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The founder hypothesis: A basis for microbiota resistance, diversity in taxa carriage, and colonization resistance against pathogens

by Yael Litvak, Andreas J. Bäumler

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Correction: Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naïve B cells, and facilitates recruitment of transcription factors to the viral genome

by Agnieszka Szymula, Richard D. Palermo, Amr Bayoumy, Ian J. Groves, Mohammed Ba abdullah, Beth Holder, Robert E. White

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Reticulate evolution in eukaryotes: Origin and evolution of the nitrate assimilation pathway

by Eduard Ocaña-Pallarès, Sebastián R. Najle, Claudio Scazzocchio, Iñaki Ruiz-Trillo

Genes and genomes can evolve through interchanging genetic material, this leading to reticular evolutionary patterns. However, the importance of reticulate evolution in eukaryotes, and in particular of horizontal gene transfer (HGT), remains controversial. Given that metabolic pathways with taxonomically-patchy distributions can be indicative of HGT events, the eukaryotic nitrate assimilation pathway is an ideal object of investigation, as previous results revealed a patchy distribution and suggested that the nitrate assimilation cluster of dikaryotic fungi (Opisthokonta) could have been originated and transferred from a lineage leading to Oomycota (Stramenopiles). We studied the origin and evolution of this pathway through both multi-scale bioinformatic and experimental approaches. Our taxon-rich genomic screening shows that nitrate assimilation is present in more lineages than previously reported, although being restricted to autotrophs and osmotrophs. The phylogenies indicate a pervasive role of HGT, with three bacterial transfers contributing to the pathway origin, and at least seven well-supported transfers between eukaryotes. In particular, we propose a distinct and more complex HGT path between Opisthokonta and Stramenopiles than the one previously suggested, involving at least two transfers of a nitrate assimilation gene cluster. We also found that gene fusion played an essential role in this evolutionary history, underlying the origin of the canonical eukaryotic nitrate reductase, and of a chimeric nitrate reductase in Ichthyosporea (Opisthokonta). We show that the ichthyosporean pathway, including this novel nitrate reductase, is physiologically active and transcriptionally co-regulated, responding to different nitrogen sources; similarly to distant eukaryotes with independent HGT-acquisitions of the pathway. This indicates that this pattern of transcriptional control evolved convergently in eukaryotes, favoring the proper integration of the pathway in the metabolic landscape. Our results highlight the importance of reticulate evolution in eukaryotes, by showing the crucial contribution of HGT and gene fusion in the evolutionary history of the nitrate assimilation pathway.

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Prolyl isomerization of FAAP20 catalyzed by PIN1 regulates the Fanconi anemia pathway

by Jingming Wang, Bryan Chan, Michael Tong, YiTing Paung, Ukhyun Jo, Dwight Martin, Markus Seeliger, John Haley, Hyungjin Kim

The Fanconi Anemia (FA) pathway is a multi-step DNA repair process at stalled replication forks in response to DNA interstrand cross-links (ICLs). Pathological mutation of key FA genes leads to the inherited disorder FA, characterized by progressive bone marrow failure and cancer predisposition. The study of FA is of great importance not only to children suffering from FA but also as a model to study cancer pathogenesis in light of genome instability among the general population. FANCD2 monoubiquitination by the FA core complex is an essential gateway that connects upstream DNA damage signaling to enzymatic steps of repair. FAAP20 is a key component of the FA core complex, and regulated proteolysis of FAAP20 mediated by the ubiquitin E3 ligase SCFFBW7 is critical for maintaining the integrity of the FA complex and FA pathway signaling. However, upstream regulatory mechanisms that govern this signaling remain unclear. Here, we show that PIN1, a phosphorylation-specific prolyl isomerase, regulates the integrity of the FA core complex, thus FA pathway activation. We demonstrate that PIN1 catalyzes cis-trans isomerization of the FAAP20 pSer48-Pro49 motif and promotes FAAP20 stability. Mechanistically, PIN1-induced conformational change of FAAP20 enhances its interaction with the PP2A phosphatase to counteract SCFFBW7-dependent proteolytic signaling at the phosphorylated degron motif. Accordingly, PIN1 deficiency impairs FANCD2 activation and the DNA ICL repair process. Together, our study establishes PIN1-dependent prolyl isomerization as a new regulator of the FA pathway and genomic integrity.

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VGLL4 plays a critical role in heart valve development and homeostasis

by Wei Yu, Xueyan Ma, Jinjin Xu, Andreas Wilhelm Heumüller, Zhaoliang Fei, Xue Feng, Xiaodong Wang, Kuo Liu, Jinhui Li, Guizhong Cui, Guangdun Peng, Hongbin Ji, Jinsong Li, Naihe Jing, Hai Song, Zhiqiang Lin, Yun Zhao, Zuoyun Wang, Bin Zhou, Lei Zhang

Heart valve disease is a major clinical problem worldwide. Cardiac valve development and homeostasis need to be precisely controlled. Hippo signaling is essential for organ development and tissue homeostasis, while its role in valve formation and morphology maintenance remains unknown. VGLL4 is a transcription cofactor in vertebrates and we found it was mainly expressed in valve interstitial cells at the post-EMT stage and was maintained till the adult stage. Tissue specific knockout of VGLL4 in different cell lineages revealed that only loss of VGLL4 in endothelial cell lineage led to valve malformation with expanded expression of YAP targets. We further semi-knockout YAP in VGLL4 ablated hearts, and found hyper proliferation of arterial valve interstitial cells was significantly constrained. These findings suggest that VGLL4 is important for valve development and manipulation of Hippo components would be a potential therapy for preventing the progression of congenital valve disease.

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Global transcriptional regulation of innate immunity by ATF-7 in <i>C</i>. <i>elegans</i>

by Marissa Fletcher, Erik J. Tillman, Vincent L. Butty, Stuart S. Levine, Dennis H. Kim

The nematode Caenorhabditis elegans has emerged as a genetically tractable animal host in which to study evolutionarily conserved mechanisms of innate immune signaling. We previously showed that the PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway regulates innate immunity of C. elegans through phosphorylation of the CREB/ATF bZIP transcription factor, ATF-7. Here, we have undertaken a genomic analysis of the transcriptional response of C. elegans to infection by Pseudomonas aeruginosa, combining genome-wide expression analysis by RNA-seq with ATF-7 chromatin immunoprecipitation followed by sequencing (ChIP-Seq). We observe that PMK-1-ATF-7 activity regulates a majority of all genes induced by pathogen infection, and observe ATF-7 occupancy in regulatory regions of pathogen-induced genes in a PMK-1-dependent manner. Moreover, functional analysis of a subset of these ATF-7-regulated pathogen-induced target genes supports a direct role for this transcriptional response in host defense. The genome-wide regulation through PMK-1– ATF-7 signaling reveals a striking level of control over the innate immune response to infection through a single transcriptional regulator.

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Independent working memory resources for egocentric and allocentric spatial information

by David Aagten-Murphy, Paul M. Bays

Visuospatial working memory enables us to maintain access to visual information for processing even when a stimulus is no longer present, due to occlusion, our own movements, or transience of the stimulus. Here we show that, when localizing remembered stimuli, the precision of spatial recall does not rely solely on memory for individual stimuli, but additionally depends on the relative distances between stimuli and visual landmarks in the surroundings. Across three separate experiments, we consistently observed a spatially selective improvement in the precision of recall for items located near a persistent landmark. While the results did not require that the landmark be visible throughout the memory delay period, it was essential that it was visible both during encoding and response. We present a simple model that can accurately capture human performance by considering relative (allocentric) spatial information as an independent localization estimate which degrades with distance and is optimally integrated with egocentric spatial information. Critically, allocentric information was encoded without cost to egocentric estimation, demonstrating independent storage of the two sources of information. Finally, when egocentric and allocentric estimates were put in conflict, the model successfully predicted the resulting localization errors. We suggest that the relative distance between stimuli represents an additional, independent spatial cue for memory recall. This cue information is likely to be critical for spatial localization in natural settings which contain an abundance of visual landmarks.

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COSMOS-E: Guidance on conducting systematic reviews and meta-analyses of observational studies of etiology

by Olaf M. Dekkers, Jan P. Vandenbroucke, Myriam Cevallos, Andrew G. Renehan, Douglas G. Altman, Matthias Egger

Background

To our knowledge, no publication providing overarching guidance on the conduct of systematic reviews of observational studies of etiology exists.

Methods and findings

Conducting Systematic Reviews and Meta-Analyses of Observational Studies of Etiology (COSMOS-E) provides guidance on all steps in systematic reviews of observational studies of etiology, from shaping the research question, defining exposure and outcomes, to assessing the risk of bias and statistical analysis. The writing group included researchers experienced in meta-analyses and observational studies of etiology. Standard peer-review was performed. While the structure of systematic reviews of observational studies on etiology may be similar to that for systematic reviews of randomised controlled trials, there are specific tasks within each component that differ. Examples include assessment for confounding, selection bias, and information bias. In systematic reviews of observational studies of etiology, combining studies in meta-analysis may lead to more precise estimates, but such greater precision does not automatically remedy potential bias. Thorough exploration of sources of heterogeneity is key when assessing the validity of estimates and causality.

Conclusion

As many reviews of observational studies on etiology are being performed, this document may provide researchers with guidance on how to conduct and analyse such reviews.

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Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen

by Fabian Sesterhenn, Marie Galloux, Sabrina S. Vollers, Lucia Csepregi, Che Yang, Delphyne Descamps, Jaume Bonet, Simon Friedensohn, Pablo Gainza, Patricia Corthésy, Man Chen, Stéphane Rosset, Marie-Anne Rameix-Welti, Jean-François Éléouët, Sai T. Reddy, Barney S. Graham, Sabine Riffault, Bruno E. Correia

Throughout the last several decades, vaccination has been key to prevent and eradicate infectious diseases. However, many pathogens (e.g., respiratory syncytial virus [RSV], influenza, dengue, and others) have resisted vaccine development efforts, largely because of the failure to induce potent antibody responses targeting conserved epitopes. Deep profiling of human B cells often reveals potent neutralizing antibodies that emerge from natural infection, but these specificities are generally subdominant (i.e., are present in low titers). A major challenge for next-generation vaccines is to overcome established immunodominance hierarchies and focus antibody responses on crucial neutralization epitopes. Here, we show that a computationally designed epitope-focused immunogen presenting a single RSV neutralization epitope elicits superior epitope-specific responses compared to the viral fusion protein. In addition, the epitope-focused immunogen efficiently boosts antibodies targeting the palivizumab epitope, resulting in enhanced neutralization. Overall, we show that epitope-focused immunogens can boost subdominant neutralizing antibody responses in vivo and reshape established antibody hierarchies.

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Correction: Heterochromatin delays CRISPR-Cas9 mutagenesis but does not influence the outcome of mutagenic DNA repair

by The PLOS Biology Staff

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