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Biological applications of ionic liquids [Applied Biological Sciences]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Biofilm-protected microbial infections in skin are a serious health risk that remains to be adequately addressed. The lack of progress in developing effective treatment strategies is largely due to the transport barriers posed by the stratum corneum of the skin and the biofilm. In this work, we report on the...

Negative regulation of Ras via Src [Medical Sciences]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Mutations in Ras GTPase and various other components of the Ras signaling pathways are among the most common genetic alterations in human cancers and also have been identified in several familial developmental syndromes. Over the past few decades it has become clear that the activity or the oncogenic potential of...

Conformational selection in CCR5 chemokine GPCR [Biochemistry]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
We predicted the structural basis for pleiotropic signaling of the C-C chemokine type 5 (CCR5) G protein-coupled receptor (GPCR) by predicting the binding of several ligands to the lower-energy conformations of the CCR5 receptor and 11 mutants. For each case, we predicted the ∼20 most stable conformations for the receptor...

Evolution of a far-red fluorescent rhodopsin [Biochemistry]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Microbial rhodopsins are a diverse group of photoactive transmembrane proteins found in all three domains of life. A member of this protein family, Archaerhodopsin-3 (Arch) of halobacterium Halorubrum sodomense, was recently shown to function as a fluorescent indicator of membrane potential when expressed in mammalian neurons. Arch fluorescence, however, is...

Calcium-dependent misfolding of a calcium sensor [Biophysics and Computational Biology]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Neurodegenerative disorders are strongly linked to protein misfolding, and crucial to their explication is a detailed understanding of the underlying structural rearrangements and pathways that govern the formation of misfolded states. Here we use single-molecule optical tweezers to monitor misfolding reactions of the human neuronal calcium sensor-1, a multispecific EF-hand...

Finite-time singularity of 3D Euler [Applied Mathematics]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
The question of finite-time blowup of the 3D incompressible Euler equations is numerically investigated in a periodic cylinder with solid boundaries. Using rotational symmetry, the equations are discretized in the (2D) meridian plane on an adaptive (moving) mesh and is integrated in time with adaptively chosen time steps. The vorticity...

HuR regulates developing neocortical polysomes [Neuroscience]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Precise spatiotemporal control of mRNA translation machinery is essential to the development of highly complex systems like the neocortex. However, spatiotemporal regulation of translation machinery in the developing neocortex remains poorly understood. Here, we show that an RNA-binding protein, Hu antigen R (HuR), regulates both neocorticogenesis and specificity of neocortical...

Models of T2D require insulin-resistant {alpha} cells [Physiology]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
To determine the role of glucagon action in diet-induced and genetic type 2 diabetes (T2D), we studied high-fat-diet–induced obese (DIO) and leptin receptor-defective (LepR−/−) rodents with and without glucagon receptors (GcgRs). DIO and LepR−/−,GcgR+/+ mice both developed hyperinsulinemia, increased liver sterol response element binding protein 1c, and obesity. DIO GcgR+/+...

Crystal structure of the twister ribozyme [Biochemistry]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Twister is a recently discovered RNA motif that is estimated to have one of the fastest known catalytic rates of any naturally occurring small self-cleaving ribozyme. We determined the 4.1-Å resolution crystal structure of a twister sequence from an organism that has not been cultured in isolation, and it shows...

UPR decreases amyloidogenic light-chain secretion [Biochemistry]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Light-chain amyloidosis (AL) is a degenerative disease characterized by the extracellular aggregation of a destabilized amyloidogenic Ig light chain (LC) secreted from a clonally expanded plasma cell. Current treatments for AL revolve around ablating the cancer plasma cell population using chemotherapy regimens. Unfortunately, this approach is limited to the ∼70%...

Nedd4-1 as a downstream target of PI3K/PTEN-mTORC1 [Neuroscience]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Protein ubiquitination is a core regulatory determinant of neural development. Previous studies have indicated that the Nedd4-family E3 ubiquitin ligases Nedd4-1 and Nedd4-2 may ubiquitinate phosphatase and tensin homolog (PTEN) and thereby regulate axonal growth in neurons. Using conditional knockout mice, we show here that Nedd4-1 and Nedd4-2 are indeed...

Barrier Canyon rock art dated by new OSL methods [Anthropology]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Rock art compels interest from both researchers and a broader public, inspiring many hypotheses about its cultural origin and meaning, but it is notoriously difficult to date numerically. Barrier Canyon-style (BCS) pictographs of the Colorado Plateau are among the most debated examples; hypotheses about its age span the entire Holocene...

Solitons in a topological mechanical insulator [Physics]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Networks of rigid bars connected by joints, termed linkages, provide a minimal framework to design robotic arms and mechanical metamaterials built of folding components. Here, we investigate a chain-like linkage that, according to linear elasticity, behaves like a topological mechanical insulator whose zero-energy modes are localized at the edge. Simple...

Klebsiella cytotoxin causes antibiotic colitis [Microbiology]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Antibiotic therapy disrupts the human intestinal microbiota. In some patients rapid overgrowth of the enteric bacterium Klebsiella oxytoca results in antibiotic-associated hemorrhagic colitis (AAHC). We isolated and identified a toxin produced by K. oxytoca as the pyrrolobenzodiazepine tilivalline and demonstrated its causative action in the pathogenesis of colitis in an...

Nanoscale structure of the BMP antagonist chordin [Biophysics and Computational Biology]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Bone morphogenetic proteins (BMPs) orchestrate key cellular events, such as proliferation and differentiation, in development and homeostasis. Extracellular antagonists, such as chordin, are essential regulators of BMP signaling. Chordin binds to BMPs blocking interaction with receptors, and cleavage by tolloid proteinases is thought to relieve this inhibition. A model has...

Black carbon and blood pressure in Chinese women [Sustainability Science]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Air pollution in China and other parts of Asia poses large health risks and is an important contributor to global climate change. Almost half of Chinese homes use biomass and coal fuels for cooking and heating. China’s economic growth and infrastructure development has led to increased emissions from coal-fired power...

Mental models of sustainable agriculture [Sustainability Science]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Linking knowledge to action requires understanding how decision-makers conceptualize sustainability. This paper empirically analyzes farmer “mental models” of sustainability from three winegrape-growing regions of California where local extension programs have focused on sustainable agriculture. The mental models are represented as networks where sustainability concepts are nodes, and links are established...

Ghrelin and hepatic lipogenesis [Medical Sciences]

PNAS Early Edition Articles - Mon, 08/25/2014 - 13:38
Although ghrelin has been demonstrated to stimulate energy intake and storage through a central mechanism, its effect on hepatic lipid metabolism remains largely uncharacterized. Ghrelin receptor antagonism or gene deletion significantly decreased obesity-associated hepatic steatosis by suppression of de novo lipogenesis, whereas exogenous ghrelin stimulated lipogenesis, leading to hepatic lipid...
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