bluuebunny/crossref_metadata_2025 huggingface dataset:
Step-like increase of quantum yield of 1.5 μm Er-related emission in SiO2 doped with Si nanocrystals
Authors: Saeed S. , de Jong E. M. L. D. , Gregorkiewicz T.
Published: February 2015

We investigate the excitation dependence of the efficiency of the Si nanocrystals-mediated photoluminescence from Er3+ ions embedded in a SiO2 matrix. We show that the quantum yield of this emission increases in a step-like manner with excitation energy. The subsequent thresholds of this characteristic dependence are approximately given by the sum of the Si nanocrystals bandgap energy and multiples of 0.8 eV, corresponding to the energy of the first excited state of Er3+ ions. By comparing differently prepared materials, we explicitly demonstrate that the actual values of the threshold energies and the rate of the observed increase of the external quantum yield depend on sample characteristics—the size, the optical activity and the concentration of Si nanocrystals as well Er3+ ions to Si nanocrystals concentration ratio. In that way, detailed insights into the efficient excitation of Er3+ ions are obtained. In particular, the essential role of the hot-carrier-mediated Er excitation route is established, with a possible application perspective for highly efficient future-generation photovoltaics.
Interfacial trap states and improvement of low-temperature mobility by doping in InSb/AlInSb quantum wells
Authors: Manago Takashi , Ishida Shuichi , Geka Hirotaka , Shibasaki Ichiro
Published: February 2015

The effect of doping on InSb/Al0.1In0.9Sb quantum wells (QWs) was investigated, and it was found that doping improves the electron mobility at low temperatures and leads to a weaker dependence of the resistivity with temperature. The dependence of the carrier density on the well width revealed trap states at the interfaces of the QW whose sheet density per interface was estimated to be about 4 × 1010 cm−2. The low mobility of undoped InSb QWs, in particular, at low temperature seems to have been caused by positively ionized impurity scattering at the interfacial trap states. Doping compensates for the trap states and enhances mobility by suppressing ionized impurity scattering. Thus, intentional doping is necessary for developing high-mobility InSb QW devices. The origin of the trap states is qualitatively discussed.
Electrical oscillation in Pt/VO2 bilayer strips
Authors: Wang Ying , Chai Jianwei , Wang Shijie , Qi Long , Yang Yumeng , Xu Yanjun , Tanaka Hidekazu , Wu Yihong
Published: February 2015

We report on the observation of stable electrical oscillation in Pt/vanadium dioxide (VO2) bilayer strips, in which the Pt overlayer serves the dual purposes of heating up the VO2 and weakening the electric field in the VO2 layer. Systematic measurements in an ultrahigh vacuum nanoprobe system show that the oscillation frequency increases with the bias current and/or with decreasing device dimension. In contrast to most VO2-based oscillators reported to date, which are electrically triggered, current-induced Joule heating in the Pt overlayer is found to play a dominant role in the generation of oscillation in Pt/VO2 bilayers. A simple model involving thermally triggered transition of VO2 on a heat sink is able to account for the experimental observations. The results in this work provide an alternative view of the triggering mechanism in VO2-based oscillators.
Bi-Nuclear Metal Complexes of 2,6-Bis(1,4,7-triazacyclonon-1-yl-methylene)pyridine with Zinc(II), Copper(II), and Nickel(II)
Authors: Coghlan Campbell J. , Campi Eva M. , Forsyth Craig M. , Jackson Roy W. , Hearn Milton T. W.
Published: February 2015

The coordination chemistry of 2,6-bis(1,4,7-triazacyclonon-1-ylmethyl)pyridine (Lpyx, 1) has been investigated and shown to yield bi-nuclear metal complexes in the presence of zinc(ii), copper(ii), or nickel(ii) ions. The reaction of (Lpyx)·7HCl (2) with Zn(NO3)2 gave the monomeric [Zn2(μ-Cl)2(Lpyx)(H2O)](ClO4)2 (3) in which the ligand encapsulates a Zn2(μ-Cl)2 moiety. Similar treatment of 2 with Cu(NO3)2 gave a bi-nuclear complex cation which exists as a 1 : 1 co-crystal {[Cu(Cl)(Lpyx)Cu(μ-Cl)(Cl)](BF4)(H2O)}2 and {[Cu(Cl)(Lpyx)Cu(μ-Cl)(H2O)](BF4)2(H2O)}2 (4) with two discrete CuII centres bridged by the Lpyx ligand and dimerised through an unsymmetrical Cu2(μ-Cl)2 interaction. Similarly, reaction of 2 with Ni(NO3)2 also gave a dimeric complex {[Ni(Cl)(μ-Cl)(Lpyx)Ni(NO3)(H2O)](PF6)}2 (5) containing two discrete NiII centres with dimerisation occurring through a symmetrical Ni2(μ-Cl)2 interaction. In all cases, the Lpyx ligand binding is unsymmetrical between the two metal centres being tridentate to one and tetradentate to the other through an additional coordination of the pyridyl linker.
Gustatory and metabolic perception of nutrient stress in
Drosophila
Authors: Linford Nancy J. , Ro Jennifer , Chung Brian Y. , Pletcher Scott D.
Published: February 2015

Significance

Starvation induces a suite of costly behavioral and metabolic responses to maximize the possibility of finding a new nutrient source. It is therefore advantageous for an organism to switch out of the starvation state when food is encountered. How does an animal know when a food source is found and ultimate starvation is unlikely? This new work addresses this fundamental question, which is essential for broadening our understanding of how organisms interpret information from their environment to enact changes in complex behaviors and physiology. We describe an intriguing mechanism that combines information from both sensory and metabolic perception depending on the nutrient density in the food source.
In-cell SHAPE reveals that free 30S ribosome subunits are in the inactive state
Authors: McGinnis Jennifer L. , Liu Qi , Lavender Christopher A. , Devaraj Aishwarya , McClory Sean P. , Fredrick Kurt , Weeks Kevin M.
Published: February 2015

Significance

It has been known for decades that purified small subunits of the ribosome can interconvert between active and inactive conformations in experiments performed under simplified conditions, but the physiological relevance of this switch has remained unclear. We probed the structure of ribosomal RNA in healthy living cells and discovered that stably assembled 30S subunits exist predominantly in the inactive conformation, with structural differences localized in the functionally important decoding region. Disrupting the ability to interconvert between active and inactive conformations compromised translation in cells. In-cell RNA structure probing supports a model in which “inactive” 30S subunits comprise an abundant in-cell state that regulates ribosome function.
Human language reveals a universal positivity bias
Authors: Dodds Peter Sheridan , Clark Eric M. , Desu Suma , Frank Morgan R. , Reagan Andrew J. , Williams Jake Ryland , Mitchell Lewis , Harris Kameron Decker , Kloumann Isabel M. , Bagrow James P. , Megerdoomian Karine , McMahon Matthew T. , Tivnan Brian F. , Danforth Christopher M.
Published: February 2015

Significance

The most commonly used words of 24 corpora across 10 diverse human languages exhibit a clear positive bias, a big data confirmation of the Pollyanna hypothesis. The study’s findings are based on 5 million individual human scores and pave the way for the development of powerful language-based tools for measuring emotion.
The second laws of quantum thermodynamics
Authors: Brandão Fernando , Horodecki Michał , Ng Nelly , Oppenheim Jonathan , Wehner Stephanie
Published: February 2015

Significance

In ordinary thermodynamics, transitions are governed by a single quantity–the free energy. Its monotonicity is a formulation of the second law. Here, we find that the second law for microscopic or highly correlated systems takes on a very different form than it does at the macroscopic scale, imposing not just one constraint on state transformations, but many. We find a family of quantum free energies which generalize the standard free energy, and can never increase. The ordinary second law corresponds to the nonincreasing of one of these free energies, with the remainder imposing additional constraints on thermodynamic transitions. In the thermodynamic limit, these additional second laws become equivalent to the standard one. We also prove a strengthened version of the zeroth law of thermodynamics, allowing a definition of temperature.
Bacterial chemoreceptor dynamics correlate with activity state and are coupled over long distances
Authors: Samanta Dipanjan , Borbat Peter P. , Dzikovski Boris , Freed Jack H. , Crane Brian R.
Published: February 2015

Significance

Bacterial chemoreceptors are a key system for understanding how conformational signals propagate over large distances in transmembrane signaling. We have applied pulsed dipolar ESR spectroscopy of spin-labeled receptors to correlate conformation and dynamics with activity state. We find that the receptor cytoplasmic domain behaves as one large dynamically coupled system, in which activation signals destabilize membrane proximal regions but stabilize the most distal protein interaction tip. Inhibitory signals or adaptations of the receptor through chemical modification produce the opposite changes in conformational properties. This reciprocal coupling of conformational stability provides a versatile mechanism for sending signals throughout large modular proteins.
Interplay of approximate planning strategies
Authors: Huys Quentin J. M. , Lally Níall , Faulkner Paul , Eshel Neir , Seifritz Erich , Gershman Samuel J. , Dayan Peter , Roiser Jonathan P.
Published: February 2015

Significance

Many problems, particularly sequential planning problems, are computationally very demanding. How humans combine strategies to approximate and simplify these problems is not understood. Using modelling to unpick performance in a planning task, we find that humans are able to exploit the structure of the task to subdivide it and reduce processing requirements nearly optimally. Subtasks are combined in a simple, greedy manner, however, and within subtasks there is evidence of inhibitory reflexes in response to losses.
Erosion during extreme flood events dominates Holocene canyon evolution in northeast Iceland
Authors: Baynes Edwin R. C. , Attal Mikaël , Niedermann Samuel , Kirstein Linda A. , Dugmore Andrew J. , Naylor Mark
Published: February 2015

Significance

The importance of high-magnitude, short-lived events in controlling the evolution of landscapes is not well understood. This matters because during such events, erosion processes can surpass thresholds and cause abrupt landscape changes that have a long-lasting legacy for landscape morphology. We show that extreme flood events, during which the flow depth exceeds the threshold for erosion through plucking rather than abrasion, are the dominant control on the evolution of a large bedrock canyon in Iceland. The erosive signature of these events is maintained within a dynamic landscape over millennial timescales, emphasizing the importance of episodic extreme events in shaping landscapes.
Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia
Authors: Yoshida Mayumi , Kataoka Naoyuki , Miyauchi Kenjyo , Ohe Kenji , Iida Kei , Yoshida Suguru , Nojima Takayuki , Okuno Yukiko , Onogi Hiroshi , Usui Tomomi , Takeuchi Akihide , Hosoya Takamitsu , Suzuki Tsutomu , Hagiwara Masatoshi
Published: February 2015

Significance

Familial dysautonomia (FD) is caused by missplicing of the IκB kinase complex-associated protein (IKAP) gene, which results in the skipping of exon 20, especially in neurons. FD would be treatable if exon 20 inclusion were increased correctly to reestablish correct splicing. Here, we have established a dual-color splicing reporter that recapitulates FD-type splicing. By using this reporter, we have identified a small chemical compound, named rectifier of aberrant splicing (RECTAS), that rectifies the aberrant splicing of FD. RECTAS promotes both exon 20 inclusion and the product IKAP expression in cells of patients with FD. Furthermore, we have demonstrated that modification levels of wobble uridine residues of several tRNAs are reduced in FD cells and that RECTAS can recover not only tRNA modifications but also cell viability of FD cells.
Massively expedited genome-wide heritability analysis (MEGHA)
Authors: Ge Tian , Nichols Thomas E. , Lee Phil H. , Holmes Avram J. , Roffman Joshua L. , Buckner Randy L. , Sabuncu Mert R. , Smoller Jordan W.
Published: February 2015

Significance

Practical tools for high-dimensional heritability-based screening are invaluable for prioritizing phenotypes for genetic studies with the dramatic expansion of available phenotypic data. Classical estimates of heritability require twin or pedigree data, which can be costly and difficult to acquire. Alternative methods based on whole-genome data from unrelated individuals exist but are computationally expensive. Here we present a novel, fast, and accurate statistical method for massively expedited genome-wide heritability analysis, making heritability-based prioritization of millions of phenotypes based on data from unrelated individuals tractable for the first time to our knowledge. We apply our method to large-scale heritability analyses of brain imaging measurements and demonstrate its potential for facilitating phenome-wide analyses and characterizing the genetic architecture of complex traits.
C-terminal sequence of amyloid-resistant type F apolipoprotein A-II inhibits amyloid fibril formation of apolipoprotein A-II in mice
Authors: Sawashita Jinko , Zhang Beiru , Hasegawa Kazuhiro , Mori Masayuki , Naiki Hironobu , Kametani Fuyuki , Higuchi Keiichi
Published: February 2015

Significance

Apolipoprotein (apo) A-II is the most important protein associated with senile amyloidosis. Because some variants of apoA-II protein have been found among inbred strains of mice, we hypothesized that investigating amyloidogenesis of the variants would improve our understanding of the molecular and biological mechanisms of senile amyloidosis. Here, we demonstrate that mice with type F apoA-II (APOA2F) protein were absolutely resistant to senile amyloidosis. Moreover, a selective C-terminal APOA2F peptide inhibited fibril formation of amyloidogenic apoA-II in vitro and prevented senile amyloidosis in mice. We propose an inhibitory model in which the C-terminal APOA2F peptide prevents further fibril extension by blocking the active ends of seeds. This approach could provide a novel therapeutic option for the treatment of senile amyloidosis.
Warning signals for eruptive events in spreading fires
Authors: Fox Jerome M. , Whitesides George M.
Published: February 2015

Significance

As flames spread through forests, buildings, or other complex environments, they can erupt, unexpectedly, into fast-moving conflagrations. This study presents evidence that characteristic patterns in the behavior of spreading flames may indicate when such eruptions are likely to occur. Our results rely on the detection of a phenomenon termed “critical slowing down”—the slowed recovery of multistable systems from perturbations as those systems approach tipping points. Using a bistable combustion system in which flames propagate either as small, slowly moving flames, or as large, rapidly moving flames stabilized by feedback between wind and fire, we provide evidence that slowing responses of spreading flames to sudden changes in environment (e.g., wind, terrain) may anticipate the onset of intense, feedback-stabilized modes of propagation.
Visualizing monolayers with a water-soluble fluorophore to quantify adsorption, desorption, and the double layer
Authors: Shieh Ian C. , Zasadzinski Joseph A.
Published: February 2015

Significance

Visualizing phase separation in monolayers at the air–water interface with fluorescence microscopy has, up to now, relied on image contrast provided by fluorescently tagged lipids. However, the tagged lipids are insoluble and cannot leave the interface, ultimately reaching high concentrations as the phase distribution changes. This can lead to alterations in phase behavior, domain shape, and fluorescence quenching. Here we show that a water-soluble dye in the subphase preferentially adsorbs into less-ordered monolayer domains and can provide quantifiable contrast in confocal microscopy images. The dye distribution in the double layer adjacent to charged monolayers can also be imaged quantitatively and used to rapidly assess the surface potential and the fractional dissociation of the monolayer lipids.
Widespread pollution of the South American atmosphere predates the industrial revolution by 240 y
Authors: Uglietti Chiara , Gabrielli Paolo , Cooke Colin A. , Vallelonga Paul , Thompson Lonnie G.
Published: February 2015

Significance

An exceptionally detailed ice core from the high-altitude location of Quelccaya (Peru) contains compelling evidence that the well-known metallurgic activities performed during the Inca Empire (A.D. 1438−1532) had a negligible impact on the South American atmosphere. In contrast, atmospheric emissions of a variety of toxic trace elements in South America started to have a widespread environmental impact around A.D. 1540, ∼240 y before the industrial revolution when colonial metallurgy began to pollute the Andean atmosphere. 20th century atmospheric pollution levels were the highest on record and remain unprecedented over the entirety of human history.
Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma
Authors: Guillaumond Fabienne , Bidaut Ghislain , Ouaissi Mehdi , Servais Stéphane , Gouirand Victoire , Olivares Orianne , Lac Sophie , Borge Laurence , Roques Julie , Gayet Odile , Pinault Michelle , Guimaraes Cyrille , Nigri Jérémy , Loncle Céline , Lavaut Marie-Noëlle , Garcia Stéphane , Tailleux Anne , Staels Bart , Calvo Ezequiel , Tomasini Richard , Iovanna Juan Lucio , Vasseur Sophie
Published: February 2015

Significance

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030. Advances in therapeutic treatments are urgently required to fight against this fatal disease. Here, elucidation of the metabolic signature of PDAC has identified the low-density lipoprotein receptor (LDLR), which facilitates cholesterol uptake, as a promising therapeutic target. Blocking of LDLR reduces the proliferative and clonogenic potential of PDAC cells and decreases activation of the ERK1/2 survival pathway. Moreover, LDLR silencing sensitizes PDAC cells to chemotherapeutic drugs and potentiates the tumoral regression promoted by chemotherapy. Finally,
Ldlr
is highly expressed at all stages of human PDAC and expression is associated with an increased risk of PDAC recurrence.
Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain
Authors: Puglia Meghan H. , Lillard Travis S. , Morris James P. , Connelly Jessica J.
Published: February 2015

Significance

Although understanding the precise nature of oxytocin’s influence on complex human social behavior has proven difficult, increasing evidence points to an anxiolytic effect. We use an imaging epigenetic approach to further parse oxytocin’s effects by examining a biological marker within the oxytocin system, DNA methylation of the oxytocin receptor gene (
OXTR
). Importantly, this epigenetic modification directly impacts the expression of oxytocin’s receptor, which is critical for the actions of oxytocin to have an effect. We find that higher levels of
OXTR
methylation are associated with increased neural response and decreased functional coupling within regions supporting social perception and emotion processing. This pattern of activity may be indicative of diminished emotion regulation to negative stimuli and increased risk of pathology.
Neuroinflammation triggered by β-glucan/dectin-1 signaling enables CNS axon regeneration
Authors: Baldwin Katherine T. , Carbajal Kevin S. , Segal Benjamin M. , Giger Roman J.
Published: February 2015

Significance

Damage to neuronal networks in the central nervous system typically results in permanent functional deficits; however, the regenerative capacity of injured neurons can be dramatically augmented by local innate immune responses. Here we investigated the molecular and cellular events that participate in immune-mediated repair of severed optic nerve axons in the mouse. We show that intraocular administration of particulate β-glucan engages the immune receptor dectin-1 expressed on retina-resident microglia and infiltrating leukocytes, to trigger enhanced axonal regeneration. Delayed administration of β-glucan by two days is as effective as administration at the time of injury, suggesting a large therapeutic window. These data elucidate a new pathway of immune-mediated neural repair that may be targeted to reverse neurological disability.
De novo production of the plant-derived alkaloid strictosidine in yeast
Authors: Brown Stephanie , Clastre Marc , Courdavault Vincent , O’Connor Sarah E.
Published: February 2015

Significance

Plants make a wide variety of complex molecules with potent biological activities including several anticancer therapeutics. Unfortunately, plants often produce these molecules in low amounts, making them expensive to obtain. Engineering simpler organisms, such as yeast, to produce these plant-derived compounds provides one solution to production challenges. One group of plant-derived molecules, the monoterpene indole alkaloids, is synthesized from a common intermediate, strictosidine. Here, we report how we developed a yeast strain that produces strictosidine. This required introducing 21 new genes and three gene deletions into the yeast genome. This yeast strain provides an important resource for the production of expensive, complex molecules that plants normally produce in small amounts.
SLO3 auxiliary subunit LRRC52 controls gating of sperm KSPER currents and is critical for normal fertility
Authors: Zeng Xu-Hui , Yang Chengtao , Xia Xiao-Ming , Liu Min , Lingle Christopher J.
Published: February 2015

Significance

Mammalian sperm fertility depends on coordinated activation of two sperm-specific ion channels, the alkalization-activated Ca2+-permeable sperm channel and a sperm pH-regulated K+current (KSPER) channel; both are required for fertility. In the mouse, the KSPER channel is thought to involve a complex of a pore-forming ion channel protein and subunit encoded by theslo3gene subunit and the leucine-rich-repeat-containing protein 52 (LRRC52) auxiliary subunit. We now show that KO of LRRC52 results in severely compromised fertility and shifts KSPER current activation away from the physiological range. Furthermore, utilizing genotypes with differing average amounts of KSPER current, we show that sperm fertility exhibits a steep dependence on the amount of available KSPER current. The results establish that LRRC52 is a critical determinant of sperm KSPER function and essential to support normal fertility.
Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates
Authors: Chou Danny Hung-Chieh , Webber Matthew J. , Tang Benjamin C. , Lin Amy B. , Thapa Lavanya S. , Deng David , Truong Jonathan V. , Cortinas Abel B. , Langer Robert , Anderson Daniel G.
Published: February 2015

Significance

Self-administered insulin is the most important therapeutic to provide control over blood glucose levels for patients with type-1 diabetes. However, standard insulin therapy introduces a number of complications and subsequent issues with control of blood glucose levels. Here, we prepared a derivative of insulin with a molecular switch to provide glucose-mediated activation of the insulin molecule, toward the generation of more autonomous therapy with improved blood glucose control. This modified insulin, when administered in a diabetic mouse model, restores blood glucose levels following a glucose challenge (i.e., a simulated meal) faster than both standard insulin and a clinically used long-lasting insulin derivative.
Efficient solar-to-fuels production from a hybrid microbial–water-splitting catalyst system
Authors: Torella Joseph P. , Gagliardi Christopher J. , Chen Janice S. , Bediako D. Kwabena , Colón Brendan , Way Jeffery C. , Silver Pamela A. , Nocera Daniel G.
Published: February 2015

Significance

Renewable-fuels generation has emphasized water splitting to produce hydrogen and oxygen. For accelerated technology adoption, bridging hydrogen to liquid fuels is critical to the translation of solar-driven water splitting to current energy infrastructures. One approach to establishing this connection is to use the hydrogen from water splitting to reduce carbon dioxide to generate liquid fuels via a biocatalyst. We describe the integration of water-splitting catalysts comprised of earth-abundant components to wild-type and engineered
Ralstonia eutropha
to generate biomass and isopropyl alcohol, respectively. We establish the parameters for bacterial growth conditions at low overpotentials and consequently achieve overall efficiencies that are comparable to or exceed natural systems.
Discovery and horizontal follow-up of an autoantibody signature in human prostate cancer
Authors: Mintz Paul J. , Rietz Anna Cecilia , Cardó-Vila Marina , Ozawa Michael G. , Dondossola Eleonora , Do Kim-Anh , Kim Jeri , Troncoso Patricia , Logothetis Christopher J. , Sidman Richard L. , Pasqualini Renata , Arap Wadih
Published: February 2015

Significance

For the management of prostate cancer it has remained a significant clinical challenge to identify biomarkers that can be used as prognostic indicators to facilitate early treatment decisions and indicate patients at risk for castrate-resistant bone-metastatic prostate cancer in need of more aggressive treatment. In this report, serum antibodies to alpha-2–Heremans–Schmidt glycoprotein (fetuin-A) were demonstrated to display increased reactivity with concomitant development of metastatic castrate-resistant disease in a large cohort of prostate cancer patients. Furthermore, metastatic prostate cancer cell lines and bone metastasis samples displayed robust fetuin-A expression. To our knowledge, this is the first report to indicate that serum autoantibodies reactive to fetuin-A show utility as a prognostic indicator for prostate cancer patients at risk for progressing to metastatic disease.
Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area
Authors: Krabbe Sabine , Duda Johanna , Schiemann Julia , Poetschke Christina , Schneider Gaby , Kandel Eric R. , Liss Birgit , Roeper Jochen , Simpson Eleanor H.
Published: February 2015

Significance

Patients with schizophrenia suffer from cognitive and negative deficits that are largely resistant to current therapeutic strategies. Here, using a genetic mouse model that displays phenotypes similar to these cognitive and negative symptoms, we found that increased postsynaptic D2 receptor (D2R) activity in the striatum leads to changes in the firing pattern of presynaptic dopamine (DA) neurons of the midbrain. These alterations occur in the ventral tegmental area (VTA) of the midbrain, but not in the substantia nigra, suggesting that DA pathways may be differently regulated by striatal D2R hyperactivity. The changes in neuron firing patterns were accompanied by a reduction in NMDA receptor subunits selectively in dopaminergic VTA neurons, providing a potential new target for the treatment of schizophrenia symptoms.
Thermodynamic mechanism for inhibition of lactose permease by the phosphotransferase protein IIA
Glc
Authors: Hariharan Parameswaran , Balasubramaniam Dhandayuthapani , Peterkofsky Alan , Kaback H. Ronald , Guan Lan
Published: February 2015

Significance

Carbohydrate uptake in many bacteria is regulated by the phosphotransferase protein IIA
Glc
, enabling cells to use glucose preferentially over other sugars. Lactose permease (LacY) is one of many sugar permeases regulated by IIA
Glc
, but the mechanism of inducer exclusion is unclear. We now show by isothermal titration calorimetry that IIA
Glc
binds to purified LacY with a stoichiometry of one, and that the interaction is driven by favorable solvation entropy. IIA
Glc
binding inhibits conformational dynamics of LacY and decreases binding affinity for sugar in a manner similar to that observed for melibiose permease (MelB). However, the thermodynamic mechanism by which the inhibitory effect is expressed differs for the two permeases.
Constraints on the evolution of a
doublesex
target gene arising from doublesex’s pleiotropic deployment
Authors: Luo Shengzhan D. , Baker Bruce S.
Published: February 2015

Significance

Most sexually dimorphic features of
Drosophila melanogaster
are specified by the action of sex-specific transcription factors encoded by the
doublesex
(
dsx
) gene. Evolutionary changes in such sexually dimorphic features are often a result of changes in the
cis
-regulatory sequences of the DSX target genes. When a particular target gene is directly regulated by DSX in multiple tissues, evolutionarily conflicting constraints may be generated. The research we present here reveals that such conflict can be solved by deploying different
cis
-regulatory modules (sharing the DSX-binding site) for different tissues. This mechanism could also apply to other transcription factors.
Response to Davies and Fuchs
Authors: Nelson Gerald
Published: February 2015

Commentary to: Davies, Mark, and Robert Fuchs. 2015. "Expanding horizons in the study of World Englishes with the 1.9 billion word Global Web-based English Corpus (GloWbE)". English World-Wide 36:1–28 (This issue). DOI:10.1075/eww.36.1.01dav
Ageing meanings of (ing)
Authors: Schleef Erik , Flynn Nicholas
Published: February 2015

This study examines the social meanings that speakers associate with variants of the variable (ing) in Manchester, focusing on a comparison of two age groups: a young age group of adolescents and those in very early adulthood, and an older age group. In most English varieties, (ing) has two possible realisations: [ɪŋ] and [ɪn]. However, in Manchester, a third possibility exists: [ɪŋg]. Social meanings differ between age groups on three scales: articulateness, poshness and reliability. When compared to the youths, those in the older age group consider [ɪŋ] to sound substantially more articulate than [ɪn], as well as posher and more reliable than [ɪŋg]. In contrast, those in the younger group consider [ɪŋg] more reliable and posher-sounding than the older speakers. This is due, we argue, to developmental constraints during adolescence, but, more importantly, to life-stage experiences, with social meanings on these three scales altering as speakers leave adolescence behind and become increasingly subject to the standardisation pressures of adult communities.
Preliminary detection method for added rice- and sugarcane-derived brewer’s alcohol in bulk samples of sake by measurement of hydrogen, oxygen, and carbon isotopes
Authors: Hashiguchi Tomokazu , Akamatsu Fumikazu , Izu Hanae , Fujii Tsutomu
Published: February 2015

The δD and δ18O of sake without ethanol extraction as well as the δ13C of ethanol were determined in order to detect rice-derived brewer’s alcohol. Brewing tests demonstrated that the δD decreases upon addition of brewer’s alcohol (both rice- and sugarcane-derived), while the δ18O has little response to either, and the δ13C increases only for added sugarcane-derived alcohol.
Evidence of different underlying processes in pattern recall and decision-making
Authors: Gorman Adam D. , Abernethy Bruce , Farrow Damian
Published: February 2015

The visual search characteristics of expert and novice basketball players were recorded during pattern recall and decision-making tasks to determine whether the two tasks shared common visual–perceptual processing strategies. The order in which participants entered the pattern elements in the recall task was also analysed to further examine the nature of the visual–perceptual strategies and the relative emphasis placed upon particular pattern features. The experts demonstrated superior performance across the recall and decision-making tasks [see also Gorman, A. D., Abernethy, B., & Farrow, D. (2012). Classical pattern recall tests and the prospective nature of expert performance. The Quarterly Journal of Experimental Psychology, 65, 1151–1160; Gorman, A. D., Abernethy, B., & Farrow, D. (2013a). Is the relationship between pattern recall and decision-making influenced by anticipatory recall? The Quarterly Journal of Experimental Psychology, 66, 2219–2236)] but a number of significant differences in the visual search data highlighted disparities in the processing strategies, suggesting that recall skill may utilize different underlying visual–perceptual processes than those required for accurate decision-making performance in the natural setting. Performance on the recall task was characterized by a proximal-to-distal order of entry of the pattern elements with participants tending to enter the players located closest to the ball carrier earlier than those located more distal to the ball carrier. The results provide further evidence of the underlying perceptual processes employed by experts when extracting visual information from complex and dynamic patterns.
The dendritic cell cytoskeleton promotes T cell adhesion and activation by constraining ICAM-1 mobility
Authors: Comrie William A. , Li Shuixing , Boyle Sarah , Burkhardt Janis K.
Published: February 2015

Integrity of the dendritic cell (DC) actin cytoskeleton is essential for T cell priming, but the underlying mechanisms are poorly understood. We show that the DC F-actin network regulates the lateral mobility of intracellular cell adhesion molecule 1 (ICAM-1), but not MHCII. ICAM-1 mobility and clustering are regulated by maturation-induced changes in the expression and activation of moesin and α-actinin-1, which associate with actin filaments and the ICAM-1 cytoplasmic domain. Constrained ICAM-1 mobility is important for DC function, as DCs expressing a high-mobility ICAM-1 mutant lacking the cytoplasmic domain exhibit diminished antigen-dependent conjugate formation and T cell priming. These defects are associated with inefficient induction of leukocyte functional antigen 1 (LFA-1) affinity maturation, which is consistent with a model in which constrained ICAM-1 mobility opposes forces on LFA-1 exerted by the T cell cytoskeleton, whereas ICAM-1 clustering enhances valency and further promotes ligand-dependent LFA-1 activation. Our results reveal an important new mechanism through which the DC cytoskeleton regulates receptor activation at the immunological synapse.
F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse
Authors: Comrie William A. , Babich Alexander , Burkhardt Janis K.
Published: February 2015

Integrin-dependent interactions between T cells and antigen-presenting cells are vital for proper T cell activation, effector function, and memory. Regulation of integrin function occurs via conformational change, which modulates ligand affinity, and receptor clustering, which modulates valency. Here, we show that conformational intermediates of leukocyte functional antigen 1 (LFA-1) form a concentric array at the immunological synapse. Using an inhibitor cocktail to arrest F-actin dynamics, we show that organization of this array depends on F-actin flow and ligand mobility. Furthermore, F-actin flow is critical for maintaining the high affinity conformation of LFA-1, for increasing valency by recruiting LFA-1 to the immunological synapse, and ultimately for promoting intracellular cell adhesion molecule 1 (ICAM-1) binding. Finally, we show that F-actin forces are opposed by immobilized ICAM-1, which triggers LFA-1 activation through a combination of induced fit and tension-based mechanisms. Our data provide direct support for a model in which the T cell actin network generates mechanical forces that regulate LFA-1 activity at the immunological synapse.
Structural and functional properties of ryanodine receptor type 3 in zebrafish tail muscle
Authors: Perni Stefano , Marsden Kurt C. , Escobar Matias , Hollingworth Stephen , Baylor Stephen M. , Franzini-Armstrong Clara
Published: February 2015

The ryanodine receptor (RyR)1 isoform of the sarcoplasmic reticulum (SR) Ca2+ release channel is an essential component of all skeletal muscle fibers. RyR1s are detectable as “junctional feet” (JF) in the gap between the SR and the plasmalemma or T-tubules, and they are required for excitation–contraction (EC) coupling and differentiation. A second isoform, RyR3, does not sustain EC coupling and differentiation in the absence of RyR1 and is expressed at highly variable levels. Anatomically, RyR3 expression correlates with the presence of parajunctional feet (PJF), which are located on the sides of the SR junctional cisternae in an arrangement found only in fibers expressing RyR3. In frog muscle fibers, the presence of RyR3 and PJF correlates with the occurrence of Ca2+ sparks, which are elementary SR Ca2+ release events of the EC coupling machinery. Here, we explored the structural and functional roles of RyR3 by injecting zebrafish (Danio rerio) one-cell stage embryos with a morpholino designed to specifically silence RyR3 expression. In zebrafish larvae at 72 h postfertilization, fast-twitch fibers from wild-type (WT) tail muscles had abundant PJF. Silencing resulted in a drop of the PJF/JF ratio, from 0.79 in WT fibers to 0.03 in the morphants. The frequency with which Ca2+ sparks were detected dropped correspondingly, from 0.083 to 0.001 sarcomere−1 s−1. The few Ca2+ sparks detected in morphant fibers were smaller in amplitude, duration, and spatial extent compared with those in WT fibers. Despite the almost complete disappearance of PJF and Ca2+ sparks in morphant fibers, these fibers looked structurally normal and the swimming behavior of the larvae was not affected. This paper provides important evidence that RyR3 is the main constituent of the PJF and is the main contributor to the SR Ca2+ flux underlying Ca2+ sparks detected in fully differentiated frog and fish fibers.
FUN-L: gene prioritization for RNAi screens
Authors: Lees Jonathan G. , Hériché Jean-Karim , Morilla Ian , Fernández José M. , Adler Priit , Krallinger Martin , Vilo Jaak , Valencia Alfonso , Ellenberg Jan , Ranea Juan A. , Orengo Christine
Published: February 2015

Motivation: Most biological processes remain only partially characterized with many components still to be identified. Given that a whole genome can usually not be tested in a functional assay, identifying the genes most likely to be of interest is of critical importance to avoid wasting resources.

Results: Given a set of known functionally related genes and using a state-of-the-art approach to data integration and mining, our Functional Lists (FUN-L) method provides a ranked list of candidate genes for testing. Validation of predictions from FUN-L with independent RNAi screens confirms that FUN-L-produced lists are enriched in genes with the expected phenotypes. In this article, we describe a website front end to FUN-L.

Availability and implementation: The website is freely available to use at http://funl.org

Contact:  ucbcjle@live.ucl.ac.uk
Large-scale exploration and analysis of drug combinations
Authors: Li Peng , Huang Chao , Fu Yingxue , Wang Jinan , Wu Ziyin , Ru Jinlong , Zheng Chunli , Guo Zihu , Chen Xuetong , Zhou Wei , Zhang Wenjuan , Li Yan , Chen Jianxin , Lu Aiping , Wang Yonghua
Published: February 2015

Motivation: Drug combinations are a promising strategy for combating complex diseases by improving the efficacy and reducing corresponding side effects. Currently, a widely studied problem in pharmacology is to predict effective drug combinations, either through empirically screening in clinic or pure experimental trials. However, the large-scale prediction of drug combination by a systems method is rarely considered.

Results: We report a systems pharmacology framework to predict drug combinations (PreDCs) on a computational model, termed probability ensemble approach (PEA), for analysis of both the efficacy and adverse effects of drug combinations. First, a Bayesian network integrating with a similarity algorithm is developed to model the combinations from drug molecular and pharmacological phenotypes, and the predictions are then assessed with both clinical efficacy and adverse effects. It is illustrated that PEA can predict the combination efficacy of drugs spanning different therapeutic classes with high specificity and sensitivity (AUC = 0.90), which was further validated by independent data or new experimental assays. PEA also evaluates the adverse effects (AUC = 0.95) quantitatively and detects the therapeutic indications for drug combinations. Finally, the PreDC database includes 1571 known and 3269 predicted optimal combinations as well as their potential side effects and therapeutic indications.

Availability and implementation: The PreDC database is available at http://sm.nwsuaf.edu.cn/lsp/predc.php.

Contact:  yh_wang@nwsuaf.edu.cn

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Up-regulation of silent information regulator 2 (Sir2) is associated with amphotericin B resistance in clinical isolates of Leishmania donovani
Authors: Purkait Bidyut , Singh Ruby , Wasnik Kirti , Das Sushmita , Kumar Ashish , Paine Mark , Dikhit Manas , Singh Dharmendra , Sardar Abul H. , Ghosh Ayan K. , Das Pradeep
Published: February 2015

Objective

Silent information regulator 2 (Sir2) is involved in parasite survival and apoptosis. Here, we aimed to explore the involvement of Sir2 in amphotericin B (AmB) resistance mechanism in Leishmania donovani.

Methods

The expression levels of Sir2, MDR1 and NAD+ biosynthetic pathway enzymes in AmB-resistant and -susceptible parasites were measured and total intracellular NAD+/NADH ratios were compared. Overexpression and knockout constructs of Sir2 were transfected in AmB-resistant and -susceptible parasites. Both resistant and susceptible parasites were inhibited with sirtinol for 4 h. The deacetylase activity of Sir2, the expression level of MDR1, the rate of AmB efflux, concentrations of reactive oxygen species (ROS) and levels of apoptosis were examined in WT, inhibited and transfected parasites, and the AmB susceptibility of the respective parasites was measured by determining the LD50 of AmB.

Results

Levels of mRNA, protein and NAD+-dependent deacetylase activity of Sir2 were elevated in resistant versus susceptible parasites. Inhibition and/or deletion of Sir2 allele showed a decreased mRNA level of MDR1, lower drug efflux, increased ROS concentration, apoptosis-like phenomenon and decreased LD50 of AmB in resistant parasites. In contrast, Sir2 overexpression in susceptible parasites reversed drug susceptibility producing a resistant phenotype. This was associated with increased LD50 of AmB along with increased expression levels of MDR1, drug efflux and reduced concentrations of ROS, corresponding to decreased apoptosis of resistant to WT sensitive.

Conclusions

Sir2 plays a critical role in AmB resistance by regulating MDR1, ROS concentration and apoptosis-like phenomena and may be a new resistance marker for visceral leishmaniasis.
Novel user interface design for medication reconciliation: an evaluation of Twinlist
Authors: Plaisant Catherine , Wu Johnny , Hettinger A. Zach , Powsner Seth , Shneiderman Ben
Published: February 2015

Objective The primary objective was to evaluate time, number of interface actions, and accuracy on medication reconciliation tasks using a novel user interface (Twinlist, which lays out the medications in five columns based on similarity and uses animation to introduce the grouping - www.cs.umd.edu/hcil/sharp/twinlist) compared to a Control interface (where medications are presented side by side in two columns). A secondary objective was to assess participant agreement with statements regarding clarity and utility and to elicit comparisons.

Material and Methods A 1 × 2 within-subjects experimental design was used with interface (Twinlist or Control) as an independent variable; time, number of clicks, scrolls, and errors were used as dependent variables. Participants were practicing medical providers with experience performing medication reconciliation but no experience with Twinlist. They reconciled two cases in each interface (in a counterbalanced order), then provided feedback on the design of the interface.

Results Twenty medical providers participated in the study for a total of 80 trials. The trials using Twinlist were statistically significantly faster (18%), with fewer clicks (40%) and scrolls (60%). Serious errors were noted 12 and 31 times in Twinlist and Control trials, respectively.

Discussion Trials using Twinlist were faster and more accurate. Subjectively, participants rated Twinlist more favorably than Control. They valued the novel layout of the drugs, but indicated that the included animation would be valuable for novices, but not necessarily for advanced users. Additional feedback from participants provides guidance for further development and clinical implementations.

Conclusions Cognitive support of medication reconciliation through interface design can significantly improve performance and safety.
Rural EMR adoption rates overtake those in urban areas
Authors: Whitacre Brian E.
Published: February 2015

Objective To assess rural-urban differences in electronic medical record (EMR) adoption among office-based physician practices in the United States.

Methods Survey data on over 270 000 office-based physician sites (representing over 1 280 000 physicians) in the United States from 2012 was used to assess differences in EMR adoption rates among practices in rural and urban areas. Logistic regression tests for differences in the determinants of EMR adoption by geography, and a nonlinear decomposition is used to quantify how much of the rural-urban gap is due to differences in measureable characteristics (such as type of practice or affiliation with a health system).

Results Overall EMR adoption rates were significantly higher for practices in rural areas (56%) vs those in urban areas (49%) in 2012 (P < 0.001). Twenty-nine states had statistically significantly different adoption rates between rural and urban areas, with only two states demonstrating higher rates in urban areas. EMR adoption continues to be higher for primary care practices when compared to specialists (51% vs 49%, P < 0.001), and state-level rural-urban differences in adoption are more pronounced for specialists. The decomposition technique finds that only 14% of the rural-urban gap can be explained by differences in measurable characteristics between practices.

Conclusions At the national level, rates of EMR adoption are higher for rural practices than for their urban counterparts, reversing earlier trends. This suggests that outreach efforts, namely the Regional Extension Centers created by the Office of the National Coordinator, have been particularly effective in increasing EMR adoption in rural areas.