PNAS Early Edition Articles

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Probabilistic models of species discovery and biodiversity comparisons [Ecology]

Tue, 03/21/2017 - 09:32
Inferring large-scale processes that drive biodiversity hinges on understanding the phylogenetic and spatial pattern of species richness. However, clades and geographic regions are accumulating newly described species at an uneven rate, potentially affecting the stability of currently observed diversity patterns. Here, we present a probabilistic model of species discovery to...

Perceptual integration without conscious access [Psychological and Cognitive Sciences]

Tue, 03/21/2017 - 09:32
The visual system has the remarkable ability to integrate fragmentary visual input into a perceptually organized collection of surfaces and objects, a process we refer to as perceptual integration. Despite a long tradition of perception research, it is not known whether access to consciousness is required to complete perceptual integration....

Experimental comparison of two quantum computing architectures [Computer Sciences]

Tue, 03/21/2017 - 09:32
We run a selection of algorithms on two state-of-the-art 5-qubit quantum computers that are based on different technology platforms. One is a publicly accessible superconducting transmon device (www.research.ibm.com/ibm-q) with limited connectivity, and the other is a fully connected trapped-ion system. Even though the two systems have different native quantum interactions,...

Balancing selection maintains polymorphisms at neurogenetic loci in field experiments [Evolution]

Tue, 03/21/2017 - 09:32
Most variation in behavior has a genetic basis, but the processes determining the level of diversity at behavioral loci are largely unknown for natural populations. Expression of arginine vasopressin receptor 1a (Avpr1a) and oxytocin receptor (Oxtr) in specific regions of the brain regulates diverse social and reproductive behaviors in mammals,...

Ab initio solution of macromolecular crystal structures without direct methods [Biophysics and Computational Biology]

Tue, 03/21/2017 - 09:32
The majority of macromolecular crystal structures are determined using the method of molecular replacement, in which known related structures are rotated and translated to provide an initial atomic model for the new structure. A theoretical understanding of the signal-to-noise ratio in likelihood-based molecular replacement searches has been developed to account...

Comprehensive and quantitative mapping of RNA-protein interactions across a transcribed eukaryotic genome [Biochemistry]

Tue, 03/21/2017 - 09:32
RNA-binding proteins (RBPs) control the fate of nearly every transcript in a cell. However, no existing approach for studying these posttranscriptional gene regulators combines transcriptome-wide throughput and biophysical precision. Here, we describe an assay that accomplishes this. Using commonly available hardware, we built a customizable, open-source platform that leverages the...

Dual-utility NLS drives RNF169-dependent DNA damage responses [Cell Biology]

Tue, 03/21/2017 - 09:32
Loading of p53-binding protein 1 (53BP1) and receptor-associated protein 80 (RAP80) at DNA double-strand breaks (DSBs) drives cell cycle checkpoint activation but is counterproductive to high-fidelity DNA repair. ring finger protein 169 (RNF169) maintains the balance by limiting the deposition of DNA damage mediator proteins at the damaged chromatin. We...

Small RNA-mediated repair of UV-induced DNA lesions by the DNA DAMAGE-BINDING PROTEIN 2 and ARGONAUTE 1 [Plant Biology]

Tue, 03/21/2017 - 09:32
As photosynthetic organisms, plants need to prevent irreversible UV-induced DNA lesions. Through an unbiased, genome-wide approach, we have uncovered a previously unrecognized interplay between Global Genome Repair and small interfering RNAs (siRNAs) in the recognition of DNA photoproducts, prevalently in intergenic regions. Genetic and biochemical approaches indicate that, upon UV...

Priming GPCR signaling through the synergistic effect of two G proteins [Pharmacology]

Tue, 03/21/2017 - 09:32
Although individual G-protein–coupled receptors (GPCRs) are known to activate one or more G proteins, the GPCR–G-protein interaction is viewed as a bimolecular event involving the formation of a ternary ligand–GPCR–G-protein complex. Here, we present evidence that individual GPCR–G-protein interactions can reinforce each other to enhance signaling through canonical downstream second...

Ion and inhibitor binding of the double-ring ion selectivity filter of the mitochondrial calcium uniporter [Biochemistry]

Tue, 03/21/2017 - 09:32
The calcium (Ca2+) uniporter of mitochondria is a holocomplex consisting of the Ca2+-conducting channel, known as mitochondrial calcium uniporter (MCU), and several accessory and regulatory components. A previous electrophysiology study found that the uniporter has high Ca2+ selectivity and conductance and this depends critically on the conserved amino acid sequence...

Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes [Biochemistry]

Tue, 03/21/2017 - 09:32
Insulin-degrading enzyme (IDE) hydrolyzes bioactive peptides, including insulin, amylin, and the amyloid β peptides. Polyanions activate IDE toward some substrates, yet an endogenous polyanion activator has not yet been identified. Here we report that inositol phosphates (InsPs) and phosphatdidylinositol phosphates (PtdInsPs) serve as activators of IDE. InsPs and PtdInsPs interact...

S. Jonathan Singer: A man who loved ideas and detested walls [Retrospectives]

Tue, 03/21/2017 - 09:32
S. Jonathan Singer, “Jon” to one and all, died February 2, 2017, at the age of 92. Educated as a physical chemist, he transitioned gracefully by way of protein and immunochemistry to become a cell and molecular biologist of huge renown. His initial bout with fame came in 1949 when...

CRISPR-Cas9-guided oncogenic chromosomal translocations with conditional fusion protein expression in human mesenchymal cells [Genetics]

Tue, 03/21/2017 - 09:32
Gene editing techniques have been extensively used to attempt to model recurrent genomic rearrangements found in tumor cells. These methods involve the induction of double-strand breaks at endogenous loci followed by the identification of breakpoint junctions within a population, which typically arise by nonhomologous end joining. The low frequency of...

Progression of type 1 diabetes from the prediabetic stage is controlled by interferon-{alpha} signaling [Immunology and Inflammation]

Tue, 03/21/2017 - 09:32
Blockade of IFN-α but not IFN-β signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouse Rip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune “antiself” T cells to the external boundaries around the islets and...

Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis [Cell Biology]

Mon, 03/20/2017 - 13:07
Genetic lesions that activate KRAS account for ∼30% of the 1.6 million annual cases of lung cancer. Despite clinical need, KRAS is still undruggable using traditional small-molecule drugs/inhibitors. When oncogenic Kras is suppressed by RNA interference, tumors initially regress but eventually recur and proliferate despite suppression of Kras. Here, we...

Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating [Physiology]

Mon, 03/20/2017 - 13:07
Acid-sensing ion channels (ASICs) are proton-activated Na+ channels expressed in the nervous system, where they are involved in learning, fear behaviors, neurodegeneration, and pain sensation. In this work, we study the role in pH sensing of two regions of the ectodomain enriched in acidic residues: the acidic pocket, which faces...

In vivo optophysiology reveals that G-protein activation triggers osmotic swelling and increased light scattering of rod photoreceptors [Neuroscience]

Mon, 03/20/2017 - 13:07
The light responses of rod and cone photoreceptors have been studied electrophysiologically for decades, largely with ex vivo approaches that disrupt the photoreceptors’ subretinal microenvironment. Here we report the use of optical coherence tomography (OCT) to measure light-driven signals of rod photoreceptors in vivo. Visible light stimulation over a 200-fold...

p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates [Cell Biology]

Mon, 03/20/2017 - 13:07
Glutamine synthetase (GS) plays an essential role in metabolism by catalyzing the synthesis of glutamine from glutamate and ammonia. Our recent study showed that CRBN, a direct protein target for the teratogenic and antitumor activities of immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide, recognizes an acetyl degron of GS,...

Structural basis for specific ligation of the peroxisome proliferator-activated receptor {delta} [Chemistry]

Mon, 03/20/2017 - 13:07
The peroxisome proliferator-activated receptor (PPAR) family comprises three subtypes: PPARα, PPARγ, and PPARδ. PPARδ transcriptionally modulates lipid metabolism and the control of energy homeostasis; therefore, PPARδ agonists are promising agents for treating a variety of metabolic disorders. In the present study, we develop a panel of rationally designed PPARδ agonists....

Glass transition imminent, resistance is futile [Commentaries]

Mon, 03/20/2017 - 13:07
The immense variety of glassy materials around us makes it is easy to get caught up in excessive detail when thinking about the structural glass transition. For decades, there have been only a few attempts to describe covalently bonded, molecular, and metallic glasses on the same footing, so different do...