@imperial.ac.uk (Mélodie Monod, a.blenkinsop@imperial.ac.uk (Nikos Pantazis, a.blenkinsop@imperial.ac.uk (Oliver Ratmann, a.blenkinsop@imperial.ac.uk (Peter Reiss, a.blenkinsop@imperial.ac.uk (Thijs van de Laar
      Abstract: Background: More than 300 cities including the city of Amsterdam in the Netherlands have joined the UNAIDS Fast-Track Cities initiative, committing to accelerate their HIV response and end the AIDS epidemic in cities by 2030. To support this commitment, we aimed to estimate the number and proportion of Amsterdam HIV infections that originated within the city, from Amsterdam residents. We also aimed to estimate the proportion of recent HIV infections during the 5-year period 2014-2018 in Amsterdam that remained undiagnosed.
      PubDate: 2022-08-03T00:00:00Z
      DOI: 10.7554/eLife.76487
       
 
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