29,051 results on '"biology"'
Search Results
2. Science Standards Near Finish Line.
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Culotta, Elizabeth
- Abstract
Provides an overview and update of the state of science education reform, specifically the science education standards. (ZWH)
- Published
- 1994
3. Ranking the Rain Forests.
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Roberts, Leslie
- Abstract
Described is the Rapid Assessment Program (RAP) in which a team of tropical biologists are able to get to remote, uncharted sites in the tropics and conduct surveys very quickly. The team uses satellite imagery, aerial reconnaissance, and field surveys to produce an inventory of species found in these areas. (KR)
- Published
- 1991
4. U.S. Tries Variations on High School Curriculum.
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Mervis, Jeffrey
- Abstract
Makes the case that the traditional sequence of biology, chemistry, and physics in U.S. high schools may be at the root of poor student performance. Reviews integrated, inverted, and coordinated science teaching. (DDR)
- Published
- 1998
5. Random Samples.
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Holden, Constance
- Abstract
Discusses the high school framework and standards developed by the National Science Teachers Association in the subjects of physics, chemistry, biology, and earth and space sciences. (MKR)
- Published
- 1995
6. Animal Rights Activism Threatens Dissection.
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Holden, Constance
- Abstract
Discussed is the movement against the use of dissections in science laboratories. Examples of protests across the United States are included. Compared is the plight of using animals in a biology classroom and the demise of the teaching of evolution in some areas. (KR)
- Published
- 1990
7. Evolution and antiviral activity of a human protein of retroviral origin
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John A. Frank, Manvendra Singh, Harrison B. Cullen, Raphael A. Kirou, Meriem Benkaddour-Boumzaouad, Jose L. Cortes, Jose Garcia Pérez, Carolyn B. Coyne, and Cédric Feschotte
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Genetics ,Natural selection ,Multidisciplinary ,biology ,Zoonotic Infection ,Genome, Human ,Placenta ,Gene Products, env ,Genomics ,Pregnancy Proteins ,biology.organism_classification ,Genome ,Betaretrovirus ,Placentation ,Transcriptome ,Evolution, Molecular ,Retrovirus ,Pregnancy ,Animals ,Humans ,Human genome ,Female ,Gene - Abstract
Summary Viruses circulating in wild and domestic animals pose a constant threat to human health1. Identifying human genetic factors that protect against zoonotic infections is a health priority. The RD-114 and Type-D retrovirus (RDR) interference group includes infectious viruses that circulate in domestic cats and various Old World monkeys (OWM), and utilize ASCT2 as a common target cell receptor2. While human ASCT2 can mediate RDR infection in cell culture, it is unknown whether humans and other hominoids encode factors that restrict RDR infection in nature2,3. Here we test the hypothesis that Suppressyn, a truncated envelope protein that binds ASCT2 and is derived from a human endogenous retrovirus4,5, restricts RDR infection. Transcriptomics and regulatory genomics reveal that Suppressyn expression initiates in the preimplantation embryo. Loss and gain of function experiments in cell culture show Suppressyn expression is necessary and sufficient to restrict RDR infection. Evolutionary analyses show Suppressyn was acquired in the genome of a common ancestor of hominoids and OWMs, but preserved by natural selection only in hominoids. Restriction assays using modern primate orthologs and reconstructed ancestral genes indicate that Suppressyn antiviral activity has been conserved in hominoids, but lost in most OWM. Thus in humans and other hominoids, Suppressyn acts as a restriction factor against retroviruses with zoonotic capacity. Transcriptomics data predict that other virus-derived proteins with potential antiviral activity lay hidden in the human genome.
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- 2022
8. Multiple causal variants underlie genetic associations in humans
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Nathan S. Abell, Stephen B. Montgomery, Emily Greenwald, Kevin S. Smith, Michael J. Gloudemans, Marianne K. DeGorter, and Zihuai S He
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Linkage disequilibrium ,Multifactorial Inheritance ,Multiple Sclerosis ,Quantitative Trait Loci ,Disease ,Quantitative trait locus ,Biology ,Linkage Disequilibrium ,Untranslated Regions ,Genetic variation ,Humans ,Genetic Predisposition to Disease ,Allele ,Alleles ,Genetics ,Multidisciplinary ,Genome, Human ,Platelet Count ,Genetic Variation ,Inflammatory Bowel Diseases ,Asthma ,Chromatin ,Histone Code ,Phenotype ,Haplotypes ,Expression quantitative trait loci ,Trait ,Genome-Wide Association Study ,Transcription Factors - Abstract
The majority of associations between genetic variation and human traits and diseases are non-coding and in strong linkage disequilibrium (LD) with surrounding genetic variation. In these cases, a single causal variant is often assumed to underlie the association, however no systematic assessment of the number of causal variants has been performed. In this study, we applied a massively parallel reporter assay (MPRA) in lymphoblastoid cells to functionally evaluate 49,256 allelic pairs, representing 30,893 genetic variants in high, local linkage disequilibrium for 744 independent cis-expression quantitative trait loci (eQTL) and assessed each for colocalization across 114 traits. We identified 8,502 allele-independent regulatory regions containing 1,264 allele-specific regulatory variants, and found that 17.7% of eQTL contained more than one significant allelic effect. We show that detected regulatory variants are highly and specifically enriched for activating chromatin structures and allelic transcription factor binding, for which ETS-domain family members are a large driver. Integration of MPRA profiles with eQTL/complex trait colocalizations identified causal variant sets for associations with blood cell measurements, Asthma, Multiple Sclerosis, Inflammatory Bowel Disease, and Crohn’s Disease. These results demonstrate that a sizable number of association signals are manifest through multiple, tightly-linked causal variants requiring high-throughput functional assays for fine-mapping.
- Published
- 2022
9. Bacterial gasdermins reveal an ancient mechanism of cell death
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Yaara Oppenheimer-Shaanan, Tanita Wein, Megan L. Mayer, Erez Yirmiya, Alex G. Johnson, Rotem Sorek, Philip J. Kranzusch, Brianna Duncan-Lowey, and Gil Amitai
- Subjects
Models, Molecular ,Protein Conformation, alpha-Helical ,Programmed cell death ,Proteases ,Protein Conformation ,Cytophagaceae ,Cleavage (embryo) ,Crystallography, X-Ray ,Article ,Immune system ,Bacterial Proteins ,Protein Domains ,medicine ,Pyroptosis ,Bacteriophages ,Bradyrhizobium ,Myxococcales ,Multidisciplinary ,biology ,Bacteria ,Chemistry ,Cell Membrane ,Eukaryota ,Inflammasome ,biology.organism_classification ,Peptide Fragments ,Cell biology ,Neoplasm Proteins ,Lytic cycle ,Lipid modification ,Apoptosis Regulatory Proteins ,medicine.drug ,Peptide Hydrolases - Abstract
Gasdermin proteins form large membrane pores in human cells that release immune cytokines and induce lytic cell death. Gasdermin pore formation is triggered by caspase-mediated cleavage during inflammasome signaling and is critical for defense against pathogens and cancer. Here we discover gasdermin homologs encoded in bacteria that execute prokaryotic cell death. Structures of bacterial gasdermins reveal a conserved pore-forming domain that is stabilized in the inactive state with a buried lipid modification. We demonstrate that bacterial gasdermins are activated by dedicated caspase-like proteases that catalyze site-specific cleavage and removal of an inhibitory C-terminal peptide. Release of autoinhibition induces the assembly of >200 Å pores that form a mesh-like structure and disrupt membrane integrity. These results demonstrate that caspase-mediated activation of gasdermins is an ancient form of regulated cell death shared between bacteria and animals.
- Published
- 2022
10. Rapid assessment of SARS-CoV-2–evolved variants using virus-like particles
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Abdullah M. Syed, Irene P. Chen, Jennifer M. Hayashi, Mir M. Khalid, Katarzyna M. Soczek, Jennifer A. Doudna, Taha Y. Taha, Melanie Ott, Alison Ciling, Takako Tabata, Bharath Sreekumar, and Pei-Yi Chen
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Genome, Viral ,Biology ,Virus ,Cell Line ,Evolution, Molecular ,Viral Matrix Proteins ,Coronavirus Envelope Proteins ,Animals ,Coronavirus Nucleocapsid Proteins ,Humans ,RNA, Messenger ,Multidisciplinary ,SARS-CoV-2 ,Viral Genome Packaging ,Virus Internalization ,Phosphoproteins ,Virology ,Rapid assessment ,Mutation ,Spike Glycoprotein, Coronavirus ,Artificial Virus-Like Particles ,Spike (software development) ,Plasmids - Abstract
A tool to probe SARS-CoV-2 biology To develop therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and emerging variants, it is important to understand the viral biology and the effect of mutations. However, this is challenging because live virus can only be studied in a few laboratories that meet stringent safety standards. Syed et al . describe a virus-like particle (VLP) that comprises the four SARS-CoV-2 structural proteins, but instead of packaging viral RNA, it packages messenger RNA (mRNA) that expresses a reporter protein (see the Perspective by Johnson and Menachery). The amount of reporter expressed in receiver cells depends on the efficiency of packaging and assembly in the producer cells and the efficiency of entry into receiver cells. Mutations in the nucleocapsid protein that are found in more transmissible variants increase mRNA packaging and expression. The VLPs provide a platform for studying the effect of mutations in the structural proteins and for screening therapeutics. —VV
- Published
- 2021
11. Membrane fusion and immune evasion by the spike protein of SARS-CoV-2 Delta variant
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Pei Tong, Yongfei Cai, Avneesh Gautam, Bing Chen, Sophia Rits-Volloch, Jun Zhang, Megan L. Mayer, Duane R. Wesemann, Wei Yang, Haisun Zhu, Michael S. Seaman, Christy L. Lavine, Hanqin Peng, Richard M. Walsh, Jianming Lu, Krishna Anand, and Tianshu Xiao
- Subjects
Models, Molecular ,Delta ,Antigenicity ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Protein Conformation ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Antibody Affinity ,Alpha (ethology) ,Biology ,Antibodies, Viral ,Membrane Fusion ,Article ,In Brief ,Cell Line ,Epitopes ,Immune system ,Protein Domains ,Antigen ,Humans ,Beta (finance) ,Antigens, Viral ,Immune Evasion ,Multidisciplinary ,SARS-CoV-2 ,Lipid bilayer fusion ,Spike Protein ,Evasion (ethics) ,Virology ,Mutation ,Spike Glycoprotein, Coronavirus ,biology.protein ,Angiotensin-Converting Enzyme 2 ,Protein Multimerization ,Antibody ,Function (biology) ,Receptors, Coronavirus - Abstract
Delta’s spike Understanding the molecular mechanisms of the increased transmissibility and immune evasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is critical to guiding current and future intervention strategies. Zhang et al . determined cryo–electron microscopy structures of the full-length spike protein trimers of the Delta, Kappa, and Gamma variants of SARS-CoV-2 and studied their function and antigenic properties. The Delta spike protein fused membranes more efficiently at low levels of the cellular receptor ACE2, and its pseudotyped viruses infected target cells substantially more rapidly than all other variants tested, possibly at least partly accounting for its heightened transmissibility. Mutations of each variant rearranged the antigenic surface of the N-terminal domain of the spike protein but only caused local changes in the receptor-binding domain, consistent with greater resistance to neutralizing antibodies. These findings elucidate the molecular events that have led these viruses to adapt in human communities and to evade host immunity. —VV
- Published
- 2021
12. Ground tissue circuitry regulates organ complexity in maize and Setaria
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Carlos Ortiz-Ramírez, Ramin Rahni, Sanqiang Zhang, Kenneth D. Birnbaum, Thomas R. Gingeras, Laura Lee, Bruno Guillotin, Poliana Coqueiro Dias Araujo, Zhe Yan, Edgar Demesa-Arevalo, Joyce Van Eck, David A. Jackson, Xiaosa Xu, and Kimberly L. Gallagher
- Subjects
Setaria ,Multidisciplinary ,Transcription, Genetic ,Plant roots ,Setaria Plant ,food and beverages ,Biology ,Flow Cytometry ,biology.organism_classification ,Plant Roots ,Zea mays ,Article ,Ground tissue ,medicine.anatomical_structure ,Symbiosis ,Cortex (anatomy) ,Botany ,medicine ,RNA-Seq ,Single-Cell Analysis ,Genome, Plant ,Plant Proteins ,Transcription Factors - Abstract
Most plant roots have multiple cortex layers that make up the bulk of the organ and play key roles in physiology, such as flood tolerance and symbiosis. However, little is known about the formation of cortical layers outside of the highly reduced anatomy of Arabidopsis. Here we use single-cell RNAseq to rapidly generate a cell resolution map of the maize root, revealing an alternative configuration of the tissue formative transcription factor SHORT-ROOT (SHR) adjacent to an expanded cortex. We show that maize SHR protein is hypermobile, moving at least eight cell layers into the cortex. Higher-order SHR mutants in both maize and Setaria have reduced numbers of cortical layers, showing that the SHR pathway controls expansion of cortical tissue to elaborate anatomical complexity.
- Published
- 2021
13. Error-prone, stress-induced 3′ flap–based Okazaki fragment maturation supports cell survival
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Amanpreet Singh, Judith L. Campbell, Jinhui Wang, Li Zheng, Zhaohui Gu, Xiwei Wu, Binghui Shen, Zhaoning Lu, Mian Zhou, Haitao Sun, Yajing Zhou, Eric Zheng, and Zunsong Hu
- Subjects
DNA Replication ,Saccharomyces cerevisiae Proteins ,Multidisciplinary ,Okazaki fragments ,Cell Survival ,Flap Endonucleases ,Stress induced ,Temperature ,DNA replication ,Cell Cycle Proteins ,DNA ,Saccharomyces cerevisiae ,Protein Serine-Threonine Kinases ,Biology ,Environmental stress ,Article ,Cell biology ,Stress, Physiological ,Apoptosis ,Nucleic Acid Conformation ,DNA, Fungal ,Cell survival ,DNA Polymerase III ,Signal Transduction - Abstract
How cells with DNA replication defects acquire mutations that allow them to escape apoptosis under environmental stress is a long-standing question. Here, we report that an error-prone Okazaki fragment maturation (OFM) pathway is activated at restrictive temperatures in rad27Δ yeast cells. Restrictive temperature stress activated Dun1, facilitating transformation of unprocessed 5′ flaps into 3′ flaps, which were removed by 3′ nucleases, including DNA polymerase δ (Polδ). However, at certain regions, 3′ flaps formed secondary structures that facilitated 3′ end extension rather than degradation, producing alternative duplications with short spacer sequences, such as pol3 internal tandem duplications. Consequently, little 5′ flap was formed, suppressing rad27Δ-induced lethality at restrictive temperatures. We define a stress-induced, error-prone OFM pathway that generates mutations that counteract replication defects and drive cellular evolution and survival.
- Published
- 2021
14. Mechanism of siRNA production by a plant Dicer-RNA complex in dicing-competent conformation
- Author
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Laixing Zhang, Steven E. Jacobsen, Jiamu Du, Zhe Wu, C. Jake Harris, Sisi Li, Zhenhui Zhong, Qian Wang, Maojun Yang, Changshi Wang, Zhenlin Yang, Suhua Feng, Jixian Zhai, Yan Xue, and Lifan Xiao
- Subjects
Models, Molecular ,Ribonuclease III ,Protein Conformation ,Arabidopsis ,Article ,Protein Domains ,Phosphorylation ,RNA, Small Interfering ,Multidisciplinary ,biology ,Arabidopsis Proteins ,Chemistry ,Mechanism (biology) ,Cryoelectron Microscopy ,RNA ,Cell biology ,enzymes and coenzymes (carbohydrates) ,Mutagenesis ,RNA, Plant ,Transfer RNA ,biology.protein ,Nucleic Acid Conformation ,Wafer dicing ,Biogenesis ,Protein Binding ,Dicer - Abstract
In eukaryotes, small RNAs (sRNAs) play critical roles in multiple biological processes. Dicer endonucleases are a central part of sRNA biogenesis. In plants, DICER-LIKE PROTEIN 3 (DCL3) produces 24-nucleotide (nt) small interfering RNAs (siRNAs) that determine the specificity of the RNA-directed DNA methylation pathway. Here, we determined the structure of a DCL3–pre-siRNA complex in an active dicing-competent state. The 5′-phosphorylated A1 of the guide strand and the 1-nt 3′ overhang of the complementary strand are specifically recognized by a positively charged pocket and an aromatic cap, respectively. The 24-nt siRNA length dependence relies on the separation between the 5′-phosphorylated end of the guide RNA and dual cleavage sites formed by the paired ribonuclease III domains. These structural studies, complemented by functional data, provide insight into the dicing principle for Dicers in general.
- Published
- 2021
15. A viral RNA hijacks host machinery using dynamic conformational changes of a tRNA-like structure
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Madeline E. Sherlock, Jeffrey S. Kieft, Steve Bonilla, and Andrea MacFadden
- Subjects
Models, Molecular ,Phaseolus ,Multidisciplinary ,Protein Conformation ,Host (biology) ,Extramural ,viruses ,Cryoelectron Microscopy ,Molecular Mimicry ,food and beverages ,RNA ,Genome, Viral ,Computational biology ,Biology ,Virus Replication ,Bromovirus ,Article ,RNA, Transfer ,Tyrosine-tRNA Ligase ,Transfer RNA ,Nucleic Acid Conformation ,RNA, Viral ,Viral rna ,Transfer RNA Aminoacylation ,Protein Binding - Abstract
Viruses require multifunctional structured RNAs to hijack their host’s biochemistry, but their mechanisms can be obscured by the difficulty of solving conformationally dynamic RNA structures. Using cryo–electron microscopy (cryo-EM), we visualized the structure of the mysterious viral transfer RNA (tRNA)–like structure (TLS) from the brome mosaic virus, which affects replication, translation, and genome encapsidation. Structures in isolation and those bound to tyrosyl-tRNA synthetase (TyrRS) show that this ~55-kilodalton purported tRNA mimic undergoes large conformational rearrangements to bind TyrRS in a form that differs substantially from that of tRNA. Our study reveals how viral RNAs can use a combination of static and dynamic RNA structures to bind host machinery through highly noncanonical interactions, and we highlight the utility of cryo-EM for visualizing small, conformationally dynamic structured RNAs.
- Published
- 2021
16. CD4 + T cells contribute to neurodegeneration in Lewy body dementia
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Douglas Galasko, Hamilton Oh, Andreas Keller, Tobias Fehlmann, Tony Wyss-Coray, Kathleen L. Poston, Michael S. Unger, Emma Tapp, David Gate, Tim J. Nonninger, Katharina Strempfl, Divya Channappa, Victor W. Henderson, Andrew C. Yang, Ludwig Aigner, Olivia Leventhal, Mark M. Davis, and Marian Shahid
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Multidisciplinary ,Lewy body ,Mechanism (biology) ,T cell ,Neurodegeneration ,Biology ,medicine.disease ,Acquired immune system ,medicine.anatomical_structure ,medicine ,Dementia ,Neuroscience ,hormones, hormone substitutes, and hormone antagonists ,Homing (hematopoietic) - Abstract
Autoimmunity in Lewy body dementia Lewy body dementia (LBD) is a brain disease that leads to progressive decline in thinking, movement, and independent function. It results from the build-up of microscopic deposits called Lewy bodies, which develop from the aggregation of a misfolded protein called α-synuclein. Gate et al . observed immune cells known as T cells in the brains of LBD patients (see the Perspective by Krot and Rolls). Genomics analysis revealed that T cells traffic to the LBD brain and are associated with neuronal damage. When stimulated with α-synuclein, LBD patient T cells secrete an inflammatory protein known to damage neurons. These findings suggest an unexpected detrimental role of the immune system in LBD. —SMH
- Published
- 2021
17. The glial framework reveals white matter fiber architecture in human and primate brains
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Aviv Mezer and Roey Schurr
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Physics ,Multidisciplinary ,Staining and Labeling ,biology ,Resolution (electron density) ,Brain ,Macaca mulatta ,White Matter ,Axons ,Corpus Callosum ,White matter ,Diffusion Magnetic Resonance Imaging ,medicine.anatomical_structure ,nervous system ,biology.animal ,Chlorocebus aethiops ,Image Processing, Computer-Assisted ,medicine ,Animals ,Humans ,Fiber architecture ,Primate ,Neuroglia ,Neuroscience - Abstract
How to quantify local axonal orientations Mapping the axonal trajectories of the brain’s white matter at cellular resolution is a long-standing goal of neuroscience. However, existing methods for mapping the axons are either limited to animal studies or require highly specialized equipment for data acquisition and processing. Nissl staining identifies cell nuclei and has been used extensively to investigate parcellations of the cortical gray matter, but the white matter has largely been neglected with this technique. Schurr and Mezer now show that Nissl staining, together with structure tensor analysis, can be used to study white matter architecture and the organization of the glial cell framework around axons over the whole brain. This technique greatly advances our knowledge regarding the organization of glial cells and the fine-grained organization of axonal projections in the brain. —PRS
- Published
- 2021
18. G 1 cyclin–Cdk promotes cell cycle entry through localized phosphorylation of RNA polymerase II
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Georgi K. Marinov, Matthew P. Swaffer, Jonathan J. Turner, Mardo Kõivomägi, and Jan M. Skotheim
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Multidisciplinary ,biology ,Cell division ,Chemistry ,Kinase ,Cyclin-dependent kinase ,Transcription (biology) ,biology.protein ,Promoter ,RNA polymerase II ,Cell cycle ,Transcription factor ,Cell biology - Abstract
Control by RNA polymerase II Evidence indicates that yeast cells initiate DNA synthesis and transition from the G 1 to the S phase of the cell cycle when cyclin 3 accumulates and causes phosphorylation of Whi5, a functional equivalent of the mammalian Rb (retinoblastoma) protein. Kõivomägi et al . now present evidence for a different cyclin-dependent kinase target (see the Perspective by Fisher). They found that the cyclin 3–cyclin-dependent kinase (Cdk) 1 complex in yeast promoted phosphorylation of RNA polymerase II and thus increased transcription at genes that control entry into the cell cycle. Cdks that regulate the cell cycle can thus act by similar mechanisms to so-called “transcriptional Cdks,” which are known to act as transcriptional regulators but not to function in control of cell division. —LBR
- Published
- 2021
19. The widespread IS200/IS605 transposon family encodes diverse programmable RNA-guided endonucleases
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Suchita P. Nety, Feng Zhang, Eugene V. Koonin, William P. Inskeep, Kira S. Makarova, Mensur Dlakić, Rachel Oshiro, Han Altae-Tran, Rhiannon K. Macrae, Soumya Kannan, Luke J. McKay, and F. Esra Demircioglu
- Subjects
Genetics ,Transposable element ,Endonuclease ,Multidisciplinary ,biology ,Extramural ,Cas9 ,Genetic variation ,biology.protein ,RNA ,Genetic code ,Conserved sequence - Abstract
Tracing the origin of CRISPR-Cas CRISPR-Cas systems have transformed genome editing and other biotechnologies; however, the broader origins and diversity of RNA-guided nucleases have largely remained unexplored. Altae-Tran et al . show that three distinct transposon-encoded proteins, IscB, IsrB, and TnpB, are naturally occurring, reprogrammable RNA-guided DNA nucleases (see the Perspective by Rousset and Sorek). In addition to identifying diverse guide-encoding mechanisms, the authors elucidate the evolutionary relationship between IsrB, IscB, and CRISPR-Cas9. Overall, these newly characterized systems, called OMEGA (for obligate mobile element–guided activity) systems, are found in all domains of life and may be harnessed for biotechnology development. —DJ
- Published
- 2021
20. MIC-Drop: A platform for large-scale in vivo CRISPR screens
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Calum A. MacRae, Korak Chakraborti, H. Joseph Yost, Zachary P. Harmer, Manu Beerens, Jing-Ruey J. Yeh, Chelsea Herdman, Randall T. Peterson, and Saba Parvez
- Subjects
Multidisciplinary ,biology ,ved/biology ,ved/biology.organism_classification_rank.species ,Mutant ,Cell Culture Techniques ,High-Throughput Nucleotide Sequencing ,Computational biology ,Microfluidic Analytical Techniques ,biology.organism_classification ,Cardiovascular System ,Article ,Animals ,CRISPR ,Genetic Testing ,CRISPR-Cas Systems ,Model organism ,Gene ,Zebrafish ,Function (biology) ,Ribonucleoprotein ,Genetic screen - Abstract
Screen time for CRISPR CRISPR-Cas9 has been used to edit the genomes of organisms ranging from fruit flies to primates, but it has not been used in large-scale genetic screens in animals because generating, validating, and keeping track of large numbers of mutant animals is prohibitively laborious. Parvez et al . have developed Multiplexed Intermixed CRISPR Droplets, or MIC-Drop, a platform combining droplet microfluidics, en masse CRISPR injections, and barcoding, to enable large-scale genetic screens. In pilot phenotypic screens in zebrafish, MIC-Drop enabled rapid identification of the target of a small molecule and discovery of several new genes governing cardiovascular development. MIC-Drop is potentially scalable to thousands of targets and adaptable to diverse organisms and experiments. —DJ
- Published
- 2021
21. Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in mice
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Elena N. Atochina-Vasserman, Ande West, Sarah R. Leist, Lisa C. Lindesmith, Alexandra Schäfer, Dapeng Li, Robert Parks, Norbert Pardi, Boyd Yount, Maggie Barr, Kevin O. Saunders, Stephanie A. Montgomery, Drew Weissman, Ralph S. Baric, Gabriela De la Cruz, Barton F. Haynes, and David R. Martinez
- Subjects
Sarbecovirus ,0301 basic medicine ,Cross Protection ,viruses ,Antibodies, Viral ,Severe Acute Respiratory Syndrome ,Virus Replication ,Neutralization ,Mice ,Immunogenicity, Vaccine ,0302 clinical medicine ,030212 general & internal medicine ,Mink ,skin and connective tissue diseases ,Lung ,Mice, Inbred BALB C ,Vaccines, Synthetic ,Multidisciplinary ,biology ,Immunogenicity ,virus diseases ,Vaccination ,Titer ,Severe acute respiratory syndrome-related coronavirus ,Spike Glycoprotein, Coronavirus ,Cytokines ,Female ,Spike (software development) ,Antibody ,Coronavirus Infections ,COVID-19 Vaccines ,Recombinant Fusion Proteins ,Heterologous ,Immunity, Heterologous ,Article ,Betacoronavirus ,03 medical and health sciences ,Protein Domains ,Immunity ,biology.animal ,Animals ,Messenger RNA ,SARS-CoV-2 ,fungi ,COVID-19 ,Viral Vaccines ,Breakthrough infection ,biology.organism_classification ,Antibodies, Neutralizing ,Virology ,respiratory tract diseases ,body regions ,universal coronavirus vaccine ,mRNA vaccine ,030104 developmental biology ,Viral replication ,Liposomes ,biology.protein ,Nanoparticles ,SARS-like virus - Abstract
The emergence of SARS-CoV and SARS-CoV-2 in the 21st century highlights the need to develop universal vaccination strategies against the SARS-related Sarbecovirus subgenus. Using structure-guided chimeric spike designs and multiplexed immunizations, we demonstrate protection against SARS-CoV, SARS-CoV-2, and bat CoV (BtCoV) RsSHC014 challenge in highly vulnerable aged mice. Chimeric spike mRNAs containing N-terminal domain (NTD), and receptor binding domains (RBD) induced high levels of broadly protective neutralizing antibodies against three high-risk sarbecoviruses: SARS-CoV, RsSHC014, and WIV-1. In contrast, SARS-CoV-2 mRNA vaccination not only showed a 10 to >500-fold reduction in neutralizing titers against heterologous sarbecovirus strains, but SARS-CoV challenge in mice resulted in breakthrough infection including measurable lung pathology. Importantly, chimeric spike mRNA vaccines efficiently neutralized both the D614G and the South African B.1.351 variants of concern despite some reduction in neutralization activity. Thus, multiplexed-chimeric spikes may provide a novel strategy to prevent pandemic and SARS-like zoonotic coronavirus infections, while revealing the limited efficacy of SARS-CoV-2 spike vaccines against other sarbecoviruses.
- Published
- 2021
22. Identification of a quality-control factor that monitors failures during proteasome assembly
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Eszter Zavodszky, Sew-Yeu Peak-Chew, Ana J. Narvaez, Ramanujan S. Hegde, and Szymon Juszkiewicz
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Proteasome Endopeptidase Complex ,Ubiquitin-Protein Ligases ,Protein subunit ,Mutation, Missense ,PSMC5 ,Article ,Mice ,Calmodulin ,Ubiquitin ,Proto-Oncogene Proteins ,Animals ,Humans ,Point Mutation ,Protein Interaction Domains and Motifs ,Adaptor Proteins, Signal Transducing ,Multidisciplinary ,biology ,Chemistry ,Ubiquitination ,Signal transducing adaptor protein ,Neurodegenerative Diseases ,Ubiquitin ligase ,Cell biology ,Protein Subunits ,Proteasome ,Chaperone (protein) ,Proteasome assembly ,Mutation ,Proteolysis ,MCF-7 Cells ,biology.protein ,ATPases Associated with Diverse Cellular Activities - Abstract
Safeguarding protein complex assembly The assembly of multiprotein complexes inside the cell requires each subunit to be produced at a defined level relative to its partners. Imbalances in subunit synthesis are inevitable, necessitating the elimination of unassembled intermediates. Zavodszky et al . found that a ubiquitin ligase called HERC1 is responsible for marking certain assembly intermediates of the proteasome for degradation. HERC1 finds these intermediates by recognizing a proteasome assembly factor that normally dissociates when assembly is complete. A point mutation in HERC1 that impairs its ability to recognize proteasome assembly intermediates causes neurodegeneration in mice, highlighting the importance of this quality control pathway. —SMH
- Published
- 2021
23. Malaria infection and severe disease risks in Africa
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Alice Kamau, George Mtove, Hugh Reyburn, Sunetra Gupta, Arthur Mpimbaza, Charles Mwandawiro, Bryan O. Nyawanda, Robert S. Paton, Amina F. Mohamed, Nancy A. Otieno, Robert W. Snow, Samuel Akech, Simon Kariuki, Philip Bejon, Neema Mturi, Ambrose Agweyu, Shebe Mohammed, José Lourenço, and Morris Ogero
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Plasmodium falciparum ,Malaria, Cerebral ,Severe disease ,macromolecular substances ,Disease ,Severity of Illness Index ,Risk Factors ,Environmental health ,parasitic diseases ,Severity of illness ,Prevalence ,East africa ,Humans ,Medicine ,Severe Malaria ,Malaria, Falciparum ,Child ,Models, Statistical ,Multidisciplinary ,biology ,business.industry ,Incidence ,Incidence (epidemiology) ,Age Factors ,Infant ,Bayes Theorem ,Africa, Eastern ,medicine.disease ,biology.organism_classification ,Hospitalization ,Child, Preschool ,Epidemiological Monitoring ,business ,Malaria - Abstract
The relationship between community prevalence of Plasmodium falciparum and the burden of severe, life-threatening disease remains poorly defined. To examine the three most common severe malaria phenotypes from catchment populations across East Africa, we assembled a dataset of 6506 hospital admissions for malaria in children aged 3 months to 9 years from 2006 to 2020. Admissions were paired with data from community parasite infection surveys. A Bayesian procedure was used to calibrate uncertainties in exposure (parasite prevalence) and outcomes (severe malaria phenotypes). Each 25% increase in prevalence conferred a doubling of severe malaria admission rates. Severe malaria remains a burden predominantly among young children (3 to 59 months) across a wide range of community prevalence typical of East Africa. This study offers a quantitative framework for linking malaria parasite prevalence and severe disease outcomes in children.
- Published
- 2021
24. Secreted pectin monooxygenases drive plant infection by pathogenic oomycetes
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Michael Csukai, Paul H. Walton, Lydia Welsh, Anna O. Avrova, Peter J. Lindley, Neil C. Bruce, Bernard Henrissat, Julie Squires, Gideon J. Davies, Stephen C. Whisson, Simon J. McQueen-Mason, Federico Sabbadin, Saioa Urresti, Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of York [York, UK], Instituto Biofisika, and Universidad del Pais Vasco / Euskal Herriko Unibertsitatea [Espagne] (UPV/EHU)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)
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Models, Molecular ,MESH: Oxidation-Reduction ,0106 biological sciences ,Protein Conformation ,[SDV]Life Sciences [q-bio] ,01 natural sciences ,Mixed Function Oxygenases ,MESH: Protein Conformation ,MESH: Plant Diseases ,Solanum lycopersicum ,MESH: Lycopersicon esculentum ,Pathogen ,2. Zero hunger ,Oomycete ,0303 health sciences ,Multidisciplinary ,biology ,food and beverages ,MESH: Mixed Function Oxygenases ,MESH: Copper ,MESH: Plant Leaves ,Lytic cycle ,Phytophthora infestans ,Pectins ,MESH: Protein Domains ,Oxidation-Reduction ,MESH: Models, Molecular ,Virulence Factors ,Virulence ,MESH: Solanum tuberosum ,Microbiology ,Cell wall ,03 medical and health sciences ,Protein Domains ,Polysaccharides ,Gene ,Plant Diseases ,Solanum tuberosum ,MESH: Virulence Factors ,030304 developmental biology ,Host (biology) ,fungi ,biology.organism_classification ,Plant Leaves ,MESH: Polysaccharides ,MESH: Phytophthora infestans ,Copper ,MESH: Pectins ,010606 plant biology & botany - Abstract
Potato pectin falls to Phytophthora Phytophthora infestans is a plant oomycete pathogen that drove the potato famines of the 1800s and continues to afflict potato fields today. The polysaccharide pectin makes up about a third of the cell wall in potatoes. Sabbadin et al . identified a family of lytic polysaccharide monooxygenases (LMPOs) that cleave pectin and are upregulated in P. infestans during infection. Silencing the relevant LMPO gene successfully inhibited P. infestans infections. These findings open doors for disease intervention targets and for biotech applications. —PJH
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- 2021
25. Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants
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Nicholas C. Wu, Xueyong Zhu, Marit J. van Gils, Jakob Kreye, Chang-Chun D Lee, Linghang Peng, Hejun Liu, Meng Yuan, Abigail M. Jackson, Dennis R. Burton, Andrew B. Ward, Rogier W. Sanders, David Nemazee, S. Momsen Reincke, Harald Prüss, Ian A. Wilson, Deli Huang, Medical Microbiology and Infection Prevention, and AII - Infectious diseases
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virology [COVID-19] ,medicine.disease_cause ,Antibodies, Viral ,metabolism [Angiotensin-Converting Enzyme 2] ,genetics [Spike Glycoprotein, Coronavirus] ,Neutralization ,Germline ,Epitopes ,genetics [Antigens, Viral] ,immunology [SARS-CoV-2] ,immunology [COVID-19] ,Antigens, Viral ,Coronavirus ,chemistry.chemical_classification ,Mutation ,Multidisciplinary ,Microbio ,genetics [SARS-CoV-2] ,spike protein, SARS-CoV-2 ,Antigenic Variation ,Vaccination ,Spike Glycoprotein, Coronavirus ,chemistry [Antigens, Viral] ,ddc:500 ,Angiotensin-Converting Enzyme 2 ,Antibody ,chemistry [SARS-CoV-2] ,Protein Binding ,chemistry [Spike Glycoprotein, Coronavirus] ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,ACE2 protein, human ,metabolism [Antibodies, Neutralizing] ,Biology ,Receptor binding site ,Article ,Antigenic drift ,immunology [Antibodies, Viral] ,Protein Domains ,Report ,medicine ,Humans ,metabolism [Receptors, Coronavirus] ,Gene ,Immune Evasion ,Binding Sites ,metabolism [Antibodies, Viral] ,immunology [Spike Glycoprotein, Coronavirus] ,SARS-CoV-2 ,Biochem ,COVID-19 ,Virology ,immunology [Antigens, Viral] ,Antibodies, Neutralizing ,immunology [Antibodies, Neutralizing] ,metabolism [Antigens, Viral] ,Enzyme ,chemistry ,metabolism [Spike Glycoprotein, Coronavirus] ,biology.protein ,Binding Sites, Antibody ,Reports ,Receptors, Coronavirus - Abstract
The protective efficacy of neutralizing antibodies (nAbs) elicited during natural infection with SARS-CoV-2 and by vaccination based on its spike protein has been compromised with emergence of the recent SARS-CoV-2 variants. Residues E484 and K417 in the receptor-binding site (RBS) are both mutated in lineages first described in South Africa (B.1.351) and Brazil (B.1.1.28.1). The nAbs isolated from SARS-CoV-2 patients are preferentially encoded by certain heavy-chain germline genes and the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2) can each bind the RBS in two different binding modes. However, their binding and neutralization are abrogated by either the E484K or K417N mutation, whereas nAbs to the cross-reactive CR3022 and S309 sites are largely unaffected. This structural and functional analysis illustrates why mutations at E484 and K417 adversely affect major classes of nAbs to SARS-CoV-2 with consequences for next-generation COVID-19 vaccines.
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- 2021
26. SARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern
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M. Alejandra Tortorici, Alessandra Franzetti Pellanda, Amalio Telenti, Alexandra C. Walls, Christian Garzoni, Jessica Bassi, Herbert W. Virgin, Mary-Jane Navarro, David Veesler, Christian Saliba, Alexander Chen, Matthew McCallum, Katja Culap, Sonja Bernasconi Guastalla, Chiara Silacci-Fregni, Gyorgy Snell, Elisabetta Cameroni, Luca Piccoli, Wesley C. Van Voorhis, Matteo Samuele Pizzuto, Laura E. Rosen, John E. Bowen, Siro Bianchi, Anna De Marco, Stefano Jaconi, Dora Pinto, Maria De Agostini, Giovanni Bona, Kaitlin R. Sprouse, Julia di Iulio, Sasha W Tilles, and Davide Corti
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chemistry.chemical_classification ,Signal peptide ,Mutation ,Messenger RNA ,Multidisciplinary ,medicine.drug_class ,Protein domain ,Biology ,medicine.disease_cause ,Monoclonal antibody ,Virology ,Neutralization ,chemistry ,Antigen ,medicine ,Glycoprotein - Abstract
SARS-CoV-2 from alpha to epsilon As battles to contain the COVID-19 pandemic continue, attention is focused on emerging variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus that have been deemed variants of concern because they are resistant to antibodies elicited by infection or vaccination or they increase transmissibility or disease severity. Three papers used functional and structural studies to explore how mutations in the viral spike protein affect its ability to infect host cells and to evade host immunity. Gobeil et al . looked at a variant spike protein involved in transmission between minks and humans, as well as the B1.1.7 (alpha), B.1.351 (beta), and P1 (gamma) spike variants; Cai et al . focused on the alpha and beta variants; and McCallum et al . discuss the properties of the spike protein from the B1.1.427/B.1.429 (epsilon) variant. Together, these papers show a balance among mutations that enhance stability, those that increase binding to the human receptor ACE2, and those that confer resistance to neutralizing antibodies. —VV
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- 2021
27. A noncoding RNA modulator potentiates phenylalanine metabolism in mice
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Yaohua Zhang, V. Reid Sutton, Youqiong Ye, Chunru Lin, Lan Liao, Zhao Zhang, Yajuan Li, Shuxing Zhang, Nenad Blau, Cristian Coarfa, Manuel Schiff, Ke Liang, Sergey D. Egranov, Zhi Tan, Preethi H. Gunaratne, Qingsong Hu, Kuang-Lei Tsai, Yi Chuan Li, Yao Jun, Jean-Louis Guéant, François Feillet, Mien Chie Hung, Chunlai Li, Nagireddy Putluri, Tina K. Nguyen, David H. Hawke, Heidi Hsiao, George A. Calin, Ania C. Muntau, Zhen Xing, Sujash S. Chatterjee, Liuqing Yang, Farès Namour, Leng Han, Yinghong Pan, and Jianming Xu
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Male ,Functional role ,Acetylgalactosamine ,RNA, Untranslated ,HULC ,Phenylalanine hydroxylase ,Phenylalanine ,Computational biology ,Plasma protein binding ,Article ,Mice ,Metabolic Diseases ,Phenylketonurias ,Drug Discovery ,medicine ,Animals ,Humans ,Pharmacology ,Mice, Knockout ,Multidisciplinary ,biology ,Chemistry ,Metabolic disorder ,Phenylalanine Hydroxylase ,RNA ,General Medicine ,medicine.disease ,Non-coding RNA ,Biopterin ,Diet ,Disease Models, Animal ,MicroRNAs ,Liver ,Biochemistry ,Hepatocytes ,biology.protein ,Nucleic Acid Conformation ,Female ,RNA, Long Noncoding ,Phenylalanine metabolism ,Protein Binding - Abstract
The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. We demonstrated that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine, musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell (hiPSC)-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive phenylalanine in Pair(−/−) and Pah(R408W/R408W) mice and improved the phenylalanine tolerance of these mice.
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- 2021
28. Plant 'helper' immune receptors are Ca 2+ -permeable nonselective cation channels
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Pierre Jacob, Li Wan, Korina Kempthorn, William G. Walton, Zhen-Ming Pei, Matthew R. Redinbo, Adam D. Lietzan, Nak Hyun Kim, Farid El-Kasmi, Jeffery L. Dangl, Fei-Hua Wu, Oliver J. Furzer, Yuan Chi, and Sruthi Sunil
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Programmed cell death ,Multidisciplinary ,Immune system ,biology ,Chemistry ,Cytoplasm ,Arabidopsis ,HEK 293 cells ,Patch clamp ,biology.organism_classification ,Receptor ,Calcium signaling ,Cell biology - Abstract
Calcium signaling for host cell death In response to microbial pathogens, some plants kill off their own cells to limit further spread of infection. The Toll/Interleukin-1 receptor/Resistance class of nucleotide-binding leucine-rich repeat receptors (known as TNLs) function in plants as immune receptors. These TNLs work together with a dedicated set of helper proteins. Jacob et al. reveal the structure of one of these helpers known as NRG1 (N REQUIREMENT GENE 1). The structure resembles a known animal cation channel. The authors demonstrate that helper NLRs directly control calcium ion influx to initiate host cell death, providing a mechanism for TNL outputs. Science , abg7917, this issue p. 420
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- 2021
29. Neural representations of space in the hippocampus of a food-caching bird
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Dmitriy Aronov, Galen F. Lynch, and Hannah L Payne
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Male ,0301 basic medicine ,Action Potentials ,Hippocampus ,Sensory system ,Cognitive neuroscience ,Hippocampal formation ,Article ,03 medical and health sciences ,0302 clinical medicine ,biology.animal ,Behavioral ecology ,Neural Pathways ,Animals ,Passeriformes ,Spatial Memory ,Neurons ,Multidisciplinary ,biology ,Vertebrate ,Feeding Behavior ,Sleep in non-human animals ,Electrophysiological Phenomena ,030104 developmental biology ,Place Cells ,Spatial ecology ,Female ,Finches ,Sleep ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Conserved spatial memory mechanisms Food-caching birds are memory specialists that can remember thousands of hidden food items. Using electrophysiological recordings from freely behaving birds, Payne et al. analyzed neuronal activity in the likely hippocampus homolog of two bird species, the tufted titmouse and the zebra finch. They chose these two species to compare, respectively, birds that do and do not display food-caching behavior. Place cells and typical hippocampal firing patterns that resembled rodent neuronal activity could be detected in the extreme memory specialists. Compared with titmice, however, spatial activity was noticeably weaker and less abundant in zebra finches. These findings provide evidence that the neural processes underlying spatial memory are remarkably conserved across widely divergent hippocampal circuits separated by millions of years of evolution. Science , abg2009, this issue p. 343
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- 2021
30. Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets
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Theodore C. Pierson, Yan Li, Debangsu Sil, W. Marston Linehan, Bernard A. P. Lafont, Tracey A. Rouault, Carsten Krebs, J. Martin Bollinger, and Nunziata Maio
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viruses ,Iron ,Protein subunit ,Amino Acid Motifs ,Coenzymes ,RNA-dependent RNA polymerase ,Viral Nonstructural Proteins ,Virus Replication ,Antiviral Agents ,Article ,Cyclic N-Oxides ,chemistry.chemical_compound ,Protein Domains ,Transcription (biology) ,Catalytic Domain ,RNA polymerase ,Chlorocebus aethiops ,Animals ,Enzyme Inhibitors ,Binding site ,Vero Cells ,Gene ,Binding Sites ,Coronavirus RNA-Dependent RNA Polymerase ,Multidisciplinary ,biology ,SARS-CoV-2 ,Helicase ,Zinc ,Biochemistry ,chemistry ,Viral replication ,biology.protein ,Spin Labels ,RNA Helicases ,Sulfur - Abstract
Mind your metals Iron–sulfur clusters are important cofactors for proteins involved in metabolism and electron transfer but are also sometimes found in enzymes involved in transcription and replication of DNA. In vitro expression of such enzymes can result in faulty cluster assembly and confusion about the composition of the functional enzyme. Using a careful anoxic purification scheme, Maio et al. found that the severe acute respiratory syndrome coronavirus 2 RNA–dependent RNA polymerase contains two iron–sulfur clusters at two sites previously observed to bind zinc ions. Mutation of the ligating cysteine residues resulted in loss of polymerase activity. A less severe loss of activity was seen in the zinc-containing enzyme. Treatment with the nitroxide drug TEMPOL resulted in degradation of the clusters, enzyme inhibition, and inhibition of viral replication in cell culture. Science , abi5224, this issue p. 236
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- 2021
31. Gut microbiome heritability is nearly universal but environmentally contingent
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Ran Blekhman, Tim L. Wango, Susan C. Alberts, Jean-Christophe Grenier, Luis B. Barreiro, Jacob B. Gordon, Trevor J. Gould, Niki H. Learn, Vania Yotova, Johannes R. Björk, Laura E. Grieneisen, David A. W. A. M. Jansen, R. S. Mututua, Jack A. Gilbert, Jenny Tung, J. Kinyua Warutere, Mauna Dasari, Laurence R. Gesquiere, Elizabeth A. Archie, Neil Gottel, and Long'ida Siodi
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Male ,0301 basic medicine ,Aging ,Genotype ,Firmicutes ,Environment ,Biology ,Feces ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Humans ,Microbiome ,Social Behavior ,Multidisciplinary ,Bacteria ,Bacteroidetes ,Extramural ,Host (biology) ,Heritability ,Phenotype ,Gut microbiome ,Diet ,Gastrointestinal Microbiome ,Large sample ,Actinobacteria ,030104 developmental biology ,Evolutionary biology ,Female ,Seasons ,030217 neurology & neurosurgery ,Papio - Abstract
Baboons inform on human gut microbiota Commensal bacteria are found throughout an organism, but it is not known whether associations between gut bacteria and their host are heritable. Grieneisen et al. examined changes in the microbiomes of 585 wild baboons from fecal samples collected over 14 years (see the Perspective by Cortes-Ortiz and Amato). Almost all microbiome traits tested demonstrated some level of statistically significant heritability. Most heritability values were low but varied over time correlating with the age of the host. Baboons live in an environment similar to that postulated for early humans and have a microbiome similar to that of humans. Thus, this heritability of the microbiome may reflect similar genetic determinants in humans, for which similar datasets are not available. Science , aba5483, this issue p. 181 ; see also abj5287, p. 159
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- 2021
32. MBD5 and MBD6 couple DNA methylation to gene silencing through the J-domain protein SILENZIO
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Yasaman Jami-Alahmadi, Gundeep Kaur, C. Jake Harris, Maverick Tan, Sascha H. Duttke, Steven E. Jacobsen, Lucia Ichino, Brandon A. Boone, Sy Redding, Matthew A. Gladstone, Xiaodong Cheng, James A. Wohlschlegel, Luke Strauskulage, and Suhua Feng
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Transposable element ,Multidisciplinary ,General Science & Technology ,1.1 Normal biological development and functioning ,Human Genome ,Protein domain ,Methylation ,Biology ,Article ,Chromatin ,Cell biology ,Underpinning research ,DNA methylation ,Genetics ,2.1 Biological and endogenous factors ,Gene silencing ,Generic health relevance ,Aetiology ,Gene ,Biotechnology ,Binding domain - Abstract
Methyl readers that repress transcription DNA methylation is a conserved epigenetic mark required for gene silencing in many different organisms. However, how the methyl mark is able to silence genes is still largely unknown. Ichino et al. discovered two Arabidopsis proteins named MBD5 and MBD6 that are recruited to DNA by direct recognition of methylation. These methyl readers recruit the class C J-domain protein SILENZIO to chromatin to silence methylated genes and transposons. SILENZIO likely acts through its interaction with heat shock chaperone proteins. Science , abg6130, this issue p. 1434
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- 2021
33. mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection
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Stephen C. De Rosa, Maria P. Lemos, Vanessa Rubin, M. Juliana McElrath, Yu Hsin Wan, Leah J. Homad, Andrés Finzi, Leonidas Stamatatos, Kristen W. Cohen, Gregory J. Mize, Zoe Moodie, Emilie Seydoux, Anna J. MacCamy, Moni B. Neradilek, Andrew T. McGuire, Junli Feng, Madeleine F. Jennewein, Hayley Glantz, and Julie Czartoski
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2019-20 coronavirus outbreak ,Messenger RNA ,Multidisciplinary ,biology ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Virology ,Neutralization ,Vaccination ,Titer ,Immunization ,biology.protein ,Medicine ,Antibody ,business - Abstract
Boosterism could save lives Postinfection immune protection against severe acute respiratory syndrome coronavirus 2 reinfection is not fully understood. It will be devastating if waves of new variants emerge that undermine natural immune protection. Stamatatos et al. investigated immune responsiveness 4 to 8 months after previously infected individuals were given a messenger RNA–based vaccine developed for the original Wuhan variant (see the Perspective by Crotty). Before vaccination, postinfection serum antibody neutralization responses to virus variants were variable and weak. Vaccination elevated postinfection serum-neutralizing capacity approximately 1000-fold against Wuhan-Hu-1 and other strains, and serum neutralization against the variant B.1.351 was enhanced. Although responses were relatively muted against the variant, they still showed characteristic memory responses. Vaccination with the Wuhan-Hu-1 variant may thus offer a valuable boost to protective responses against subsequent infection with variant viruses. Science , abg9175, this issue p. 1413 ; see also abj2258, p. 1392
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- 2021
34. Prior SARS-CoV-2 infection rescues B and T cell responses to variants after first vaccine dose
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Thomas A. Treibel, Tim Brooks, Rosemary J. Boyton, Marianna Fontana, Mahdad Noursadeghi, Joseph M Gibbons, UK COVIDsortium Investigators, James C. Moon, David Butler, Mala K. Maini, Angelique Smit, Jane E. Sackville-West, Corinna Pade, Catherine J. Reynolds, Amanda Semper, Ashley Otter, Ana M. Valdes, Áine McKnight, Charlotte Manisty, Katia Menacho, Teresa Cutino-Moguel, Benjamin M. Chain, Daniel M. Altmann, Medical Research Council (MRC), UKRI, and Temperton, Nigel J.
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0301 basic medicine ,General Science & Technology ,T cell ,Immunology ,UK COVIDsortium Immune Correlates Network ,Heterologous ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,Report ,medicine ,030212 general & internal medicine ,Memory B cell ,Neutralizing antibody ,B cell ,QR355 ,Multidisciplinary ,biology ,business.industry ,Vaccination ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,Antibody ,business ,Reports ,UK COVIDsortium Investigators - Abstract
A boost from infection During clinical trials of severe acute respiratory syndrome coronavirus 2 vaccines, no one who had survived infection with the virus was tested. A year after the pandemic was declared, vaccination of previously infected persons is a reality. Reynolds et al. address the knowledge gap in a cohort of UK health care workers given the Pfizer/BioNTech vaccine in which half of the participants had experienced natural virus infections early in the pandemic (see the Perspective by Crotty). Genotyping indicated that a genetic component underlies heterogeneity in immune responses to vaccine and to natural infection. After vaccination, naïve individuals developed antibody responses similar to those seen in naturally infected persons, but T cell responses were more limited and sometimes absent. However, antibody and memory responses in individuals vaccinated after infection were substantially boosted to the extent that a single vaccine dose is likely to protect against the more aggressive B.1.1.7 variant. It is possible that the messenger RNA vaccine has an adjuvant effect, biasing responses toward antibody generation. Science , abh1282, this issue p. 1418 ; see also abj2258, p. 1392
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- 2021
35. Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2
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Alessandra Franzetti Pellanda, Jun Siong Low, Michela Perotti, Sandra Jovic, Laurent Perez, Rosalia Cacciatore, Christian Garzoni, Maira Biggiogero, Federico Mele, Josipa Jerak, Mathilde Foglierini, Antonio Lanzavecchia, Daniela Vaqueirinho, Federica Sallusto, Paolo Ferrari, David Jarrossay, Alessandro Ceschi, Tatiana Terrot, and Antonino Cassotta
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,HLA-DP Antigens ,T Follicular Helper Cells ,Receptors, Antigen, T-Cell, alpha-beta ,T cell ,Immunology ,Epitopes, T-Lymphocyte ,Immunodominance ,Cross Reactions ,Biology ,medicine.disease_cause ,Cross-reactivity ,Epitope ,03 medical and health sciences ,0302 clinical medicine ,Protein Domains ,Antigen ,T-Lymphocyte Subsets ,Report ,medicine ,Humans ,Coronavirus ,Multidisciplinary ,Immunodominant Epitopes ,SARS-CoV-2 ,Effector ,COVID-19 ,HLA-DR Antigens ,Nucleocapsid Proteins ,Virology ,Nucleoprotein ,030104 developmental biology ,medicine.anatomical_structure ,Genes, T-Cell Receptor beta ,Spike Glycoprotein, Coronavirus ,Medicine ,Immunologic Memory ,030217 neurology & neurosurgery ,Reports - Abstract
Probing CD4 T cell immunity to SARS-CoV-2 A better understanding of CD4 + T cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to the design of effective next-generation vaccines. Low et al. defined and estimated the CD4 + T cell repertoire of convalescent COVID-19 patients. After sorting various CD4 + T cell subsets, they generated numerous T cell clones that reacted to the SARS-CoV-2 spike protein. A large number of T cell clones from almost all individuals recognized a small conserved immunodominant region within the spike protein receptor-binding domain (RBD). The researchers isolated T cell clones that broadly reacted to the spike protein of other coronaviruses, providing evidence for the recall of preexisting cross-reactive memory T cells after SARS-CoV-2 infection. Science , abg8985, this issue p. 1336
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- 2021
36. Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT
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Stephen B. Long, Thomas L. Benz, and Yiyang Jiang
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Models, Molecular ,Cell signaling ,Acylation ,Lipoylation ,Molecular Dynamics Simulation ,Endoplasmic Reticulum ,Protein Structure, Secondary ,Article ,03 medical and health sciences ,0302 clinical medicine ,Protein structure ,Palmitoylation ,HHAT ,Catalytic Domain ,Humans ,Hedgehog Proteins ,Protein Interaction Domains and Motifs ,Hedgehog ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Palmitoyl Coenzyme A ,biology ,Chemistry ,Endoplasmic reticulum ,Cryoelectron Microscopy ,Wnt signaling pathway ,Active site ,Intracellular Membranes ,Peptide Fragments ,Cell biology ,Biocatalysis ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Protein Processing, Post-Translational ,Acyltransferases ,030217 neurology & neurosurgery - Abstract
How Hedgehog gets its lipid tail Phospholipid membranes serve as barriers between different cellular environments but are also crucial platforms for biosynthesis, signaling, and transport. In animals, the developmental signaling protein Hedgehog must be modified with an acyl group by the membrane-embedded enzyme Hedgehog acyltransferase (HHAT) to be recognized by its receptor. Using cryo–electron microscopy, Jiang et al. determined structures of HHAT bound to palmitoyl–coenzyme A or a palmitoylated peptide product. Two cavities connect at the active site, enabling acylation of Hedgehog in the lumen of the endoplasmic reticulum by lipid substrates from the cytosolic face of the membrane. Science , abg4998, this issue p. 1215
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- 2021
37. Sense codon reassignment enables viral resistance and encoded polymer synthesis
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Sarah L. Maslen, Salvador Buse, Martin Spinck, Louise F. H. Funke, Daniel de la Torre, George P. C. Salmond, Wesley E. Robertson, Thomas S. Elliott, Franz L. Böge, Daniele Cervettini, Julius Fredens, Jason W. Chin, Yonka Christova, and Kim C. Liu
- Subjects
Macrocyclic Compounds ,Polymers ,Computational biology ,Biology ,Sense Codon ,Bacteriolysis ,RNA, Transfer ,Escherichia coli ,Amino Acids ,Codon ,Codon Usage ,RNA, Transfer, Ser ,Multidisciplinary ,Ubiquitin ,Escherichia coli Proteins ,RNA ,Translation (biology) ,Genetic code ,Stop codon ,RNA, Bacterial ,Terminator (genetics) ,Genetic Code ,Mutagenesis ,Protein Biosynthesis ,Codon usage bias ,Codon, Terminator ,T-Phages ,Directed Molecular Evolution ,Release factor ,Gene Deletion ,Genome, Bacterial ,Peptide Termination Factors - Abstract
Designing bacterial superpowers Biological systems read all 64 triplet codons in DNA to encode the synthesis of proteins composed of 20 canonical amino acids. Robertson et al. created cells that do not read several codons and showed that this confers complete resistance to viruses, which normally rely on the host cell's ability to read all the codons in the viral genome to reproduce (see the Perspective by Jewel and Chatterjee). The authors reassigned each codon to several noncanonical amino acids (ncAAs). This advance enables the efficient synthesis of proteins containing three distinct ncAAs and the encoded synthesis of entirely noncanonical polymers and macrocycles. Science , abg3029, this issue p. 1057 ; see also abi9892, p. 1040
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- 2021
38. Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes
- Author
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Lori A. Rowe, Ilya J. Finkelstein, Kamyab Javanmardi, Daniel R. Boutz, Jin Eyun Kim, Shivaprakash Gangappa, Jonathan R. McDaniel, Ralph S. Baric, Dhwani Batra, Maria D. Person, George Georgiou, William N. Voss, Brent L. Iverson, Gregory C. Ippolito, Katia George, Andrew S. Herbert, Yuri Tanno, Foteini Bartzoka, Shawn A. Abbasi, Jason S. McLellan, Jimmy Gollihar, Suryaprakash Sambhara, Daniel Billick, Jule Goike, Chelsea J. Paresi, Whitney Pickens, George Delidakis, Justin S. Lee, Nicole V. Johnson, Yixuan J. Hou, Nianshuang Wang, Andrew P. Horton, Jason J. Lavinder, Jan Pohl, Michelle Gadush, Chia Wei Chou, John M. Dye, and Dalton M Towers
- Subjects
Proteomics ,Protein domain ,Antibody Affinity ,Immunoglobulin Variable Region ,Antibodies, Viral ,medicine.disease_cause ,Article ,Epitope ,Immunoglobulin G ,Epitopes ,Mice ,Protein Domains ,medicine ,Animals ,Humans ,Immune Evasion ,chemistry.chemical_classification ,Mice, Inbred BALB C ,Mutation ,Multidisciplinary ,biology ,SARS-CoV-2 ,Repertoire ,Antibodies, Monoclonal ,COVID-19 ,Antibodies, Neutralizing ,Virology ,chemistry ,Spike Glycoprotein, Coronavirus ,biology.protein ,Immunoglobulin heavy chain ,Antibody ,Immunoglobulin Heavy Chains ,Glycoprotein - Abstract
Although humoral immunity is essential for control of SARS-CoV-2, the molecular composition, binding epitopes and effector functions of the immunoglobulin G (IgG) antibodies that circulate in blood plasma following infection are unknown. Proteomic deconvolution of the circulating IgG repertoire (Ig-Seq (1) ) to the spike ectodomain (S-ECD (2) ) in four convalescent study subjects revealed that the plasma response is oligoclonal and directed predominantly (>80%) to S-ECD epitopes that lie outside the receptor binding domain (RBD). When comparing antibodies directed to either the RBD, the N-terminal domain (NTD) or the S2 subunit (S2) in one subject, just four IgG lineages (1 anti-S2, 2 anti-NTD and 1 anti-RBD) accounted for 93.5% of the repertoire. Although the anti-RBD and one of the anti-NTD antibodies were equally potently neutralizing in vitro , we nonetheless found that the anti-NTD antibody was sufficient for protection to lethal viral challenge, either alone or in combination as a cocktail where it dominated the effect of the other plasma antibodies. We identified in vivo protective plasma anti-NTD antibodies in 3/4 subjects analyzed and discovered a shared class of antibodies targeting the NTD that utilize unmutated or near-germline IGHV1-24, the most electronegative IGHV gene in the human genome. Structural analysis revealed that binding to NTD is dominated by interactions with the heavy chain, accounting for 89% of the entire interfacial area, with germline residues uniquely encoded by IGHV1-24 contributing 20% (149 Å (2) ). Together with recent reports of germline IGHV1-24 antibodies isolated by B-cell cloning (3,4) our data reveal a class of shared IgG antibodies that are readily observed in convalescent plasma and underscore the role of NTD-directed antibodies in protection against SARS-CoV-2 infection.
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- 2021
39. Noncanonical crRNAs derived from host transcripts enable multiplexable RNA detection by Cas9
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Chunlei Jiao, Sahil Sharma, Lars Barquist, Yanying Yu, Oliver Kurzai, Christoph Schoen, Gaurav Dugar, Natalia L. Peeck, Franziska Wimmer, Cynthia M. Sharma, Thorsten Bischler, and Chase L. Beisel
- Subjects
Molec Biol ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Computational biology ,Campylobacter jejuni ,Bacterial genetics ,Nucleic acid thermodynamics ,CRISPR-Associated Protein 9 ,Humans ,CRISPR ,Clustered Regularly Interspaced Short Palindromic Repeats ,RNA, Messenger ,Research Articles ,Gene Editing ,Trans-activating crRNA ,Multidisciplinary ,Base Sequence ,biology ,Diagnostic Tests, Routine ,SARS-CoV-2 ,Cas9 ,R-Articles ,COVID-19 ,Nucleic Acid Hybridization ,RNA ,Microbio ,biology.organism_classification ,RNA, Bacterial ,COVID-19 Nucleic Acid Testing ,Spike Glycoprotein, Coronavirus ,RNA, Viral ,CRISPR-Cas Systems ,Research Article ,RNA, Guide, Kinetoplastida - Abstract
Cellular RNAs guide CRISPR-Cas9 The Cas9 nuclease widely used for genome editing is derived from natural bacterial defense systems that protect against invading viruses. Cas9 is directed by RNA guides to cut matching viral DNA. Jiao et al. discovered that RNA guides can also originate from cellular RNAs unassociated with viral defense (see the Perspective by Abudayyeh and Gootenberg). They rendered this process programmable, linking the presence of virtually any RNA to cutting of matching DNA by Cas9. This capability is the basis of a new CRISPR diagnostic method developed by the authors that can detect many biomarkers at once. Named LEOPARD, this method can detect, for example, RNAs from severe acute respiratory syndrome coronavirus 2 and other viruses, thereby translating a new CRISPR discovery into a powerful diagnostic tool. Science, abe7106, this issue p. 941; see also abi9335, p. 914, Cas9 guide RNAs can be derived from cellular RNAs, inspiring a multiplexable diagnostic platform., CRISPR-Cas systems recognize foreign genetic material using CRISPR RNAs (crRNAs). In type II systems, a trans-activating crRNA (tracrRNA) hybridizes to crRNAs to drive their processing and utilization by Cas9. While analyzing Cas9-RNA complexes from Campylobacter jejuni, we discovered tracrRNA hybridizing to cellular RNAs, leading to formation of “noncanonical” crRNAs capable of guiding DNA targeting by Cas9. Our discovery inspired the engineering of reprogrammed tracrRNAs that link the presence of any RNA of interest to DNA targeting with different Cas9 orthologs. This capability became the basis for a multiplexable diagnostic platform termed LEOPARD (leveraging engineered tracrRNAs and on-target DNAs for parallel RNA detection). LEOPARD allowed simultaneous detection of RNAs from different viruses in one test and distinguished severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its D614G (Asp614→Gly) variant with single-base resolution in patient samples.
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- 2021
40. Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil
- Author
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Esmenia C. Rocha, Vitor H. Nascimento, Pedro S. Peixoto, Thomas A. Mellan, Lucas A M Franco, Henrique Hoeltgebaum, Michaela A. C. Vollmer, Oliver Ratmann, Leonardo José Tadeu de Araújo, Nuno R. Faria, Philippe Lemey, Raphael Sonabend, Myuki A E Crispim, Nelson Gaburo, Charles Whittaker, Joice do P. Silva, Ruben J.G. Hulswit, Ricardo P Schnekenberg, Cecilia da C. Camilo, Mariana C. Pinho, Darlan da Silva Candido, Neil M. Ferguson, Helem M. dos Santos, Ester Cerdeira Sabino, Patrick G T Walker, Hannah M. Schlüter, Carlos A. Prete, Thais M. Coletti, Erika R. Manuli, Oliver G. Pybus, Samir Bhatt, Alessandro C. S. Ferreira, Mariana S. Ramundo, Danielle A G Zauli, Aline B. de Lima, Jaqueline Goes de Jesus, Iwona Hawryluk, Frederico S V Malta, Marc A. Suchard, Leandro Marques de Souza, Seth Flaxman, Moritz U. G. Kraemer, James A. Hay, Valentina S. Del Caro, Rosinaldo M. F. Filho, Axel Gandy, Pamela S Andrade, Andrew Rambaut, Ingra Morales Claro, Ana L. P. dos Santos, Christopher Dye, José Luiz Proença-Módena, Swapnil Mishra, Daniel J Laydon, William Marciel de Souza, Renato Santana Aguiar, Xenia Miscouridou, Camila A. M. Silva, Maria S. Vidal, John T. McCrone, Maria Perpétuo Socorro Sampaio Carvalho, Nicholas J. Loman, Giulia M. Ferreira, Bruce Walker Nelson, Chieh-Hsi Wu, Thomas A. Bowden, Melodie Monod, Helen Coupland, Rafael Henrique Moraes Pereira, Flavia C. S. Sales, Sergei L Kosakovsky Pond, Nelson Abrahim Fraiji, Bill & Melinda Gates Foundation, Wellcome Trust, and Medical Research Council (MRC)
- Subjects
DYNAMICS ,0301 basic medicine ,MATEMÁTICA APLICADA ,Lineage (genetic) ,General Science & Technology ,LOCAL TRANSMISSION ,Genomics ,Genome, Viral ,Communicable Diseases, Emerging ,Genome ,DNA sequencing ,03 medical and health sciences ,0302 clinical medicine ,Molecular evolution ,Humans ,030212 general & internal medicine ,Molecular clock ,Molecular Epidemiology ,SITES ,Science & Technology ,RECEPTOR-BINDING DOMAIN ,Multidisciplinary ,Molecular epidemiology ,biology ,SARS-CoV-2 ,MOLECULAR CLOCK ,COVID-19 ,Models, Theoretical ,Viral Load ,PERFORMANCE ,biology.organism_classification ,Virology ,3. Good health ,Multidisciplinary Sciences ,030104 developmental biology ,Epidemiological Monitoring ,Mutation ,Spike Glycoprotein, Coronavirus ,Science & Technology - Other Topics ,Angiotensin-Converting Enzyme 2 ,RESPIRATORY-SYNDROME-CORONAVIRUS ,Brazil ,Betacoronavirus ,Protein Binding - Abstract
Unmitigated spread in Brazil Despite an extensive network of primary care availability, Brazil has suffered profoundly during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Using daily data from state health offices, Castro et al. analyzed the pattern of spread of COVID-19 cases and deaths in the country from February to October 2020. Clusters of deaths before cases became apparent indicated unmitigated spread. SARS-CoV-2 circulated undetected in Brazil for more than a month as it spread north from Sã o Paulo. In Manaus, transmission reached unprecedented levels after a momentary respite in mid-2020. Faria et al. tracked the evolution of a new, more aggressive lineage called P.1, which has 17 mutations, including three (K417T, E484K, and N501Y) in the spike protein. After a period of accelerated evolution, this variant emerged in Brazil during November 2020. Coupled with the emergence of P.1, disease spread was accelerated by stark local inequalities and political upheaval, which compromised a prompt federal response. Science , abh1558 and abh2644, this issue p. 821 and p. 815
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- 2021
41. Shared B cell memory to coronaviruses and other pathogens varies in human age groups and tissues
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Khoa D. Nguyen, Grace H. Jean, Claus U. Niemann, Katherine J. L. Jackson, Tho D. Pham, Ramona A. Hoh, Emily Haraguchi, Katharina Röltgen, Julie Parsonnet, Yi Liu, Sandra C. A. Nielsen, Fan Yang, Kari C. Nadeau, Ji-Yeun Lee, Scott D. Boyd, Krishna M. Roskin, Robert S. Ohgami, Eleanor M. Osborne, and Oliver F. Wirz
- Subjects
Male ,0301 basic medicine ,Aging ,viruses ,Antibodies, Viral ,medicine.disease_cause ,Serology ,0302 clinical medicine ,Coronavirus ,Aged, 80 and over ,B-Lymphocytes ,Multidisciplinary ,Genes, Immunoglobulin ,virus diseases ,Middle Aged ,Ebolavirus ,Fetal Blood ,medicine.anatomical_structure ,Child, Preschool ,Medicine ,Female ,Antibody ,Immunoglobulin Heavy Chains ,Clone (B-cell biology) ,Adult ,Adolescent ,Immunology ,Receptors, Antigen, B-Cell ,Somatic hypermutation ,Spleen ,Cross Reactions ,Biology ,Young Adult ,03 medical and health sciences ,Report ,medicine ,Humans ,B cell ,Aged ,SARS-CoV-2 ,Infant ,Immunoglobulin D ,Immunoglobulin Class Switching ,030104 developmental biology ,Immunoglobulin M ,Immunoglobulin class switching ,biology.protein ,Lymph Nodes ,Somatic Hypermutation, Immunoglobulin ,Immunologic Memory ,Reports ,030215 immunology - Abstract
Kids armed with anti-coronavirus B cells It remains unclear whether B cell repertoires against coronaviruses and other pathogens differ between adults and children and how important these distinctions are. Yang et al. analyzed blood samples from young children and adults, as well as tissues from deceased organ donors, characterizing the B cell receptor (BCR) repertoires specific to six common pathogens and two viruses that they had not seen before: Ebola virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Children had higher frequencies of B cells with convergent BCR heavy chains against previously encountered pathogens and higher frequencies of class-switched convergent B cell clones against SARS-CoV-2 and related coronaviruses. These findings suggest that encounters with coronaviruses in early life may produce cross-reactive memory B cell populations that contribute to divergent COVID-19 susceptibilities. Science, this issue p. 738, Blood taken from children before the COVID-19 pandemic contains memory B cells that bind SARS-CoV-2., Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated pediatric and adult blood and deceased adult organ donor tissues to determine convergent antigen-specific antibody genes of similar sequences shared between individuals. B cell memory varied for different pathogens. Polysaccharide antigenspecific clones were not exclusive to the spleen. Adults had higher clone frequencies and greater class switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones. Consistent with reported serology, prepandemic children had class-switched convergent clones to severe acute respiratory syndrome coronavirus 2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. These results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens.
- Published
- 2021
42. Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis
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Isaac Adatto, Ying Wang, Stuart L. Schreiber, Leonard I. Zon, Lucas B. Sullivan, Raha Weigert, Chad A. Cowan, Bilguujin Dorjsuren, Partha P. Nag, Marlies P. Rossmann, Siegfried Hekimi, Ilaria Elia, Richard A. Young, Sejal Vyas, James Mullahoo, Julie R. Perlin, Curtis R. Warren, Brian J. Abraham, Alexander Meissner, Song Yang, Malvina Papanastasiou, Sara Hetzel, Victoria Chan, Karen Hoi, Marcia C. Haigis, Elliott J. Hagedorn, Eugenia Custo Greig, and Steven A. Carr
- Subjects
Oxidoreductases Acting on CH-CH Group Donors ,Embryo, Nonmammalian ,Transcription, Genetic ,Ubiquinone ,Citric Acid Cycle ,Dihydroorotate Dehydrogenase ,Biology ,Cell fate determination ,Methylation ,Article ,Electron Transport ,Histones ,03 medical and health sciences ,Oxygen Consumption ,0302 clinical medicine ,Transcription (biology) ,Histone methylation ,Transcriptional regulation ,Animals ,Erythropoiesis ,Enzyme Inhibitors ,Transcription factor ,Zebrafish ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Multidisciplinary ,DNA Methylation ,Zebrafish Proteins ,Mitochondria ,Cell biology ,Gene Expression Regulation ,DNA methylation ,Dihydroorotate dehydrogenase ,Leflunomide ,Metabolic Networks and Pathways ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Metabolic pathway regulates cell fate Lineage-specific regulators direct cell fate decisions, but the precise mechanisms are not well known. Using an in vivo chemical suppressor screen of a bloodless zebrafish mutant, Rossmann et al. show that the lineage-specific chromatin factor tif1γ directly regulates mitochondrial genes to drive red blood cell differentiation. Loss of tif1γ reduces coenzyme Q synthesis and function, impeding mitochondrial respiration and leading to epigenetic alterations and repression of erythropoiesis. The loss of blood in the mutant fish can be rescued by the addition of coenzyme Q. This work establishes a mechanism by which a chromatin factor tunes a metabolic pathway in a tissue-specific manner. Science , this issue p. 716
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- 2021
43. Timing the SARS-CoV-2 index case in Hubei province
- Author
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Michael Worobey, Jonathan Pekar, Konrad Scheffler, Niema Moshiri, and Joel O. Wertheim
- Subjects
Epidemiology ,viruses ,Inference ,Viral Zoonoses ,Coalescent theory ,Theoretical ,Models ,Pandemic ,Viral ,Molecular clock ,Lung ,Index case ,Phylogeny ,Genome ,Multidisciplinary ,Mortality rate ,Zoonosis ,Geography ,Infectious Diseases ,Pneumonia & Influenza ,Infection ,2019-20 coronavirus outbreak ,China ,Coronavirus disease 2019 (COVID-19) ,Evolution ,General Science & Technology ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Genome, Viral ,Biology ,Article ,Vaccine Related ,Evolution, Molecular ,Report ,Biodefense ,Environmental health ,medicine ,Animals ,Humans ,Computer Simulation ,Pandemics ,Retrospective Studies ,SARS-CoV-2 ,Prevention ,Molecular ,COVID-19 ,Pneumonia ,Models, Theoretical ,medicine.disease ,body regions ,Emerging Infectious Diseases ,Good Health and Well Being ,Genetic Fitness ,Reports - Abstract
Backtracking a pandemic Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have had a history of abortive human infections before a variant established a productive enough infection to create a transmission chain with pandemic potential. Therefore, the Wuhan cluster of infections identified in late December of 2019 may not have represented the initiating event. Pekar et al. used genome data collected from the early cases of the COVID-19 pandemic combined with molecular clock inference and epidemiological simulation to estimate when the most successful variant gained a foothold in humans. This analysis pushes human-to-human transmission back to mid-October to mid-November of 2019 in Hubei Province, China, with a likely short interval before epidemic transmission was initiated. Science, this issue p. 412, SARS-CoV-2 human-to-human transmission likely initiated in mid-October to mid-November 2019 in Hubei, China., Understanding when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged is critical to evaluating our current approach to monitoring novel zoonotic pathogens and understanding the failure of early containment and mitigation efforts for COVID-19. We used a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations to determine how long SARS-CoV-2 could have circulated before the time of the most recent common ancestor of all sequenced SARS-CoV-2 genomes. Our results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province, China. By characterizing the likely dynamics of the virus before it was discovered, we show that more than two-thirds of SARS-CoV-2like zoonotic events would be self-limited, dying out without igniting a pandemic. Our findings highlight the shortcomings of zoonosis surveillance approaches for detecting highly contagious pathogens with moderate mortality rates.
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- 2021
44. Replication timing maintains the global epigenetic state in human cells
- Author
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David M. Gilbert, Shin-ichiro Hiraga, Toyoaki Natsume, Danny Leung, Ipek Tasan, Xuemeng Zhou, Anne D. Donaldson, Meng Zhang, Daniel A. Bartlett, Xiaowen Lyu, Takayo Sasaki, Timour Baslan, Amar M. Singh, Victor G. Corces, Masato T. Kanemaki, Lotte P. Watts, Kyle N. Klein, Stephen Dalton, Huimin Zhao, and Peiyao A. Zhao
- Subjects
DNA Replication ,DNA Replication Timing ,Telomere-Binding Proteins ,Gene Expression ,Article ,Cell Line ,Epigenesis, Genetic ,Histones ,Epigenome ,Gene Knockout Techniques ,03 medical and health sciences ,0302 clinical medicine ,Heterochromatin ,Humans ,Histone code ,Epigenetics ,030304 developmental biology ,0303 health sciences ,Replication timing ,Multidisciplinary ,biology ,Genome, Human ,DNA replication ,Chromatin Assembly and Disassembly ,Chromatin ,Cell biology ,Histone Code ,Histone ,biology.protein ,030217 neurology & neurosurgery - Abstract
Replication timing organizes epigenome The temporal order of DNA replication is conserved from yeast to humans, but its biological significance remains unclear. Klein et al. eliminated the protein RIF1, a master regulator of replication timing, in several human cell lines. RIF1 loss during the G1 phase of the cell cycle resulted in a heterogeneous, nearly random replication timing program from the first S phase that persisted even in stable RIF1-null clones. Altered replication timing was followed by replication-dependent redistribution of active and repressive histone modifications and alterations in genome architecture. These results support a model in which replication timing orchestrates the epigenetic state of newly replicated chromatin. Science , this issue p. 371
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- 2021
45. Decoupling transcription factor expression and activity enables dimmer switch gene regulation
- Author
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Michael Springer, Jing Wang, Chiara Ricci-Tam, Julius Palme, Yonatan Savir, Ishay Ben-Zion, and Ang Li
- Subjects
Saccharomyces cerevisiae Proteins ,Transcription, Genetic ,Dimmer ,Gene regulatory network ,Saccharomyces cerevisiae ,Biology ,Article ,Galactokinase ,03 medical and health sciences ,0302 clinical medicine ,Transcription (biology) ,Gene Expression Regulation, Fungal ,Gene Regulatory Networks ,Promoter Regions, Genetic ,Gene ,Transcription factor ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Multidisciplinary ,Models, Genetic ,Galactose ,Promoter ,Chromatin ,Cell biology ,DNA-Binding Proteins ,Repressor Proteins ,Glucose ,Genetic Fitness ,Metabolic Networks and Pathways ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Circuit design for control of metabolism A transcriptional control mechanism in yeast that allows cells to respond to changes in nutrient concentrations works very much like a household light-dimmer switch. That is, the system separately controls whether gene expression is “on” or “off” and the extent of gene expression. The galactose-responsive pathway is activated when yeast need to switch from metabolizing glucose to metabolizing galactose. Ricci-Tam et al. found that, rather than using two separate elements for the switch and dimmer controls, yeast use a single transcription factor, Gal4p, separately regulating its abundance (through transcriptional regulation) and its catalytic activity (through interaction with a protein-binding partner). Such regulation may be common and can allow responses to the environment on physiological and evolutionary time scales. Science , this issue p. 292
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- 2021
46. Bilateral visual projections exist in non-teleost bony fish and predate the emergence of tetrapods
- Author
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Karine Duroure, Robin J. Vigouroux, Rodrigo Suárez, Juliette Vougny, Kim T. Nguyen-Ba-Charvet, Alain Chédotal, Eloisa Herrera, Shahad Albadri, Filippo Del Bene, Ingo Braasch, Peter Kozulin, Agence Nationale de la Recherche (France), National Institutes of Health (US), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Queensland [Brisbane], Michigan State University [East Lansing], Michigan State University System, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HAL-SU, Gestionnaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Instituto de Neurociencias de Alicante
- Subjects
Fish Proteins ,Retinal Ganglion Cells ,genetic structures ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Visual system ,Eye ,ZIC2 ,Retinal ganglion ,Functional Laterality ,Retina ,Article ,[PHYS] Physics [physics] ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Visual Pathways ,14. Life underwater ,Zebrafish ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,[PHYS]Physics [physics] ,Vision, Binocular ,0303 health sciences ,Multidisciplinary ,biology ,Fishes ,Brain ,Nuclear Proteins ,Cell Differentiation ,Anatomy ,biology.organism_classification ,Biological Evolution ,eye diseases ,Ganglion ,[SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis ,medicine.anatomical_structure ,Retinal ganglion cell ,Laterality ,sense organs ,Binocular vision ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
In most vertebrates, camera-style eyes contain retinal ganglion cell neurons that project to visual centers on both sides of the brain. However, in fish, ganglion cells were thought to innervate only the contralateral side, suggesting that bilateral visual projections appeared in tetrapods. Here we show that bilateral visual projections exist in non-teleost fishes and that the appearance of ipsilateral projections does not correlate with terrestrial transition or predatory behavior. We also report that the developmental program that specifies visual system laterality differs between fishes and mammals, as the Zic2 transcription factor, which specifies ipsilateral retinal ganglion cells in tetrapods, appears to be absent from fish ganglion cells. However, overexpression of human ZIC2 induces ipsilateral visual projections in zebrafish. Therefore, the existence of bilateral visual projections likely preceded the emergence of binocular vision in tetrapods., This work was supported by Programme Investissements d’Avenir IHU FOReSIGHT (ANR-18-IAHU-01) (A.C. and F.D.B.), INSERM cross-cutting program HuDeCA 2018 (A.C.), NIH R01OD011116 (I.B.), and UQ Amplify Fellowship (R.S.)
- Published
- 2021
47. Control of meiotic chromosomal bouquet and germ cell morphogenesis by the zygotene cilium
- Author
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Mytlis, Avishag, Kumar, Vineet, Qiu, Tao, Deis, Rachael, Hart, Neta, Levy, Karine, Masek, Markus, Shawahny, Amal, Ahmad, Adam, Eitan, Hagai, Nather, Farouq, Adar-Levor, Shai, Birnbaum, Ramon Y, Elia, Natalie, Bachmann-Gagescu, Ruxandra, Roy, Sudipto, Elkouby, Yaniv M, and University of Zurich
- Subjects
10039 Institute of Medical Genetics ,Ovary* / growth & development ,Zebrafish / genetics ,Centromere ,610 Medicine & health ,Mice ,Oogenesis ,Centromere / genetics ,Morphogenesis ,Animals ,Mice Morphogenesis Oocytes* / growth & development ,Cilia ,Zebrafish ,Female Fertility / physiology ,1000 Multidisciplinary ,Multidisciplinary ,Cilia* / physiology ,Centromere / physiology ,Ovary ,Chromosome Pairing* / genetics ,Telomere / genetics ,Chromosome Pairing* / physiology ,Telomere ,10124 Institute of Molecular Life Sciences ,Chromosome Pairing ,Fertility ,Telomere / physiology ,Oocytes ,570 Life sciences ,biology ,Female ,Zebrafish / physiology ,Oogenesis* / physiology ,Oogenesis* / genetics - Abstract
A hallmark of meiosis is chromosomal pairing, which requires telomere tethering and rotation on the nuclear envelope through microtubules, driving chromosome homology searches. Telomere pulling toward the centrosome forms the “zygotene chromosomal bouquet.” Here, we identified the “zygotene cilium” in oocytes. This cilium provides a cable system for the bouquet machinery and extends throughout the germline cyst. Using zebrafish mutants and live manipulations, we demonstrate that the cilium anchors the centrosome to counterbalance telomere pulling. The cilium is essential for bouquet and synaptonemal complex formation, oogenesis, ovarian development, and fertility. Thus, a cilium represents a conserved player in zebrafish and mouse meiosis, which sheds light on reproductive aspects in ciliopathies and suggests that cilia can control chromosomal dynamics.
- Published
- 2022
48. Landmarks of human embryonic development inscribed in somatic mutations
- Author
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Christopher A. Walsh, Sara Bizzotto, Peter J. Park, Min-Seok Kwon, Craig L. Bohrson, Ryan N. Doan, Sonia N. Kim, Alexej Abyzov, Yanmei Dou, Javier Ganz, and Taejeong Bae
- Subjects
Whole genome sequencing ,0303 health sciences ,Multidisciplinary ,Somatic cell ,Germ layer ,Biology ,Embryonic stem cell ,Chromatin ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,Single-cell analysis ,Human embryogenesis ,Progenitor cell ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Mutations provide an enduring record Somatic mutations pepper our cells with change, but because they are not in the germline, they do not propagate to the next generation. Bizzotto et al. leveraged data on the distribution of somatic mutations in adults to take a backward look at the earliest moments of human development. Calculation of cellular lineages on the basis of shared somatic mutations shows the number of cells from which the body will develop when the human embryo gastrulates. The lineage for forebrain cells is identifiable, as are the asymmetrical fates spun out of many of the gastrula cells. Science , this issue p. 1249
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- 2021
49. Debaryomyces is enriched in Crohn’s disease intestinal tissue and impairs healing in mice
- Author
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Umang Jain, Jonathan Braun, Deborah A. Hogan, Shanshan Xiong, Elora G. Demers, Derek A.G. Barisas, Ta-Chiang Liu, Martin H. Gregory, Chin-Wen Lai, Philip Debbas, Aaron M. Ver Heul, David M. Underhill, Justin Kern, J. Steven Leal-Ekman, Matthew A. Ciorba, Parakkal Deepak, Brian D. Muegge, Dermot P.B. McGovern, and Thaddeus S. Stappenbeck
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Debaryomyces ,Inflammation ,medicine.disease_cause ,Inflammatory bowel disease ,Article ,Autoimmunity ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Crohn Disease ,Gastrointestinal Agents ,Debaryomyces hansenii ,Animals ,Medicine ,Wound Healing ,Crohn's disease ,Multidisciplinary ,Innate immune system ,biology ,business.industry ,medicine.disease ,biology.organism_classification ,Infliximab ,Pathophysiology ,030104 developmental biology ,030211 gastroenterology & hepatology ,medicine.symptom ,business - Abstract
Fungal aggravation The gut microbiota includes not only prokaryotes, viruses, protists, and occasionally helminths, but also fungi. The role that fungi play in this symbiosis has long been overlooked. While investigating alterations to the gut microbiota in mice with mucosal damage and human subjects with Crohn's disease, Jain et al. discovered the fungus Debaryomyces hansenii localized to wounds in inflamed mucosal tissue (see the Perspective by Chiaro and Round). Impaired healing was associated with antibiotic treatment, overgrowth of the fungus, and subsequent induction of a type I interferon–CCL5 axis by macrophages. The fungus was observed within macrophages. Such persistent injury stimulus is a hallmark of inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. It is not known whether this salt-tolerant fungus is a natural symbiont, but it is used in the food industry for surface ripening of cheese and meat products. Science , this issue p. 1154 ; see also p. 1102
- Published
- 2021
50. C. elegans discriminates colors to guide foraging
- Author
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Dongyeop Lee, H. Robert Horvitz, Xin Jin, D. Dipon Ghosh, and Michael N. Nitabach
- Subjects
Opsin ,Multidisciplinary ,biology ,Phylum ,Color vision ,Evolutionary biology ,Cellular stress response ,Foraging ,biology.organism_classification ,Gene ,Caenorhabditis elegans ,Conserved sequence - Abstract
A new way to “see” color Color perception is an important aspect of the way many organisms navigate their world. The ability to perceive color has thus far thought to depend on the presence of either eyes or minimally receptive cells containing opsin receptor genes. Ghosh et al. show that foraging Caenorhabditis elegans roundworms, which do not have eyes or opsins, can distinguish a blue color indicative of a toxin released by bacterial mats (see the Perspective by Neal and Vosshall). They suggest that the worms do this through the detection of the ratio between blue and amber light, a process dependent on at least two cellular stress-response genes. Different strains of C. elegans responded to different ratios, suggesting that this pathway plays an ecological role. Science , this issue p. 1059 ; see also p. 995
- Published
- 2021
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