bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrasting Predictions of Low- and High-Threshold Models for the Detection of Changing Visual Features
Authors: Burmester Alex , Wallis Guy
Published: August 2012

Change blindness is the failure of observers to notice otherwise obvious changes to a visual scene when those changes are masked in some way (eg by blotches or a blanking of the screen). Typically, change blindness is taken as evidence that our representation of the visual world is capacity limited. The locus of this capacity limit is thought to be visual short-term memory (vSTM). The capacity of vSTM is usually estimated with a high-threshold model which assumes that each element in the stimulus array is either fully encoded or not encoded at all, and, furthermore, that false alarms can arise only by guessing, not by noise. Low-threshold models, by contrast, suggest that false alarms can arise by noise at the level of detection/discrimination and/or decision. In this study, we use a well-controlled stimulus display in which a single element changes over a blanking of the screen and contrast predictions from a popular high-threshold model of vSTM with the predictions of a low-threshold model (specifically, the sample-size model) of visual search and vSTM. The data were better predicted by the low-threshold model.
Farm-scale nitrogen, phosphorus, potassium and sulfur balances and use efficiencies on Australian dairy farms
Authors: Gourley Cameron J. P. , Dougherty Warwick J. , Weaver David M. , Aarons Sharon R. , Awty Ivor M. , Gibson Donna M. , Hannah Murray C. , Smith Andrew P. , Peverill Ken I.
Published: August 2012

Efficient and effective nutrient management decisions are critical to profitable and sustainable milk production on modern Australian dairy farms. Whole-farm nutrient balances are commonly used as nutrient management tools and also for regulatory assessment on dairy farms internationally, but are rarely used in Australia. In this study, nitrogen (N), phosphorus (P), potassium (K), and sulfur (S) imports and exports were measured during a standardised production year on 41 contrasting Australian dairy farms, representing a broad range of geographic locations, milk production, herd and farm size, reliance on irrigation, and soil types. The quantity of nutrients imported varied markedly – with feed and fertiliser generally the most substantial imports – and were principally determined by stocking rate and type of imported feed. Milk exports were the largest source of nutrient exports. Nitrogen balance ranged from 47 to 601 kg N/ha.year. Nitrogen-use efficiency ranged from 14 to 50%, with a median value of 26%. Phosphorus balance ranged from –7 to 133 kg P/ha.year, with a median value of 28 kg P/ha. Phosphorus-use efficiencies ranged from 6 to 158%, with a median value of 35%. Potassium balances ranged from 13 to 452 kg K/ha, with a median value of 74 kg K/ha; K-use efficiency ranged from 9 to 48%, with a median value of 20%. Sulfur balances ranged from –1 to 184 kg S/ha, with a median value of 27 kg S/ha; S-use efficiency ranged from 6 to 110%, with a median value of 21%. Nitrogen, P, K and S balances were all positively correlated (P < 0.001) with stocking rate and milk production per ha. Poor relationship between P, K and S fertiliser inputs and milk production from home-grown pasture reflected the already high soil fertility levels measured on many of these farms. The results from this study demonstrate that increasing milk production per ha will be associated with greater nutrient surpluses at the farm scale, with the potential for greater environmental impacts. We suggest that simplified and standardised nutrient balance methodologies should be used on dairy farms in Australia to help identify opportunities for improvements in nutrient management decisions and to develop appropriate industry benchmarks and targets.
Effect of intercropping forage peas (Pisum sativum L.) with winter wheat (Tritium vulgare L.) or triticale (Triticale hexaploide Lart.) on DM yield, nutritive characteristics when harvested at different stages of growth
Authors: Jacobs J. L. , Ward G. N.
Published: August 2012

An experiment was undertaken over 2 years (2007–09) to determine the effect of intercropping forage peas with either forage winter wheat or triticale for whole-crop silage. Monocultures of triticale (T100), wheat (W100) and forage peas (P100) and plus cereal–pea combinations of 75% triticale : 25% pea (T75), 50% triticale : 50% pea (T50), 25% triticale : 75% pea (T25), 75% wheat : 25% pea (W75), 50% wheat : 50% pea (W50), 25% wheat : 75% pea (W25), with ratios based on sowing rate, were evaluated for DM yield and nutritional characteristics at a range of growth stages. It was hypothesised that an increase in the ratio of peas to cereal would not adversely affect DM yield and would have a positive impact on nutritive characteristics across a range of harvest times based on growth stages of the cereal component of mixes. In Year 1, at the boot stage of growth of cereals, P100 had a lower DM yield than W100 and all triticale-based treatments, while in Year 2 P100 had a lower DM yield than all other treatments. By the soft dough growth stage in Year 1, all triticale treatments except T25 had higher DM yields than P100 and in Year 2 P100 had a lower DM yield than all triticale treatments and W100. The crude protein (CP) concentration of P100 at the boot stage of growth was higher than T100, T75, T50, W100 and W50 in Year 1 and all treatments in Year 2. At soft dough, P100 had a higher CP concentration than all other treatments in both years, while T25 and W25 had higher CP concentrations than their respective monocultures. In Year 1 at soft dough, W100 had a lower estimated ME concentration than other wheat treatments and P100, while in Year 2, T50 and W50 had higher values than T100 and W100, respectively. Bi-cropping forage peas with winter cereal forage crops did not adversely affect DM yields at a range of different harvest times, but did not consistently and significantly improve nutritive characteristics. Despite relatively high sowing rates of forage peas, their total contribution in mixes with cereals to DM yield was low, indicating that their ability to compete with winter cereals under the high fertility conditions of the experiment was low. When grown as a monoculture peas tended to produce lower DM yields but had higher CP concentrations and a higher harvested CP/ha at the soft dough stage of growth. The timing of harvesting will affect DM yields and nutritive characteristics and can be manipulated depending upon the end use of the feed grown and also to allow greater flexibility in the sowing of subsequent forages. Consideration should also be given to the growing of monocultures of winter cereals and forage peas and developing systems to mix during ensiling to capture both DM yield potential and optimum nutritive characteristics.
Role of the Chronic Dental Disease Scheme in Enhanced Primary Care: allied health or allied outlier?
Authors: Lam Raymond , Kruger Estie , Tennant Marc
Published: August 2012

This study aims to provide a comparative analysis of the Chronic Dental Disease Scheme (CDSS) and the Allied Health Profession (AHP) program as they related to the greater Enhanced Primary Care Scheme introduced by the Australian Government to manage patients with chronic and complex diseases. A retrospective analysis of data pertaining to Medicare items related to dentistry and the allied health professions were extracted from the Medicare Benefits Schedule database online, and formed the basis of this study. The highest proportion of services was provided in the state of New South Wales. There appears to be synergy in the utilisation of services with jurisdictions either overutilising or underutilising services. Costs to the Enhanced Primary Care Scheme under the CDSS model (fee for service) were up to 40 times more expensive compared with the AHP model (fee per visit). Costs and treatment associated with the CDSS experienced an increase of 13350% during the period 2007–08, coincident with an increase in subsidisation. Reconstructive dentistry accounted for the majority of the increase. Gender disparities in dentistry were less distinct when compared with AHPs and were postulated to be due to males presenting with conditions that were more progressive requiring more invasive treatment. A comparative analysis indicates significant differences in costs, nature of treatment and the manner of remuneration between dentistry and the AHPs. A fee for service schedule as evidenced by the CDSS is dependent on the degree of financial incentive as indicated by patterns in utilisation over time. The amount of treatment considered necessary may be influenced by the level of subsidy with treatment that may not reflect disease management. The AHP model, which is based around a fee for visit schedule, is not without its deficiencies but has not experienced significant rises in cost compared with the CDSS.
Sustainable sheep management using continuous grazing and variable stocking rates in Patagonia: a case study
Authors: Oliva Gabriel , Ferrante Daniela , Puig Silvina , Williams Marcos
Published: August 2012

Adaptive rangeland management based on continuous grazing by sheep was implemented at Los Pozos station, on the Magellan tussock steppes of southern Patagonia, between 1990 and 2010. The numbers of sheep were adjusted annually following a stocking strategy tracking the herbage mass. Herbage mass was assessed by harvesting short grass species at peak herbage mass and grazing capacity was estimated based on sheep requirements. Historic production records under a traditional continuous grazing management (1930–89) were contrasted with those of the adaptive management period (1990–2010). Stocking rates of 0.59 sheep ha–1 year–1 in the period from 1930 to 1989 dropped to 0.35 sheep ha–1 year–1 in the adaptive management period. Mean herbage mass of short grasses during this latter period was 194 ± 12 kg DM ha–1 and the stubble height of the key species, Poa spiciformis, was 24 ± 0.7 mm. Lamb marking rates and extraction rates increased from 72 to 87%, and from 28 to 48%, respectively, under adaptive management when compared with historic management, and historic levels of sheep sales were maintained: 4405 v. 4602 animals year–1. Wool production fell from 36 102 to 26 771 kg year–1. Annual sheep production under adaptive management was less variable, as the annual coefficient of variation fell by 41% for lambing rates, by 25.8% for wool production, and by 40% for sheep extraction rates, compared with historic records, even though the inter-annual rainfall coefficient of variation increased by 25% over the same period. It is concluded that, under adaptive management, herbage production, stubble height and sheep production remained stable over 20 years. The adaptive strategy allowed a stabilisation of production and is a potentially valuable management tool in view of the expected increase in variability of rainfall predicted by global climate models for Patagonia and other rangeland areas.
Escape from Adaptive Conflict follows from weak functional trade-offs and mutational robustness
Authors: Sikosek Tobias , Chan Hue Sun , Bornberg-Bauer Erich
Published: August 2012

A fundamental question in molecular evolution is how proteins can adapt to new functions while being conserved for an existing function at the same time. Several theoretical models have been put forward to explain this apparent paradox. The most popular models include neofunctionalization, subfunctionalization (SUBF) by degenerative mutations, and dosage models. All of these models focus on adaptation after gene duplication. A newly proposed model named “Escape from Adaptive Conflict” (EAC) includes adaptive processes before and after gene duplication that lead to multifunctional proteins, and divergence (SUBF). Support for the importance of multifunctionality for the evolution of new protein functions comes from two experimental observations. First, many enzymes have highly evolvable promiscuous side activities. Second, different structural states of the same protein can be associated with different functions. How these observations may be related to the EAC model, under which conditions EAC is possible, and how the different models relate to each other is still unclear. Here, we present a theoretical framework that uses biophysical principles to infer the roles of functional promiscuity, gene dosage, gene duplication, point mutations, and selection pressures in the evolution of proteins. We find that selection pressures can determine whether neofunctionalization or SUBF is the more likely evolutionary process. Multifunctional proteins, arising during EAC evolution, allow rapid adaptation independent of gene duplication. This becomes a crucial advantage when gene duplications are rare. Finally, we propose that an increase in mutational robustness, not necessarily functional optimization, can be the sole driving force behind SUBF.
Universal mechanism for Anderson and weak localization
Authors: Filoche Marcel , Mayboroda Svitlana
Published: August 2012

Localization of stationary waves occurs in a large variety of vibrating systems, whether mechanical, acoustical, optical, or quantum. It is induced by the presence of an inhomogeneous medium, a complex geometry, or a quenched disorder. One of its most striking and famous manifestations is Anderson localization, responsible for instance for the metal-insulator transition in disordered alloys. Yet, despite an enormous body of related literature, a clear and unified picture of localization is still to be found, as well as the exact relationship between its many manifestations. In this paper, we demonstrate that both Anderson and weak localizations originate from the same universal mechanism, acting on any type of vibration, in any dimension, and for any domain shape. This mechanism partitions the system into weakly coupled subregions. The boundaries of these subregions correspond to the valleys of a hidden landscape that emerges from the interplay between the wave operator and the system geometry. The height of the landscape along its valleys determines the strength of the coupling between the subregions. The landscape and its impact on localization can be determined rigorously by solving one special boundary problem. This theory allows one to predict the localization properties, the confining regions, and to estimate the energy of the vibrational eigenmodes through the properties of one geometrical object. In particular, Anderson localization can be understood as a special case of weak localization in a very rough landscape.
Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation
Authors: van der Goot Annemieke T. , Zhu Wentao , Vázquez-Manrique Rafael P. , Seinstra Renée I. , Dettmer Katja , Michels Helen , Farina Francesca , Krijnen Jasper , Melki Ronald , Buijsman Rogier C. , Ruiz Silva Mariana , Thijssen Karen L. , Kema Ido P. , Neri Christian , Oefner Peter J. , Nollen Ellen A. A.
Published: August 2012

Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer’s diseases. Here, we identify tryptophan 2,3-dioxygenase (
tdo-2
), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related α-synuclein toxicity in a
Caenorhabditis elegans
model. Depletion of
tdo-2
also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-β and polyglutamine proteins, and endogenous metastable proteins that are sensors of normal protein homeostasis. This finding suggests that
tdo-2
functions as a general regulator of protein homeostasis. Analysis of metabolite levels in
C. elegans
strains with mutations in enzymes that act downstream of
tdo-2
indicates that this suppression of toxicity is independent of downstream metabolites in the kynurenine pathway. Depletion of
tdo-2
increases tryptophan levels, and feeding worms with extra
l
-tryptophan also suppresses toxicity, suggesting that
tdo-2
regulates proteotoxicity through tryptophan. Depletion of
tdo-2
extends lifespan in these worms. Together, these results implicate
tdo-2
as a metabolic switch of age-related protein homeostasis and lifespan. With TDO and Indoleamine 2,3-dioxygenase as evolutionarily conserved human orthologs of TDO-2, intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases.
No third-party punishment in chimpanzees
Authors: Riedl Katrin , Jensen Keith , Call Josep , Tomasello Michael
Published: August 2012

Punishment can help maintain cooperation by deterring free-riding and cheating. Of particular importance in large-scale human societies is third-party punishment in which individuals punish a transgressor or norm violator even when they themselves are not affected. Nonhuman primates and other animals aggress against conspecifics with some regularity, but it is unclear whether this is ever aimed at punishing others for noncooperation, and whether third-party punishment occurs at all. Here we report an experimental study in which one of humans' closest living relatives, chimpanzees (Pan troglodytes), could punish an individual who stole food. Dominants retaliated when their own food was stolen, but they did not punish when the food of third-parties was stolen, even when the victim was related to them. Third-party punishment as a means of enforcing cooperation, as humans do, might therefore be a derived trait in the human lineage.
Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes
Authors: Delfosse Vanessa , Grimaldi Marina , Pons Jean-Luc , Boulahtouf Abdelhay , le Maire Albane , Cavailles Vincent , Labesse Gilles , Bourguet William , Balaguer Patrick
Published: August 2012

Bisphenol A (BPA) is an industrial compound and a well known endocrine-disrupting chemical with estrogenic activity. The widespread exposure of individuals to BPA is suspected to affect a variety of physiological functions, including reproduction, development, and metabolism. Here we report that the mechanisms by which BPA and two congeners, bisphenol AF and bisphenol C (BPC), bind to and activate estrogen receptors (ER) α and β differ from that used by 17β-estradiol. We show that bisphenols act as partial agonists of ERs by activating the N-terminal activation function 1 regardless of their effect on the C-terminal activation function 2, which ranges from weak agonism (with BPA) to antagonism (with BPC). Crystallographic analysis of the interaction between bisphenols and ERs reveals two discrete binding modes, reflecting the different activities of compounds on ERs. BPA and 17β-estradiol bind to ERs in a similar fashion, whereas, with a phenol ring pointing toward the activation helix H12, the orientation of BPC accounts for the marked antagonist character of this compound. Based on structural data, we developed a protocol for in silico evaluation of the interaction between bisphenols and ERs or other members of the nuclear hormone receptor family, such as estrogen-related receptor γ and androgen receptor, which are two known main targets of bisphenols. Overall, this study provides a wealth of tools and information that could be used for the development of BPA substitutes devoid of nuclear hormone receptor-mediated activity and more generally for environmental risk assessment.
Global distribution of microbial abundance and biomass in subseafloor sediment
Authors: Kallmeyer Jens , Pockalny Robert , Adhikari Rishi Ram , Smith David C. , D’Hondt Steven
Published: August 2012

The global geographic distribution of subseafloor sedimentary microbes and the cause(s) of that distribution are largely unexplored. Here, we show that total microbial cell abundance in subseafloor sediment varies between sites by
ca.
five orders of magnitude. This variation is strongly correlated with mean sedimentation rate and distance from land. Based on these correlations, we estimate global subseafloor sedimentary microbial abundance to be 2.9⋅10
29
cells [corresponding to 4.1 petagram (Pg) C and ∼0.6% of Earth’s total living biomass]. This estimate of subseafloor sedimentary microbial abundance is roughly equal to previous estimates of total microbial abundance in seawater and total microbial abundance in soil. It is much lower than previous estimates of subseafloor sedimentary microbial abundance. In consequence, we estimate Earth’s total number of microbes and total living biomass to be, respectively, 50–78% and 10–45% lower than previous estimates.
MARCKS protein mediates hydrogen peroxide regulation of endothelial permeability
Authors: Jin Benjamin Y. , Lin Alison J. , Golan David E. , Michel Thomas
Published: August 2012

Impairment of endothelial barrier function is implicated in many vascular and inflammatory disorders. One prevalent mechanism of endothelial dysfunction is an increase in reactive oxygen species under oxidative stress. Previous reports have demonstrated that hydrogen peroxide (H
2
O
2
), a highly stable reactive oxygen species that modulates physiological signaling pathways, also enhances endothelial permeability, but the mechanism of this effect is unknown. Here, we identify the actin-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) as a key mediator of the H
2
O
2
-induced permeability change in bovine aortic endothelial cells. MARCKS knockdown and H
2
O
2
treatment alter the architecture of the actin cytoskeleton in endothelial cells, and H
2
O
2
induces the phosphorylation and translocation of MARCKS from the cell membrane to the cytosol. Using pharmacological inhibitors and small interference RNA constructs directed against specific proteins, we uncover a signaling cascade from Rac1 to Abl1, phospholipase Cγ1, and PKCδ that is triggered by H
2
O
2
and leads to MARCKS phosphorylation. Our findings establish a distinct role for MARCKS in the regulation of H
2
O
2
-induced permeability change in endothelial cells, and suggest potential new therapeutic targets for the treatment of disorders involving oxidative stress and altered endothelial permeability.
Fine-tuning gene networks using simple sequence repeats
Authors: Egbert Robert G. , Klavins Eric
Published: August 2012

The parameters in a complex synthetic gene network must be extensively tuned before the network functions as designed. Here, we introduce a simple and general approach to rapidly tune gene networks in
Escherichia coli
using hypermutable simple sequence repeats embedded in the spacer region of the ribosome binding site. By varying repeat length, we generated expression libraries that incrementally and predictably sample gene expression levels over a 1,000-fold range. We demonstrate the utility of the approach by creating a bistable switch library that programmatically samples the expression space to balance the two states of the switch, and we illustrate the need for tuning by showing that the switch’s behavior is sensitive to host context. Further, we show that mutation rates of the repeats are controllable in vivo for stability or for targeted mutagenesis—suggesting a new approach to optimizing gene networks via directed evolution. This tuning methodology should accelerate the process of engineering functionally complex gene networks.
The Monod-Wyman-Changeux allosteric model accounts for the quaternary transition dynamics in wild type and a recombinant mutant human hemoglobin
Authors: Levantino Matteo , Spilotros Alessandro , Cammarata Marco , Schirò Giorgio , Ardiccioni Chiara , Vallone Beatrice , Brunori Maurizio , Cupane Antonio
Published: August 2012

The acknowledged success of the Monod-Wyman-Changeux (MWC) allosteric model stems from its efficacy in accounting for the functional behavior of many complex proteins starting with hemoglobin (the paradigmatic case) and extending to channels and receptors. The kinetic aspects of the allosteric model, however, have been often neglected, with the exception of hemoglobin and a few other proteins where conformational relaxations can be triggered by a short and intense laser pulse, and monitored by time-resolved optical spectroscopy. Only recently the application of time-resolved wide-angle X-ray scattering (TR-WAXS), a direct structurally sensitive technique, unveiled the time scale of hemoglobin quaternary structural transition. In order to test the generality of the MWC kinetic model, we carried out a TR-WAXS investigation in parallel on adult human hemoglobin and on a recombinant protein (HbYQ) carrying two mutations at the active site [Leu(B10)Tyr and His(E7)Gln]. HbYQ seemed an ideal test because, although exhibiting allosteric properties, its kinetic and structural properties are different from adult human hemoglobin. The structural dynamics of HbYQ unveiled by TR-WAXS can be quantitatively accounted for by the MWC kinetic model. Interestingly, the main structural change associated with the R–T allosteric transition (i.e., the relative rotation and translation of the dimers) is approximately 10-fold slower in HbYQ, and the drop in the allosteric transition rate with ligand saturation is steeper. Our results extend the general validity of the MWC kinetic model and reveal peculiar thermodynamic properties of HbYQ. A possible structural interpretation of the characteristic kinetic behavior of HbYQ is also discussed.
Memory CD4+T-cell–mediated protection depends on secondary effectors that are distinct from and superior to primary effectors
Authors: Strutt Tara M. , McKinstry K. Kai , Kuang Yi , Bradley Linda M. , Swain Susan L.
Published: August 2012

Whether differences between naive cell-derived primary (1°) and memory cell-derived secondary (2°) CD4+T-cell effectors contribute to protective recall responses is unclear. Here, we compare these effectors directly after influenza A virus infection. Both develop with similar kinetics, but 2° effectors accumulate in greater number in the infected lung and are the critical component of memory CD4+T-cell–mediated protection against influenza A virus, independent of earlier-acting memory-cell helper functions. Phenotypic, functional, and transcriptome analyses indicate that 2° effectors share organ-specific expression patterns with 1° effectors but are more multifunctional, with more multicytokine (IFN-γ+/IL-2+/TNF+)-producing cells and contain follicular helper T-cell populations not only in the spleen and draining lymph nodes but also in the lung. In addition, they express more CD127 and NKG2A but less ICOS and Lag-3 than 1° effectors and express higher levels of several genes associated with survival and migration. Targeting two differentially expressed molecules, NKG2A and Lag-3, reveals differential regulation of 1° and 2° effector functions during pathogen challenge.
Brown carbon and internal mixing in biomass burning particles
Authors: Lack Daniel A. , Langridge Justin M. , Bahreini Roya , Cappa Christopher D. , Middlebrook Ann M. , Schwarz Joshua P.
Published: August 2012

Biomass burning (BB) contributes large amounts of black carbon (BC) and particulate organic matter (POM) to the atmosphere and contributes significantly to the earth’s radiation balance. BB particles can be a complicated optical system, with scattering and absorption contributions from BC, internal mixtures of BC and POM, and wavelength-dependent absorption of POM. Large amounts of POM can also be externally mixed. We report on the unique ability of multi-wavelength photo-acoustic measurements of dry and thermal-denuded absorption to deconstruct this complicated wavelength-dependent system of absorption and mixing. Optical measurements of BB particles from the Four Mile Canyon fire near Boulder, Colorado, showed that internal mixtures of BC and POM enhanced absorption by up to 70%. The data supports the assumption that the POM was very weakly absorbing at 532 nm. Enhanced absorption at 404 nm was in excess of 200% above BC absorption and varied as POM mass changed, indicative of absorbing POM. Absorption by internal mixing of BC and POM contributed 19( ± 8)% to total 404-nm absorption, while BC alone contributed 54( ± 16)%. Approximately 83% of POM mass was externally mixed, the absorption of which contributed 27( ± 15)% to total particle absorption (at 404 nm). The imaginary refractive index and mass absorption efficiency (MAE) of POM at 404 nm changed throughout the sampling period and were found to be 0.007 ± 0.005 and 0.82 ± 0.43 m2 g-1, respectively. Our analysis shows that the MAE of POM can be biased high by up to 50% if absorption from internal mixing of POM and BC is not included.
Net −1 frameshifting on a noncanonical sequence in a herpes simplex virus drug-resistant mutant is stimulated by nonstop mRNA
Authors: Pan Dongli , Coen Donald M.
Published: August 2012

Ribosomal frameshifting entails slippage of the translational machinery during elongation. Frameshifting permits expression of more than one polypeptide from an otherwise monocistronic mRNA, and can restore expression of polypeptides in the face of frameshift mutations. A common mutation conferring acyclovir resistance in patients with herpes simplex virus disease deletes one cytosine from a run of six cytosines (C-chord) in the viral
thymidine kinase
(
tk
) gene. However, this mutation does not abolish TK activity, which is important for pathogenicity. To investigate how this mutant retains TK activity, we engineered and analyzed viruses expressing epitope-tagged TK. We found that the mutant's TK activity can be accounted for by low levels of full-length TK polypeptide produced by net −1 frameshifting during translation. The efficiency of frameshifting was relatively high, 3–5%, as the polypeptide from the reading frame generated by the deletion, which lacks stop codons (nonstop), was poorly expressed mainly because of inefficient protein synthesis. Stop codons introduced into this reading frame greatly increased its expression, but greatly decreased the level of full-length TK, indicating that frameshifting is strongly stimulated by a new mechanism, nonstop mRNA, which we hypothesize involves stalling of ribosomes on the polyA tail. Mutational studies indicated that frameshifting occurs on or near the C-chord, a region lacking a canonical slippery sequence. Nonstop stimulation of frameshifting also occurred when the C-chord was replaced with a canonical slippery sequence from HIV. This mechanism thus permits biologically and clinically relevant TK synthesis, and may occur more generally.
Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation
Authors: El Kebir Driss , Gjorstrup Per , Filep János G.
Published: August 2012

Inappropriate neutrophil activation contributes to the pathogenesis of acute lung injury (ALI). Apoptosis is essential for removal of neutrophils from inflamed tissues and timely resolution of inflammation. Resolvin E1 (RvE1) is an endogenous lipid mediator derived from the ω-3 polyunsaturated fatty acid eicosapentaenoic acid that displays proresolving actions. Because the balance of prosurvival and proapoptosis signals determines the fate of neutrophils, we investigated the impact of RvE1 on neutrophil apoptosis and the outcome of neutrophil-mediated pulmonary inflammation in mice. Culture of human neutrophils with RvE1 accelerated apoptosis evoked by phagocytosis of opsonized
Escherichia coli
or yeast. RvE1 through the leukotriene B
4
receptor BLT1 enhanced NADPH oxidase-derived reactive oxygen species generation and subsequent activation of caspase-8 and caspase-3. RvE1 also attenuated ERK and Akt-mediated apoptosis-suppressing signals from myeloperoxidase, serum amyloid A, and bacterial DNA, shifting the balance of pro- and anti-survival signals toward apoptosis via induction of mitochondrial dysfunction. In mice, RvE1 treatment enhanced the resolution of established neutrophil-mediated pulmonary injury evoked by intratracheal instillation or i.p. administration of live
E. coli
or intratracheal instillation of carrageenan plus myeloperoxidase via facilitating neutrophil apoptosis and their removal by macrophages. The actions of RvE1 were prevented by the pan-caspase inhibitor zVAD-fmk. These results identify a mechanism, promotion of phagocytosis-induced neutrophil apoptosis and mitigation of potent anti-apoptosis signals, by which RvE1 could enhance resolution of acute lung inflammation.
Interactions between the termini of lumen enzymes and shell proteins mediate enzyme encapsulation into bacterial microcompartments
Authors: Fan Chenguang , Cheng Shouqiang , Sinha Sharmistha , Bobik Thomas A.
Published: August 2012

Bacterial microcompartments (MCPs) are a widespread family of proteinaceous organelles that consist of metabolic enzymes encapsulated within a protein shell. For MCPs to function specific enzymes must be encapsulated. We recently reported that a short N-terminal targeting sequence of propionaldehyde dehydrogenase (PduP) is necessary and sufficient for the packaging of enzymes into a MCP that functions in 1,2-propanediol (1,2-PD) utilization (Pdu) by
Salmonella enterica
. Here we show that encapsulation is mediated by binding of the PduP targeting sequence to a short C-terminal helix of the PduA shell protein. In vitro studies indicated binding between PduP and PduA (and PduJ) but not other MCP shell proteins. Alanine scanning mutagenesis determined that the key residues involved in binding are E7, I10, and L14 of PduP and H81, V84, and L88 of PduA. In vivo targeting studies indicated that the binding between the N terminus of PduP and the C terminus of PduA is critical for encapsulation of PduP within the Pdu MCP. Structural models suggest that the N terminus of PduP and C terminus of PduA both form helical structures that bind one another via the key residues identified by mutagenesis. Cumulatively, these results show that the N-terminal targeting sequence of PduP promotes its encapsulation by binding to MCP shell proteins. This is a unique report determining the mechanism by which a MCP targeting sequence functions. We propose that specific interactions between the termini of shell proteins and lumen enzymes have general importance for guiding the assembly and the higher level organization of bacterial MCPs.
Landau spectrum and twin boundaries of bismuth in the extreme quantum limit
Authors: Zhu Zengwei , Fauqué Benoît , Malone Liam , Antunes Arlei Borba , Fuseya Yuki , Behnia Kamran
Published: August 2012

The Landau spectrum of bismuth is complex and includes many angle-dependent lines in the extreme quantum limit. The adequacy of single-particle theory to describe this spectrum in detail has been an open issue. Here, we present a study of angle-resolved Nernst effect in bismuth, which maps the angle-resolved Landau spectrum for the entire solid angle up to 28 T. The experimental map is in good agreement with the results of a theoretical model with parabolic dispersion for holes and an extended Dirac Hamiltonian for electrons. The angular dependence of additional lines in the Landau spectrum allows us to uncover the mystery of their origin. They correspond to the lines expected for the hole Landau levels in a secondary crystal tilted by 108°, the angle between twinned crystals in bismuth. According to our results, the electron reservoirs of the two identical tilted crystals have different chemical potentials, and carriers across the twin boundary have different concentrations. An exceptional feature of this junction is that it separates two electron-hole compensated reservoirs. The link between this edge singularity and the states wrapping a three-dimensional electron gas in the quantum limit emerges as an outstanding open question.
In situ observation of peptide bond formation at the water–air interface
Authors: Griffith Elizabeth C. , Vaida Veronica
Published: August 2012

We report unambiguous spectroscopic evidence of peptide bond formation at the air–water interface, yielding a possible mechanism providing insight into the formation of modern ribosomal peptide bonds, and a means for the emergence of peptides on early Earth. Protein synthesis in aqueous environments, facilitated by sequential amino acid condensation forming peptides, is a ubiquitous process in modern biology, and a fundamental reaction necessary in prebiotic chemistry. Such reactions, however, are condensation reactions, requiring the elimination of a water molecule for every peptide bond formed, and are thus unfavorable in aqueous environments both from a thermodynamic and kinetic point of view. We use the hydrophobic environment of the air–water interface as a favorable venue for peptide bond synthesis, and demonstrate the occurrence of this chemistry with in situ techniques using Langmuir-trough methods and infrared reflection absorption spectroscopy. Leucine ethyl ester (a small amino acid ester) first partitions to the water surface, then coordinates with Cu2+ions at the interface, and subsequently undergoes a condensation reaction selectively forming peptide bonds at the air–water interface.
Chemical synthesis and X-ray structure of a heterochiral {D-protein antagonist
plus
vascular endothelial growth factor} protein complex by racemic crystallography
Authors: Mandal Kalyaneswar , Uppalapati Maruti , Ault-Riché Dana , Kenney John , Lowitz Joshua , Sidhu Sachdev S. , Kent Stephen B.H.
Published: August 2012

Total chemical synthesis was used to prepare the mirror image (
D
-protein) form of the angiogenic protein vascular endothelial growth factor (VEGF-A). Phage display against
D
-VEGF-A was used to screen designed libraries based on a unique small protein scaffold in order to identify a high affinity ligand. Chemically synthesized
D
- and
L
- forms of the protein ligand showed reciprocal chiral specificity in surface plasmon resonance binding experiments: The
L
-protein ligand bound only to
D
-VEGF-A, whereas the
D
-protein ligand bound only to
L
-VEGF-A. The
D
-protein ligand, but not the
L
-protein ligand, inhibited the binding of natural VEGF
165
to the VEGFR1 receptor. Racemic protein crystallography was used to determine the high resolution X-ray structure of the heterochiral complex consisting of {
D
-protein antagonist + 
L
-protein form ofVEGF-A}. Crystallization of a racemic mixture of these synthetic proteins in appropriate stoichiometry gave a racemic protein complex of more than 73 kDa containing six synthetic protein molecules. The structure of the complex was determined to a resolution of 1.6 Å. Detailed analysis of the interaction between the
D
-protein antagonist and the VEGF-A protein molecule showed that the binding interface comprised a contact surface area of approximately 800 
Å
2
in accord with our design objectives, and that the
D
-protein antagonist binds to the same region of VEGF-A that interacts with VEGFR1-domain 2.
Heritable yeast prions have a highly organized three-dimensional architecture with interfiber structures
Authors: Saibil Helen R. , Seybert Anja , Habermann Anja , Winkler Juliane , Eltsov Mikhail , Perkovic Mario , Castaño-Diez Daniel , Scheffer Margot P. , Haselmann Uta , Chlanda Petr , Lindquist Susan , Tyedmers Jens , Frangakis Achilleas S.
Published: August 2012

Yeast prions constitute a “protein-only” mechanism of inheritance that is widely deployed by wild yeast to create diverse phenotypes. One of the best-characterized prions, [

PSI
+

], is governed by a conformational change in the prion domain of Sup35, a translation-termination factor. When this domain switches from its normal soluble form to an insoluble amyloid, the ensuing change in protein synthesis creates new traits. Two factors make these traits heritable: (
i
) the amyloid conformation is self-templating; and (
ii
) the protein-remodeling factor heat-shock protein (Hsp)104 (acting together with Hsp70 chaperones) partitions the template to daughter cells with high fidelity. Prions formed by several other yeast proteins create their own phenotypes but share the same mechanistic basis of inheritance. Except for the amyloid fibril itself, the cellular architecture underlying these protein-based elements of inheritance is unknown. To study the 3D arrangement of prion assemblies in their cellular context, we examined yeast [

PSI
+

] prions in the native, hydrated state in situ, taking advantage of recently developed methods for cryosectioning of vitrified cells. Cryo–electron tomography of the vitrified sections revealed the prion assemblies as aligned bundles of regularly spaced fibrils in the cytoplasm with no bounding structures. Although the fibers were widely spaced, other cellular complexes, such as ribosomes, were excluded from the fibril arrays. Subtomogram image averaging, made possible by the organized nature of the assemblies, uncovered the presence of an additional array of densities between the fibers. We suggest these structures constitute a self-organizing mechanism that coordinates fiber deposition and the regulation of prion inheritance.
Neural coding and perceptual detection in the primate somatosensory thalamus
Authors: Vázquez Yuriria , Zainos Antonio , Alvarez Manuel , Salinas Emilio , Romo Ranulfo
Published: August 2012

The contribution of the sensory thalamus to perception and decision making is not well understood. We addressed this problem by recording single neurons in the ventral posterior lateral (VPL) nucleus of the somatosensory thalamus while trained monkeys judged the presence or absence of a vibrotactile stimulus of variable amplitude applied to the skin of a fingertip. We found that neurons in the VPL nucleus modulated their firing rate as a function of stimulus amplitude, and that such modulations accounted for the monkeys’ overall psychophysical performance. These neural responses did not predict the animals' decision reports in individual trials, however. Moreover, the sensitivity to changes in stimulus amplitude was similar when the monkeys’ performed the detection task and when they were not required to report stimulus detection. These results suggest that the primate somatosensory thalamus likely provides a reliable neural representation of the sensory input to the cerebral cortex, where sensory information is transformed and combined with other cognitive components associated with behavioral performance.
Structural basis for entropy-driven cellulose binding by a type-A cellulose-binding module (CBM) and bacterial expansin
Authors: Georgelis Nikolaos , Yennawar Neela H. , Cosgrove Daniel J.
Published: August 2012

Components of modular cellulases, type-A cellulose-binding modules (CBMs) bind to crystalline cellulose and enhance enzyme effectiveness, but structural details of the interaction are uncertain. We analyzed cellulose binding by EXLX1, a bacterial expansin with ability to loosen plant cell walls and whose domain D2 has type-A CBM characteristics. EXLX1 strongly binds to crystalline cellulose via D2, whereas its affinity for soluble cellooligosaccharides is weak. Calorimetry indicated cellulose binding was largely entropically driven. We solved the crystal structures of EXLX1 complexed with cellulose-like oligosaccharides to find that EXLX1 binds the ligands through hydrophobic interactions of three linearly arranged aromatic residues in D2. The crystal structures revealed a unique form of ligand-mediated dimerization, with the oligosaccharide sandwiched between two D2 domains in opposite polarity. This report clarifies the molecular target of expansin and the specific molecular interactions of a type-A CBM with cellulose.
Innovation and experience goods: a critical appraisal of a missing dimension in innovation theory
Authors: Hawkins Richard , Davis Charles H.
Published: August 2012

This paper discusses how the concept of experience goods could be integrated conceptually into innovation studies. Experience goods are distinguishable in that their value or utility cannot be determined until after they have been consumed. The concept encompasses an enormous variety of consumer goods whose value is determined largely or entirely by subjective and non-rational factors that are difficult to accommodate in the established framework of innovation theory. This theory has a strong historical orientation to manufactured goods and to technology producer goods. The paper provides some critical perspectives on the conceptual evolution of ‘value’ in innovation theory. It then introduces the experience goods dimension, demonstrating its potential for exploring how historical, social, cultural and economic factors combine in the construction of value-producing innovations. Drawing on the literature of marketing, consumer research, and cultural economics, various dimensions of experience as a factor in innovation are mapped onto Schumpeter’s innovation typology. The paper concludes by discussing some of the implications for future research.
How do innovation systems interact? Schumpeterian innovation in seven Australian sectors
Authors: Dalitz Robert , Holmén Magnus , Scott-Kemmis Don
Published: August 2012

This paper analyses how and why different types of innovation systems interact through analysing seven Australian sectors. We find that there are sets of mechanisms or systems that ‘articulate’; i.e. structure and shape the interaction among sectoral innovation systems and other types of innovation systems. Drawing on the Schumpeterian and evolutionary legacy, we contribute a theoretical explanation of how interaction among innovation systems influences innovation. First, this interaction enables and enhances variety creation by expanding the new combinations of knowledge and resources a firm can achieve. Second, it allows for more efficient and effective scaling up of useful knowledge recombination to achieve increasing returns. Empirically, this is supported in that the more successful sectors have active articulation systems with alignment with other systems, while weaker sectors have unplanned and patchy linkages. No simple model seems to explain successful articulation. However, important factors are active receptor firms with the motivation and capabilities to absorb and use resources from external systems, high quality and responsive education systems, and international linkages. Public research, labour markets, and intermediaries varied in importance.
Putting SUMO and SoxE into context
Authors: Short Ben
Published: August 2012

Study reveals how SUMOylation converts a transcriptional activator into a repressor.
The FATP1–DGAT2 complex facilitates lipid droplet expansion at the ER–lipid droplet interface
Authors: Xu Ningyi , Zhang Shaobing O. , Cole Ronald A. , McKinney Sean A. , Guo Fengli , Haas Joel T. , Bobba Sudheer , Farese Robert V. , Mak Ho Yi
Published: August 2012

At the subcellular level, fat storage is confined to the evolutionarily conserved compartments termed lipid droplets (LDs), which are closely associated with the endoplasmic reticulum (ER). However, the molecular mechanisms that enable ER–LD interaction and facilitate neutral lipid loading into LDs are poorly understood. In this paper, we present evidence that FATP1/acyl-CoA synthetase and DGAT2/diacylglycerol acyltransferase are components of a triglyceride synthesis complex that facilitates LD expansion. A loss of FATP1 or DGAT2 function blocked LD expansion in Caenorhabditis elegans. FATP1 preferentially associated with DGAT2, and they acted synergistically to promote LD expansion in mammalian cells. Live imaging indicated that FATP1 and DGAT2 are ER and LD resident proteins, respectively, and electron microscopy revealed FATP1 and DGAT2 foci close to the LD surface. Furthermore, DGAT2 that was retained in the ER failed to support LD expansion. We propose that the evolutionarily conserved FATP1–DGAT2 complex acts at the ER–LD interface and couples the synthesis and deposition of triglycerides into LDs both physically and functionally.