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Real space renormalization group theory of disordered models of glasses [Applied Physical Sciences]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
We develop a real space renormalization group analysis of disordered models of glasses, in particular of the spin models at the origin of the random first-order transition theory. We find three fixed points, respectively, associated with the liquid state, with the critical behavior, and with the glass state. The latter...

Identification of productive and futile encounters in an electron transfer protein complex [Biophysics and Computational Biology]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Well-defined, stereospecific states in protein complexes are often in exchange with an ensemble of more dynamic orientations: the encounter states. The structure of the stereospecific complex between cytochrome P450cam and putidaredoxin was solved recently by X-ray diffraction as well as paramagnetic NMR spectroscopy. Other than the stereospecific complex, the NMR...

Generalized myoclonic epilepsy with photosensitivity in juvenile dogs caused by a defective DIRAS family GTPase 1 [Genetics]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
The clinical and electroencephalographic features of a canine generalized myoclonic epilepsy with photosensitivity and onset in young Rhodesian Ridgeback dogs (6 wk to 18 mo) are described. A fully penetrant recessive 4-bp deletion was identified in the DIRAS family GTPase 1 (DIRAS1) gene with an altered expression pattern of DIRAS1...

Hypermutation signature reveals a slippage and realignment model of translesion synthesis by Rev3 polymerase in cisplatin-treated yeast [Genetics]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Gene–gene or gene–drug interactions are typically quantified using fitness as a readout because the data are continuous and easily measured in high throughput. However, to what extent fitness captures the range of other phenotypes that show synergistic effects is usually unknown. Using Saccharomyces cerevisiae and focusing on a matrix of...

Ancient X chromosomes reveal contrasting sex bias in Neolithic and Bronze Age Eurasian migrations [Anthropology]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Dramatic events in human prehistory, such as the spread of agriculture to Europe from Anatolia and the late Neolithic/Bronze Age migration from the Pontic-Caspian Steppe, can be investigated using patterns of genetic variation among the people who lived in those times. In particular, studies of differing female and male demographic...

Inhibition of {alpha}9{alpha}10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain [Biochemistry]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Opioids are first-line drugs for moderate to severe acute pain and cancer pain. However, these medications are associated with severe side effects, and whether they are efficacious in treatment of chronic nonmalignant pain remains controversial. Medications that act through alternative molecular mechanisms are critically needed. Antagonists of α9α10 nicotinic acetylcholine...

Nondestructive nanostraw intracellular sampling for longitudinal cell monitoring [Cell Biology]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Here, we report a method for time-resolved, longitudinal extraction and quantitative measurement of intracellular proteins and mRNA from a variety of cell types. Cytosolic contents were repeatedly sampled from the same cell or population of cells for more than 5 d through a cell-culture substrate, incorporating hollow 150-nm-diameter nanostraws (NS)...

Conformational dynamics of a neurotransmitter:sodium symporter in a lipid bilayer [Biochemistry]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Neurotransmitter:sodium symporters (NSSs) are integral membrane proteins responsible for the sodium-dependent reuptake of small-molecule neurotransmitters from the synaptic cleft. The symporters for the biogenic amines serotonin (SERT), dopamine (DAT), and norepinephrine (NET) are targets of multiple psychoactive agents, and their dysfunction has been implicated in numerous neuropsychiatric ailments. LeuT, a...

Rps3/uS3 promotes mRNA binding at the 40S ribosome entry channel and stabilizes preinitiation complexes at start codons [Biochemistry]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
The eukaryotic 43S preinitiation complex (PIC) bearing Met-tRNAiMet in a ternary complex (TC) with eukaryotic initiation factor (eIF)2-GTP scans the mRNA leader for an AUG codon in favorable “Kozak” context. AUG recognition provokes rearrangement from an open PIC conformation with TC bound in a state not fully engaged with the...

Distinct conformations of GPCR-{beta}-arrestin complexes mediate desensitization, signaling, and endocytosis [Biophysics and Computational Biology]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
β-Arrestins (βarrs) interact with G protein-coupled receptors (GPCRs) to desensitize G protein signaling, to initiate signaling on their own, and to mediate receptor endocytosis. Prior structural studies have revealed two unique conformations of GPCR–βarr complexes: the “tail” conformation, with βarr primarily coupled to the phosphorylated GPCR C-terminal tail, and the...

Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain [Neuroscience]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain inhibition, mainly because of its restricted expression in nociceptors within the peripheral nervous system. However, constrained by species differences across Mrgprs, drug candidates that activate MRGPRX1 do not activate rodent receptors, leaving no responsive animal model to...

Heart failure drug changes the mechanoenzymology of the cardiac myosin powerstroke [Biochemistry]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Omecamtiv mecarbil (OM), a putative heart failure therapeutic, increases cardiac contractility. We hypothesize that it does this by changing the structural kinetics of the myosin powerstroke. We tested this directly by performing transient time-resolved FRET on a ventricular cardiac myosin biosensor. Our results demonstrate that OM stabilizes myosin’s prepowerstroke structural...

Integrated view of internal friction in unfolded proteins from single-molecule FRET, contact quenching, theory, and simulations [Biophysics and Computational Biology]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Internal friction is an important contribution to protein dynamics at all stages along the folding reaction. Even in unfolded and intrinsically disordered proteins, internal friction has a large influence, as demonstrated with several experimental techniques and in simulations. However, these methods probe different facets of internal friction and have been...

Robust sampling of decision information during perceptual choice [Psychological and Cognitive Sciences]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Humans move their eyes to gather information about the visual world. However, saccadic sampling has largely been explored in paradigms that involve searching for a lone target in a cluttered array or natural scene. Here, we investigated the policy that humans use to overtly sample information in a perceptual decision...

Membrane integration of an essential {beta}-barrel protein prerequires burial of an extracellular loop [Biochemistry]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
The Bam complex assembles β-barrel proteins into the outer membrane (OM) of Gram-negative bacteria. These proteins comprise cylindrical β-sheets with long extracellular loops and create pores to allow passage of nutrients and waste products across the membrane. Despite their functional importance, several questions remain about how these proteins are assembled...

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models [Medical Sciences]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson’s disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression remain unclear. Here, we investigated...

Single-neuron identification of chemical constituents, physiological changes, and metabolism using mass spectrometry [Biochemistry]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
The use of single-cell assays has emerged as a cutting-edge technique during the past decade. Although single-cell mass spectrometry (MS) has recently achieved remarkable results, deep biological insights have not yet been obtained, probably because of various technical issues, including the unavoidable use of matrices, the inability to maintain cell...

Selective autophagy limits cauliflower mosaic virus infection by NBR1-mediated targeting of viral capsid protein and particles [Plant Biology]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Autophagy plays a paramount role in mammalian antiviral immunity including direct targeting of viruses and their individual components, and many viruses have evolved measures to antagonize or even exploit autophagy mechanisms for the benefit of infection. In plants, however, the functions of autophagy in host immunity and viral pathogenesis are...

Rational design of adjuvants targeting the C-type lectin Mincle [Chemistry]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
The advances in subunit vaccines development have intensified the search for potent adjuvants, particularly adjuvants inducing cell-mediated immune responses. Identification of the C-type lectin Mincle as one of the receptors underlying the remarkable immunogenicity of the mycobacterial cell wall, via recognition of trehalose-6,6′-dimycolate (TDM), has opened avenues for the rational...

C-terminal phosphorylation regulates the kinetics of a subset of melanopsin-mediated behaviors in mice [Neuroscience]

PNAS Early Edition Articles - Tue, 02/21/2017 - 12:14
Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin and mediate several non–image-forming visual functions, including circadian photoentrainment and the pupillary light reflex (PLR). ipRGCs act as autonomous photoreceptors via the intrinsic melanopsin-based phototransduction pathway and as a relay for rod/cone input via synaptically driven responses. Under low light...
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