Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (Tregs) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in Treg responses to OMVs. We propose that polymorphisms in susceptibility genes promote disease through defects in “sensing” protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD.
Authors: Hiutung Chu, Arya Khosravi, Indah P. Kusumawardhani, Alice H. K. Kwon, Anilton C. Vasconcelos, Larissa D. Cunha, Anne E. Mayer, Yue Shen, Wei-Li Wu, Amal Kambal, Stephan R. Targan, Ramnik J. Xavier, Peter B. Ernst, Douglas R. Green, Dermot P. B. McGovern, Herbert W. Virgin, Sarkis K. Mazmanian
Error-free genome duplication and segregation are ensured through the timely activation of ubiquitylation enzymes. The anaphase-promoting complex or cyclosome (APC/C), a multisubunit E3 ubiquitin ligase, is regulated by phosphorylation. However, the mechanism remains elusive. Using systematic reconstitution and analysis of vertebrate APC/Cs under physiological conditions, we show how cyclin-dependent kinase 1 (CDK1) activates the APC/C through coordinated phosphorylation between Apc3 and Apc1. Phosphorylation of the loop domains by CDK1 in complex with p9/Cks2 (a CDK regulatory subunit) controlled loading of coactivator Cdc20 onto APC/C. A phosphomimetic mutation introduced into Apc1 allowed Cdc20 to increase APC/C activity in interphase. These results define a previously unrecognized subunit-subunit communication over a distance and the functional consequences of CDK phosphorylation. Cdc20 is a potential therapeutic target, and our findings may facilitate the development of specific inhibitors.
Authors: Kazuyuki Fujimitsu, Margaret Grimaldi, Hiroyuki Yamano
The position and orientation of the mitotic spindle is precisely regulated to ensure the accurate partition of the cytoplasm between daughter cells and the correct localization of the daughters within growing tissue. Using magnetic tweezers to perturb the position of the spindle in intact cells, we discovered a force-generating machinery that maintains the spindle at the cell center during metaphase and anaphase in one- and two-cell Caenorhabditis elegans embryos. The forces increase with the number of microtubules and are larger in smaller cells. The machinery is rigid enough to suppress thermal fluctuations to ensure precise localization of the mitotic spindle, yet compliant enough to allow molecular force generators to fine-tune the position of the mitotic spindle to facilitate asymmetric division.
Authors: Carlos Garzon-Coral, Horatiu A. Fantana, Jonathon Howard
A weekly roundup of information on newly offered instrumentation, apparatus, and laboratory materials of potential interest to researchers.
It is notable that the same pathways governing the cell growth, death, and differentiation decisions made during embryonic development are also common drivers of adult malignancy. In this webinar, we will explore the idea that a better understanding of developmental biology signaling pathways will advance our understanding of adult tumors and cancer stem cells as well as boost our ability to create effective therapeutics to fight a broad array of cancers.View the Webinar
Authors: Elaine Fuchs, Benjamin L. Allen, Rik Derynck
Author: Michael J. Orsini
Ninety percent of lignocellulose-degrading fungi contain genes encoding lytic polysaccharide monooxygenases (LPMOs). These enzymes catalyze the initial oxidative cleavage of recalcitrant polysaccharides after activation by an electron donor. Understanding the source of electrons is fundamental to fungal physiology and will also help with the exploitation of LPMOs for biomass processing. Using genome data and biochemical methods, we characterized and compared different extracellular electron sources for LPMOs: cellobiose dehydrogenase, phenols procured from plant biomass or produced by fungi, and glucose-methanol-choline oxidoreductases that regenerate LPMO-reducing diphenols. Our data demonstrate that all three of these electron transfer systems are functional and that their relative importance during cellulose degradation depends on fungal lifestyle. The availability of extracellular electron donors is required to activate fungal oxidative attack on polysaccharides.
Authors: Daniel Kracher, Stefan Scheiblbrandner, Alfons K. G. Felice, Erik Breslmayr, Marita Preims, Karolina Ludwicka, Dietmar Haltrich, Vincent G. H. Eijsink, Roland Ludwig
Metal acquisition is a vital microbial process in metal-scarce environments, such as inside a host. Using metabolomic exploration, targeted mutagenesis, and biochemical analysis, we discovered an operon in Staphylococcus aureus that encodes the different functions required for the biosynthesis and trafficking of a broad-spectrum metallophore related to plant nicotianamine (here called staphylopine). The biosynthesis of staphylopine reveals the association of three enzyme activities: a histidine racemase, an enzyme distantly related to nicotianamine synthase, and a staphylopine dehydrogenase belonging to the DUF2338 family. Staphylopine is involved in nickel, cobalt, zinc, copper, and iron acquisition, depending on the growth conditions. This biosynthetic pathway is conserved across other pathogens, thus underscoring the importance of this metal acquisition strategy in infection.
Authors: Ghassan Ghssein, Catherine Brutesco, Laurent Ouerdane, Clémentine Fojcik, Amélie Izaute, Shuanglong Wang, Christine Hajjar, Ryszard Lobinski, David Lemaire, Pierre Richaud, Romé Voulhoux, Akbar Espaillat, Felipe Cava, David Pignol, Elise Borezée-Durant, Pascal Arnoux
Linkage and association studies have mapped thousands of genomic regions that contribute to phenotypic variation, but narrowing these regions to the underlying causal genes and variants has proven much more challenging. Resolution of genetic mapping is limited by the recombination rate. We developed a method that uses CRISPR (clustered, regularly interspaced, short palindromic repeats) to build mapping panels with targeted recombination events. We tested the method by generating a panel with recombination events spaced along a yeast chromosome arm, mapping trait variation, and then targeting a high density of recombination events to the region of interest. Using this approach, we fine-mapped manganese sensitivity to a single polymorphism in the transporter Pmr1. Targeting recombination events to regions of interest allows us to rapidly and systematically identify causal variants underlying trait differences.
Authors: Meru J. Sadhu, Joshua S. Bloom, Laura Day, Leonid Kruglyak
Authors: Guoyou Qi, Yanhong Jia, Saixing Zeng, Jonathan J. Shi
Authors: Steven G. Ball, Debashish Bhattacharya, Andreas P. M. Weber
Experts brainstorm ways to allow a more diverse community of science and technology innovators
Author: Ginger Pinholster
With federal funding of firearm injury prevention stalled, a top scientist says policies to reduce gun violence not as polarizing as politicians may think
Author: Kathleen O'Neil
Author: Kristen L. Mueller
Author: Beverly A. Purnell
Author: Kristen L. Mueller
Author: Nicolas S. Wigginton
The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of diseases associated with exacerbated inflammation. We identified topoisomerase 1 (Top1) as a positive regulator of RNA polymerase II transcriptional activity at pathogen-induced genes. Depletion or chemical inhibition of Top1 suppresses the host response against influenza and Ebola viruses as well as bacterial products. Therapeutic pharmacological inhibition of Top1 protected mice from death in experimental models of lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life-threatening infections characterized by an acutely exacerbated immune response.
Authors: Alex Rialdi, Laura Campisi, Nan Zhao, Arvin Cesar Lagda, Colette Pietzsch, Jessica Sook Yuin Ho, Luis Martinez-Gil, Romain Fenouil, Xiaoting Chen, Megan Edwards, Giorgi Metreveli, Stefan Jordan, Zuleyma Peralta, Cesar Munoz-Fontela, Nicole Bouvier, Miriam Merad, Jian Jin, Matthew Weirauch, Sven Heinz, Chris Benner, Harm van Bakel, Christopher Basler, Adolfo García-Sastre, Alexander Bukreyev, Ivan Marazzi
Cyclase enzymes weave simple polyprenyl chains into the elaborate polycyclic ring systems of terpenes, a sequence that is often difficult to emulate under abiotic conditions. Here we report a disparate synthetic approach to complex terpenes whereby simple prenyl-derived chains are cyclized using radical, rather than cationic, reaction pathways. This strategy allowed us to efficiently forge the intricate 5-8-5 fused ring systems found in numerous complex natural product classes and also enabled a nine-step total synthesis of (–)-6-epi-ophiobolin N, a member of the large family of cytotoxic ophiobolin sesterterpenes. A small-molecule thiol catalyst was found to override the inherent diastereoselectivity observed during a reductive radical cascade cyclization process. This work lays the foundation for efficient synthesis of terpenoid ring systems of interest in medicinal research, particularly those that have been historically challenging to access.
Authors: Zachary G. Brill, Huck K. Grover, Thomas J. Maimone
Six years after it backed down from approving cultivation of a transgenic food crop, India's government is trying again. But it is encountering stiff headwinds as it mulls whether to approve what would be India's first such crop, a genetically modified (GM) mustard. Environmentalists argue that the mustard, grown for its edible leaves and for cooking oil, could harm local varieties and that the toxicity tests being carried out to evaluate GM mustard's safety as a food are inadequate. Heightening suspicion, regulators have repeatedly spurned calls to release biosafety data. But India's environment minister, Prakash Javadekar, is determined to open the door to GM food technologies, saying they can help ensure food security and that rejecting them is like "saying 'no' to science."
Author: Priyanka Pulla
Biomass-degrading microorganisms use lytic polysaccharide monooxygenase (LPMO) enzymes to help digest cellulose, chitin, and starch. By cleaving otherwise inaccessible crystalline cellulose chains, these enzymes provide access to hydrolytic enzymes. LPMOs are of interest to biotechnology because efficient depolymerization of cellulose is a major bottleneck for the production of biologically based chemicals and fuels. On page 1098 of this issue, Kracher et al. (1) compare LPMO-reducing substrates in fungi from different taxonomic groups and lifestyles, based on both biochemical and genomic evidence. The results provide insights into reductive activation of LPMO that are important for developing more efficient industrial enzymes for lignocellulose biorefineries.
Author: Angel T. Martínez
Studies of rare cancer predisposition syndromes often lead to the identification of genes critical to carcinogenesis. In 1969, Li and Fraumeni described a constellation of various cancers in the family members of four unrelated children who were diagnosed with soft tissue sarcomas (1). They posited that the cancers best fit an autosomal dominant pattern of inheritance, attributable to a genetic defect. At that time, cancer was not generally thought of as a genetic disease. Their hypothesis set the stage for establishing germline mutations in the tumor suppressor gene TP53 as the underlying genetic event in Li-Fraumeni syndrome (LFS) families (2) (see the figure). It also foreshadowed dozens of discoveries, still ongoing, that associate mutations in tumor suppressor genes, activated oncogenes, mitochondrial genes, and DNA repair genes with cancer predisposition phenotypes in which multiple different neoplasms occur across generations.
Authors: David Malkin, Judy E. Garber, Louise C. Strong, Stephen H. Friend
Staphylococcus aureus is a Gram-positive bacterium that is a leading cause of life-threatening infections in humans. Knowledge of how this pathogen colonizes the human host and causes disease is crucial for the development of strategies to prevent and treat S. aureus infections (see the image, next page). On page 1105 of this issue, Ghssein et al. report the discovery, isolation, and functional evaluation of staphylopine (see the figure), a compound biosynthesized by S. aureus that captures metal ions from the pathogen's surroundings and thereby enables it to grow (1).
Author: Elizabeth M. Nolan
The inflammatory response is coordinated by hundreds of genes that promote host defense against infection and injury. Inducible expression of these genes is mediated by distinct mechanisms, including transcriptional elongation, histone modifications, and nucleosome remodeling. On page 1074 of this issue, Rialdi et al. (1) report that a subset of the genes activated by viral infections depends on topoisomerase 1 (Top1) for induced expression. Pharmacological targeting of specific gene subsets has many clinical applications in inflammatory diseases. Because Top1 inhibition primarily affects genes dependent on nucleosome remodeling, many of which are key drivers of inflammation, it holds promise for gene-specific manipulation of the inflammatory response.
Authors: Scott D. Pope, Ruslan Medzhitov
Imagine a young man with hemophilia A who no longer has to self-administer factor VIII replacement; an individual with sickle cell disease who is free of chronic pain and intermittent crises; a girl functionally blind since the age of 5 who can now see; or a baby rescued from a fatal, inherited neurodegenerative disease. For decades, gene therapy has tantalized us with such futuristic scenarios. However, these goals are now coming into focus, and it is the time to consider some of the consequences of success.
Authors: Stuart H. Orkin, Philip Reilly
We all have it. Implicit bias was the shorthand that allowed our distant ancestors to make split-second decisions (friend or foe?) based on incomplete information. It provided a razor-thin reaction-time advantage that could mean life or death. But today, we no longer need to assume that people who do not look or sound like us pose an immediate threat. Instead, successful organizations and people welcome those who do not necessarily look, think, and act like they do. They must overcome that implicit bias wired into the human DNA if they are to reap the benefits of diversity. To explore the extent of implicit bias in peer review, and what can be done to counter it, the American Association for the Advancement of Science (AAAS, the publisher of Science) recently convened a day-long forum of editors, publishers, funders, and experts on implicit bias in Washington, DC (see p. 1067).
Author: Marcia McNutt
In science news around the world, a new U.S. labor law would require more pay for postdocs—or that they receive overtime pay, the World Health Organization determines that yellow fever outbreaks in urban regions of Angola and the Democratic Republic of the Congo do not yet constitute an international health emergency, South Africa plans to launch a new trial of an HIV vaccine approach that showed modest efficacy 7 years ago in Thailand, the French government is tightening clinical trial rules in the aftermath of the final report about a study that killed one person and landed five others in the hospital earlier this year, U.S. President Barack Obama contends that funding proposals from the Senate and House of Representatives are both insufficient to effectively combat the Zika epidemic, and more. Also, just weeks after the announcement of the privately funded Breakthrough Starshot project to send tiny spacecraft to Alpha Centauri, a U.S. lawmaker urges NASA to develop its own interstellar probes bound for our nearest star neighbor. And dog lovers are flocking to a citizen science project that aims to study the genetic basis of canine behavior.
Over the past 5 years, on behalf of state governments, nearly 100,000 Americans were gently manipulated by a team of social scientists. In 15 randomized, controlled trials, people in need of social services either encountered the standard application process or received a psychological nudge, in which the information was presented slightly differently—a postcard reminded them of deadlines, for example, or one choice was made easier than another. In 11 of the trials, the nudge modestly increased a person's response rate or influenced them to make financially smarter choices. The results, presented this week at a meeting in Chicago, add to the growing evidence that nudges developed by psychologists can make a real difference in the success of government programs.
Author: John Bohannon
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
[Errata] Erratum for the Research Article “De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity” by S. E. Boyken, Z. Chen, B. Groves, R. A. Langan, G. Oberdorfer, A. Ford, J. M. Gilmore, C. Xu, F. DiMaio,
