Changes in genetic selection differentials and generation intervals in US Holstein dairy cattle as a result of genomic selection
Adriana García-Ruiz, John B. Cole, Paul M. VanRaden, George R. Wiggans, Felipe J. Ruiz-López, and Curtis P. Van Tassell
The introduction of genomic selection in dairy cattle improvement programs in 2008 was expected to increase rates of genetic gain, particularly for traits with low heritabilities, such as fertility and longevity. Our analysis of the US national dairy database found that generation intervals have decreased dramatically over the past 6 y, and selection intensity for lowly heritable traits has increased considerably. Genetic trends rapidly increased for fertility, lifespan, and udder health. These results clearly demonstrate the positive impact of genomic selection in US dairy cattle, even though this technology has only been in use for a short time. This progress in US Holsteins will have a favorable impact on other populations worldwide due to the widespread dissemination of US germplasm. (See pp. E3995–E4004.)
Structural basis of viral RNA-dependent RNA polymerase catalysis and translocation
Bo Shu and Peng Gong
RNA viruses encode a unique class of RNA-dependent RNA polymerases (RdRPs) to carry out their fully RNA-based genome replication and transcription. Although the chemical nature of nucleotide addition is essentially shared by all nucleic acid polymerases, the structural and mechanistic details taken by each polymerase class differ to various extents. Here we report seven crystal structures of enterovirus 71 RdRP elongation complex at 2.5–2.8 Å resolution. In these structures the polymerases are poised at various distinct stages to reveal mechanistic details of initial NTP binding, key amino acid side-chain conformational switches during active site closure, and in particular the postcatalysis movement of the RNA duplex on the way to vacate the active site for the next nucleotide addition cycle. (See pp. E4005–E4014.)
Htm1p–Pdi1p is a folding-sensitive mannosidase that marks N-glycoproteins for ER-associated protein degradation
Yi-Chang Liu, Danica Galonić Fujimori, and Jonathan S. Weissman
During the biogenesis of proteins destined for the secretory pathway, proteins that fail to fold correctly are retained in the endoplasmic reticulum (ER) and targeted for degradation through a quality-control system called “ER-associated protein degradation” (ERAD), but how misfolded proteins are defined has remained unknown. Here we studied the ERAD pathway for misfolded N-glycoproteins, whose ERAD commitment requires the generation of a unique N-glycan structure by the action of the complex of the mannosidase Htm1p and the protein disulfide isomerase Pdi1p (Htm1p–Pdi1p). We found that Htm1p–Pdi1p differentiates the conformations of different N-glycoproteins and preferentially targets proteins trapped in partially structured states. In summary, our study reveals a conformational standard of how ERAD targets the right proteins for degradation. (See pp. E4015–E4024.)
Algorithmic methods to infer the evolutionary trajectories in cancer progression
Giulio Caravagna, Alex Graudenzi, Daniele Ramazzotti, Rebeca Sanz-Pamplona, Luca De Sano, Giancarlo Mauri, Victor Moreno, Marco Antoniotti, and Bud Mishra
A causality-based machine learning Pipeline for Cancer Inference (PiCnIc) is introduced to infer the underlying somatic evolution of ensembles of tumors from next-generation sequencing data. PiCnIc combines techniques for sample stratification, driver selection, and identification of fitness-equivalent exclusive alterations to exploit an algorithm based on Suppes’ probabilistic causation. The accuracy and translational significance of the results are studied in detail, with an application to colorectal cancer. The PiCnIc pipeline has been made publicly accessible for reproducibility, interoperability, and future enhancements. (See pp. E4025–E4034.)
Macronutrient ratios in pollen shape bumble bee (Bombus impatiens) foraging strategies and floral preferences
Anthony D. Vaudo, Harland M. Patch, David A. Mortensen, John F. Tooker, and Christina M. Grozinger
Bees pollinate the majority of flowering plant species, including agricultural crops. The pollen they obtain is their main protein and lipid source that fuels development and reproduction. Bee populations are declining globally, in large part because of landscape-level loss of host-plant species contributing to a nutritional shortage. To mitigate declines, we must understand how the nutritional requirements of bees influence foraging behavior. We demonstrate that bumble bees selectively collect pollen from host-plant species based on the protein:lipid ratios of pollen. Our research indicates that bees evaluate pollen quality and adjust foraging decisions to meet their nutritional needs. To be effective, conservation initiatives must include host-plant species that provide pollen that satisfies the nutritional demands of bees to support their populations. (See pp. E4035–E4042.)
Large-scale climatic and geophysical controls on the leaf economics spectrum
Gregory P. Asner, David E. Knapp, Christopher B. Anderson, Roberta E. Martin, and Nicholas Vaughn
Ecology seeks general principles describing how the biota respond to multiple environmental factors, partly to build a more prognostic science in the face of global climate change. One such principle to emerge is the “leaf economics spectrum” (LES), which relates ecologically important plant nutrients to leaf construction and growth along simple relational axes. However, interrelationships between LES traits have not been tested at large geographic scales. Using airborne imaging spectroscopy and geospatial modeling, we discovered strong climatic and geophysical controls on LES traits and their interrelationships throughout Andean and western Amazonian forest canopies. This finding highlights the need for biogeographically explicit treatment of plant traits, afforded by imaging spectroscopy, in the next generation of biospheric models. (See pp. E4043–E4051.)
Chromosome-level assembly of Arabidopsis thaliana Ler reveals the extent of translocation and inversion polymorphisms
Luis Zapata, Jia Ding, Eva-Maria Willing, Benjamin Hartwig, Daniela Bezdan, Wen-Biao Jiao, Vipul Patel, Geo Velikkakam James, Maarten Koornneef, Stephan Ossowski, and Korbinian Schneeberger
Despite widespread reports on deciphering the sequences of all kinds of genomes, most of these reconstructed genomes rely on a comparison of short DNA sequencing reads to a reference sequence, rather than being independently reconstructed. This method limits the insights on genomic differences to local, mostly small-scale variation, because large rearrangements are likely overlooked by current methods. We have de novo assembled the genome of a common strain of Arabidopsis thaliana Landsberg erecta and revealed hundreds of rearranged regions. Some of these differences suppress meiotic recombination, impacting the haplotypes of a worldwide population of A. thaliana. In addition to sequence changes, this work, which, to our knowledge is the first comparison of an independent, chromosome-level assembled A. thaliana genome, revealed hundreds of unknown, accession-specific genes. (See pp. E4052–E4060.)
Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis
Reitaro Tokumasu, Kosuke Yamaga, Yuji Yamazaki, Hiroyuki Murota, Koya Suzuki, Atsushi Tamura, Kana Bando, Yasuhide Furuta, Ichiro Katayama, and Sachiko Tsukita
Claudin-1 (CLDN1), which is thought to be a key gene for human skin disease, especially atopic dermatitis (AD), encodes the dominant claudin responsible for the paracellular barrier at tight junctions in the epidermis. Although decreased CLDN1 expression levels are reported in AD patients, it has been difficult to study how CLDN1 contributes to AD development, mainly because Cldn1 knock-out mice die within 1 d after birth from dehydration. In this report, we reproduced features of human AD in mice, by systematically regulating the Cldn1 expression level. Our experimental approach contributes to the understanding of AD’s etiology and suggests a therapeutic target for this disorder. (See pp. E4061–E4068.)
Visualizing in situ translational activity for identifying and sorting slow-growing archaeal−bacterial consortia
Roland Hatzenpichler, Stephanie A. Connon, Danielle Goudeau, Rex R. Malmstrom, Tanja Woyke, and Victoria J. Orphan
One of the biggest challenges in environmental microbiology is to determine the activity of uncultured cells directly in their habitat. We report on the application of bioorthogonal noncanonical amino acid tagging (BONCAT), a high-throughput approach to detecting protein synthesis in individual cells by fluorescence staining, on deep-sea methane seep sediments. By combining BONCAT with fluorescence in situ hybridization, we visualized active archaeal−bacterial consortia catalyzing the anaerobic oxidation of methane. We further developed a novel approach that combines BONCAT with fluorescence-activated cell sorting (FACS) to separate translationally active cells from complex samples. BONCAT-FACS enabled us to directly link the identities of anaerobic methane-oxidizing archaea with their partner bacteria for individual active consortia, uncovering previously unknown interactions between these archaea and Verrucomicrobia. (See pp. E4069–E4078.)
Solid tumor therapy by selectively targeting stromal endothelial cells
Shihui Liu, Jie Liu, Qian Ma, Liu Cao, Rasem J. Fattah, Zuxi Yu, Thomas H. Bugge, Toren Finkel, and Stephen H. Leppla
Anthrax toxin proteins engineered to require activation by tumor-associated proteases show high specificity and potency in suppression of solid tumor growth through actions on tumor endothelial cells. The toxin strongly inhibits proliferation of tumor endothelial cells. Importantly, an immunosuppressive regimen (pentostatin plus cyclophosphamide) not only prevents induction of toxin-neutralizing antibodies, allowing multiple courses of toxin treatment, but also has strong synergy with the toxin on solid tumors. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelium, suggests that our strategy should be efficacious for a wide range of solid tumors, meriting its clinical evaluation. (See pp. E4079–E4087.)
A face-selective ventral occipito-temporal map of the human brain with intracerebral potentials
Jacques Jonas, Corentin Jacques, Joan Liu-Shuang, Hélène Brissart, Sophie Colnat-Coulbois, Louis Maillard, and Bruno Rossion
Understanding the neural basis of face perception, arguably the most important visual function for human social ecology, is of the utmost importance. With an original fast periodic visual stimulation approach, we provide a comprehensive quantification of selective brain responses to faces throughout the ventral visual stream with direct recordings in the gray matter. Selective responses to faces are distributed in the whole ventral occipito-temporal cortex, with a right hemispheric and regional specialization supporting two decades of indirect recordings of human brain activity in neuroimaging. We also disclose three distinct face-selective regions in the anterior temporal lobe, an undersampled region in neuroimaging, and reveal exclusive responses to faces at the neural population level in these regions. (See pp. E4088–E4097.)
ATP: The crucial component of secretory vesicles
Judith Estévez-Herrera, Natalia Domínguez, Marta R. Pardo, Ayoze González-Santana, Edward W. Westhead, Ricardo Borges, and José David Machado
ATP is highly concentrated in secretory vesicles. In vitro experiments suggest that the association of ATP with catecholamines reduces their osmotic forces, permitting the extraordinary accumulation of amines within chromaffin granules. However, this has yet to be proved in living cells. Because functional cells cannot be deprived of ATP, we manipulated the vesicular nucleotide carrier, demonstrating that the extent of vesicular ATP is closely linked to the quantum catecholamine size. This is particularly evident in newly synthesized vesicles, the first to be released. This is the in vivo demonstration that vesicular ATP is an essential factor in the accumulation of neurotransmitters, which may well be a wider mechanism supporting quantal transmission. (See pp. E4098–E4106.)
β-arrestin–biased signaling through the β2-adrenergic receptor promotes cardiomyocyte contraction
Richard Carr III, Justin Schilling, Jianliang Song, Rhonda L. Carter, Yang Du, Sungsoo M. Yoo, Christopher J. Traynham, Walter J. Koch, Joseph Y. Cheung, Douglas G. Tilley, and Jeffrey L. Benovic
Commonly prescribed drugs for congestive heart failure (CHF) include β-adrenergic receptor antagonists or β-blockers. These drugs operate by inhibiting deleterious apoptotic signaling and normalizing inotropic signaling from these receptors. As the β-adrenergic receptor (β1AR) (dominant subtype in the heart) is systematically down-regulated during CHF while Gi (a G protein that antagonizes contractile signaling) is up-regulated, the ability to selectively control β2AR signaling becomes an attractive therapeutic approach. It is proposed that biasing receptor interaction with β-arrestins (promoting antiapoptotic signaling and possibly contraction) over G proteins may be therapeutically advantageous for the treatment of CHF. Here, we report a β-arrestin–biased pepducin of the β2AR that is able to induce cardiomyocyte contractility and antiapoptotic signaling to provide a pharmacological template for next-generation cardiovascular pharmaceuticals. (See pp. E4107–E4116.)