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RUNX1 regulates mesenchymal stem cell biology [Cell Biology]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Myofibroblasts are a key cell type in wound repair, cardiovascular disease, and fibrosis and in the tumor-promoting microenvironment. The high accumulation of myofibroblasts in reactive stroma is predictive of the rate of cancer progression in many different tumors, yet the cell types of origin and the mechanisms that regulate proliferation...

Serpin latency transition at atomic resolution [Biophysics and Computational Biology]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Protease inhibition by serpins requires a large conformational transition from an active, metastable state to an inactive, stable state. Similar reactions can also occur in the absence of proteases, and these latency transitions take hours, making their time scales many orders of magnitude larger than are currently accessible using conventional...

Distinguishing DNA templates by random mutation [Biophysics and Computational Biology]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Presently, inferring the long-range structure of the DNA templates is limited by short read lengths. Accurate template counts suffer from distortions occurring during PCR amplification. We explore the utility of introducing random mutations in identical or nearly identical templates to create distinguishable patterns that are inherited during subsequent copying. We...

Cretaceous lamprey larva shows 3-phased life cycle [Evolution]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Lampreys are one of the two surviving jawless vertebrate groups and one of a few vertebrate groups with the best exemplified metamorphosis during their life cycle, which consists of a long-lasting larval stage, a peculiar metamorphosis, and a relatively short adulthood with a markedly different anatomy. Although the fossil records...

Phosphorus redox biogeochemistry [Earth, Atmospheric, and Planetary Sciences]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
The element phosphorus (P) controls growth in many ecosystems as the limiting nutrient, where it is broadly considered to reside as pentavalent P in phosphate minerals and organic esters. Exceptions to pentavalent P include phosphine—PH3—a trace atmospheric gas, and phosphite and hypophosphite, P anions that have been detected recently in...

Structural basis of T{beta}4/profilin exchange [Biophysics and Computational Biology]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Thymosin-β4 (Tβ4) and profilin are the two major sequestering proteins that maintain the pool of monomeric actin (G-actin) within cells of higher eukaryotes. Tβ4 prevents G-actin from joining a filament, whereas profilin:actin only supports barbed-end elongation. Here, we report two Tβ4:actin structures. The first structure shows that Tβ4 has two...

rRNA base pairing required for HCV IRES [Biochemistry]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Degeneracy in eukaryotic translation initiation is evident in the initiation strategies of various viruses. Hepatitis C virus (HCV) provides an exceptional example—translation of the HCV RNA is facilitated by an internal ribosome entry site (IRES) that can autonomously bind a 40S ribosomal subunit and accurately position it at the initiation...

Metabolic links between neurons and glia in retina [Neuroscience]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Symbiotic relationships between neurons and glia must adapt to structures, functions, and metabolic roles of the tissues they are in. We show here that Müller glia in retinas have specific enzyme deficiencies that can enhance their ability to synthesize Gln. The metabolic cost of these deficiencies is that they impair...

Nonconsensus protein-DNA binding [Biochemistry]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Until now, it has been reasonably assumed that specific base-pair recognition is the only mechanism controlling the specificity of transcription factor (TF)−DNA binding. Contrary to this assumption, here we show that nonspecific DNA sequences possessing certain repeat symmetries, when present outside of specific TF binding sites (TFBSs), statistically control TF−DNA...

Transmission of mitochondrial heteroplasmies [Evolution]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe...

Oil platforms among most productive fish habitats [Ecology]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Secondary (i.e., heterotrophic or animal) production is a main pathway of energy flow through an ecosystem as it makes energy available to consumers, including humans. Its estimation can play a valuable role in the examination of linkages between ecosystem functions and services. We found that oil and gas platforms off...

WGS study of heterogeneity and anticipation in LFS [Genetics]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
The Li–Fraumeni syndrome (LFS) and its variant form (LFL) is a familial predisposition to multiple forms of childhood, adolescent, and adult cancers associated with germ-line mutation in the TP53 tumor suppressor gene. Individual disparities in tumor patterns are compounded by acceleration of cancer onset with successive generations. It has been...

Bacterial regulatory switching [Microbiology]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Understanding the mechanisms that generate variation is a common pursuit unifying the life sciences. Bacteria represent an especially striking puzzle, because closely related strains possess radically different metabolic and ecological capabilities. Differences in protein repertoire arising from gene transfer are currently considered the primary mechanism underlying phenotypic plasticity in bacteria....

Spleen-supplied innate-like B cells in obesity [Immunology and Inflammation]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Lipid accumulation in obesity triggers a low-grade inflammation that results from an imbalance between pro- and anti-inflammatory components of the immune system and acts as the major underlying mechanism for the development of obesity-associated diseases, notably insulin resistance and type 2 diabetes. Innate-like B cells are a subgroup of B...

Transferability of a designed specificity switch [Biophysics and Computational Biology]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Reengineering protein–protein recognition is an important route to dissecting and controlling complex interaction networks. Experimental approaches have used the strategy of “second-site suppressors,” where a functional interaction is inferred between two proteins if a mutation in one protein can be compensated by a mutation in the second. Mimicking this strategy,...

Opponent melanopsin and S-cone pupil responses [Neuroscience]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
In the human, cone photoreceptors (L, M, and S) and the melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs) are active at daytime light intensities. Signals from cones are combined both additively and in opposition to create the perception of overall light and color. Similar mechanisms seem to be at work...

Antibiotic-induced ribosome stalling [Biochemistry]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
The prevailing “plug-in-the-bottle” model suggests that macrolide antibiotics inhibit translation by binding inside the ribosome tunnel and indiscriminately arresting the elongation of every nascent polypeptide after the synthesis of six to eight amino acids. To test this model, we performed a genome-wide analysis of translation in azithromycin-treated Staphylococcus aureus. In...

PUMA-MCL-1 folding and binding mechanism [Biophysics and Computational Biology]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Protein–protein interactions are at the heart of regulatory and signaling processes in the cell. In many interactions, one or both proteins are disordered before association. However, this disorder in the unbound state does not prevent many of these proteins folding to a well-defined, ordered structure in the bound state. Here...

Fluorophore ligase for protein labeling in cells [Chemistry]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
Chemical fluorophores offer tremendous size and photophysical advantages over fluorescent proteins but are much more challenging to target to specific cellular proteins. Here, we used Rosetta-based computation to design a fluorophore ligase that accepts the red dye resorufin, starting from Escherichia coli lipoic acid ligase. X-ray crystallography showed that the...

Loss of entropy in protein folding [Chemistry]

PNAS Early Edition Articles - Mon, 10/13/2014 - 13:05
The loss of conformational entropy is a major contribution in the thermodynamics of protein folding. However, accurate determination of the quantity has proven challenging. We calculate this loss using molecular dynamic simulations of both the native protein and a realistic denatured state ensemble. For ubiquitin, the total change in entropy...
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