bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of nitrogen vacancies in the luminescence of Mg-doped GaN
Authors: Yan Qimin , Janotti Anderson , Scheffler Matthias , Van de Walle Chris G.
Published: April 2012

Defects may cause compensation or act as recombination centers in Mg-doped GaN. Using hybrid functional calculations, we investigate the effects of nitrogen vacancies (VN) and Mg-vacancy complexes (MgGa-VN) on the electrical and optical properties of GaN. We find that MgGa-VN are compensating centers in p-type but electrically inactive in n-type GaN. They give rise to a broad emission at 1.8 eV, explaining the red luminescence that is frequently observed in Mg-doped GaN, regardless of the Fermi level. Nitrogen vacancies are also compensating centers in p-type GaN and likely contribute to the yellow luminescence that has been observed in Mg-doped GaN.
Structural destabilization of chignolin under the influence of oscillating electric fields
Authors: Astrakas Loukas G. , Gousias Christos , Tzaphlidou Margaret
Published: April 2012

The structural response of chignolin to 1 V/nm electric fields of different frequencies has been studied with molecular dynamics simulations and stochastic modeling. It was found that oscillating electric fields induce conformational changes to chignolin that are frequency dependent. For frequencies comparable with or smaller from the orientational self-diffusion rate, the peptide destabilizes after performing an oscillatory motion between the two possible directions of the electric field axis. For higher frequencies the field effects are averaged out and chignolin performs a Brownian rotation diffusion maintaining its native conformation. Stochastic modeling can describe chignolin’s oscillatory motion equally well with the molecular dynamics simulations. The time needed for these changes to take place has a stochastic nature depending, beyond frequency, on factors related with the hydrogen bonds’ stability and their geometrical arrangement in the structure.
New rationale for large metazoan embryo manipulations on chip-based devices
Authors: Khoshmanesh Khashayar , Akagi Jin , Hall Chris J. , Crosier Kathryn E. , Crosier Philip S. , Cooper Jonathan M. , Wlodkowic Donald
Published: April 2012

The lack of technologies that combine automated manipulation, sorting, as well as immobilization of single metazoan embryos remains the key obstacle to high-throughput organism-based ecotoxicological analysis and drug screening routines. Noticeably, the major obstacle hampering the automated trapping and arraying of millimetre-sized embryos on chip-based devices is their substantial size and mass, which lead to rapid gravitational-induced sedimentation and strong inertial forces. In this work, we present a comprehensive mechanistic and design rationale for manipulation and passive trapping of individual zebrafish embryos using only hydrodynamic forces. We provide evidence that by employing innovative design features, highly efficient hydrodynamic positioning of large embryos on a chip can be achieved. We also show how computational fluid dynamics-guided design and the Lagrangian particle tracking modeling can be used to optimize the chip performance. Importantly, we show that rapid prototyping and medium scale fabrication of miniaturized devices can be greatly accelerated by combining high-speed laser prototyping with replica moulding in poly(dimethylsiloxane) instead of conventional photolithography techniques. Our work establishes a new paradigm for chip-based manipulation of large multicellular organisms with diameters well above 1 mm and masses often exceeding 1 mg. Passive docking of large embryos is an attractive alternative to provide high level of automation while alleviating potentially deleterious effects associated with the use of active chip actuation. This greatly expands the capabilities of bioanalyses performed on small model organisms and offers numerous and currently inaccessible laboratory automation advantages.
A numerical analysis of multicellular environment for modeling tissue electroporation
Authors: Essone Mezeme M. , Pucihar G. , Pavlin M. , Brosseau C. , Miklavčič D.
Published: April 2012

Simulations probing the conductivity changes of three-dimensional models of biological tissues consisting of random ternary core-shell sphere packings with different spatial scales are described. We investigate the temporal evolution of the electric conductivity of these packings during application of an electric field with magnitude either below or above the value leading to cell membrane electroporation. The fraction of electroporated cells can be described by a hyperbolic tangent function of the electric field. The collective physical processes causing the transient permeability of the cell membranes can be understood by analogy with the physics of a two-state system with an external field.
Effect of TaOx thickness on the resistive switching of Ta/Pr0.7Ca0.3MnO3/Pt films
Authors: Liu Ziyu , Zhang Peijian , Meng Yang , Tian Huanfang , Li Jianqi , Pan Xinyu , Liang Xuejin , Chen Dongmin , Zhao Hongwu
Published: April 2012

The influence of interfacial structure on the resistance switching behavior of Ta/Pr0.7Ca0.3MnO3/Pt films was investigated by varying the reactive Ta electrode thickness. Structure and component analyses revealed that a TaOx layer formed at the interface and its thickness increased with the Ta thickness in the thin region while staying the same in the thick region. The similar thickness dependences of the negative differential resistance and resistance switching characteristics were observed and interpreted by the TaOx thickness dependent oxidization and reduction reaction across the interfacial region. This study demonstrates that the resistance switching characteristics could be improved by suitable interfacial engineering.
Vibrational frequencies of anti-diabetic drug studied by terahertz time-domain spectroscopy
Authors: Du S. Q. , Li H. , Xie L. , Chen L. , Peng Y. , Zhu Y. M. , Li H. , Dong P. , Wang J. T.
Published: April 2012

By using terahertz time-domain spectroscopy, the absorption spectra of seven anti-diabetic pills have been investigated. For gliquidone, glipizide, gliclazide, and glimepiride, an obvious resonance peak is found at 1.37 THz. Furthermore, to overcome the limit of density functional theory that can analyze the normal mode frequencies of the ground state of organic material, we also present a method that relies on pharmacophore recognition, from which we can obtain the resonance peak at 1.37 THz can be attributed to the vibration of sulfonylurea group. The results indicate that the veracity of density functional theory can be increased by combining pharmacophore recognition.
Notable internal thermal effect on the yielding of metallic glasses
Authors: Liu W. D. , Liu K. X.
Published: April 2012

We revealed a notable internal thermal effect on the yielding of metallic glasses with the aid of a newly developed microscopic model focusing on the interaction of incipient localized shear events. It is shown that at the high strain rate, localized heating in metallic glasses instead of localized structure change plays the dominant role in shear softening. Using the modified cooperative shear model with the ingredient of the thermal effect, we captured the sudden decrease of the strength of metallic glasses after a critical strain rate, which was found in experiments.
Nanocrystal-based Ohmic contacts on n and p-type germanium
Authors: Pavan Kishore V. , Paramahans Prashanth , Sadana Sunny , Ganguly Udayan , Lodha Saurabh
Published: April 2012

We report a simple method of forming Ohmic contacts to n and p-type germanium (Ge) simultaneously using Au nanocrystals embedded in Ti contact metal. The electric field due to the work-function difference of Ti and Au reduces the tunneling resistance at the Ti-Au/Ge interface for n and p-type contacts. The nanocrystal-based contacts on n-Ge exhibit quasi-Ohmic current-voltage characteristics with >1000× increase in current density and an apparent reduction of 0.18 eV in the barrier height over Ti/n-Ge and Au/n-Ge contacts that show rectifying characteristics due to Fermi level pinning. On n+-Ge, the nanocrystal-based contacts exhibit Ohmic characteristics with >35× reduction in zero-bias resistance over Ti/n+-Ge contacts. Similar to Ti and Au contacts on p-Ge, Au nanocrystals embedded in Ti continue to exhibit Ohmic characteristics. This is in contrast to methods that convert p-type contacts from Ohmic to rectifying in the process of forming an Ohmic contact on n-Ge by inserting a thin dielectric layer between the metal and Ge. Device simulations reinforce the observed decrease in tunneling resistance due to the enhanced electric field at the Ti-Au/Ge interface.
Dependence of charge carrier injection on the interface energy barrier in short-channel polymeric field effect transistors
Authors: Alborghetti S. , Coey J. M. D. , Stamenov P.
Published: April 2012

The influence of contact materials on the electrical characteristics of field-effect transistors made from poly(3-hexylthiophene) with short-channel lengths of 80 nm is investigated. The thermally activated output current indicates the presence of a potential barrier at the electrode/organic contact. The barrier is not related to surface oxide and results in non-linear junction characteristics with activation voltage that can be only partially controlled via the work function of the contact metal. A Schottky contact at the metal/polymer interface arises from the band offset of the two materials and from interfacial dipole layers. Transistor operation with on/off ratio over 103 is achieved with five different electrode materials.
Using genes differentially expressed in bulls to classify steers divergently selected for high and low residual feed intake
Authors: Chen Y. , Arthur P. F. , Herd R. M. , Quinn K. , Barchia I. M.
Published: April 2012

Feed efficiency is an economically important trait in livestock and residual feed intake (RFI) is a commonly used measure of the trait in beef cattle. Residual feed intake is the difference between the actual feed intake recorded over a test period and the expected feed intake of an animal based on its size and growth rate. It is a heritable trait, and efficient animals have lower RFI values. Several genes have been identified as being differentially expressed in the liver of Angus bulls that have been divergently selected for RFI. The objective of this study was to use genes that are differentially expressed in bulls to classify Angus steers from the same divergent RFI selection lines. Liver samples were collected at slaughter from 40 high RFI and 40 low RFI steers that were ~23 months old, and had just completed a 251-day feedlot feeding period. RNA samples from the livers were assayed by quantitative real-time PCR for 14 genes, which have been identified previously in bulls. Steers were not measured for RFI, hence the estimated breeding values (EBV) for RFI of their parents were used to calculate their mid-parent (average of the two parents) RFI-EBV. Correlation and discriminant analyses were conducted on the normalised quantitative real-time PCR data from the steers. Discriminant analysis was also conducted on the bull data for comparison. In the steers, 8 out of the 14 genes were significantly (P < 0.05) correlated with RFI-EBV. Two genes from the glutathione S-transferase mu family (GSTM1 and GSTM2) and the S100 calcium-binding protein A10 (S100A10) had the highest correlations with RFI-EBV, with correlation coefficients of 0.59, 0.44 and 0.36, respectively. Based on the 14 expressed genes, 84% of the steers and 98% of the bulls were correctly classified into their respective RFI selection lines. The results of this study indicate that a high proportion of the genes that were differentially expressed in the original study with bulls were also differentially expressed in this study with steers. The high accuracy in classification obtained in this study shows that the transcriptional approach to the study of the biological processes involved in variation in RFI has great potential for identification of candidate genes.
Trapped and Escaping Orbits in an Axially Symmetric Galactic-Type Potential
Authors: Zotos Euaggelos E.
Published: April 2012

In the present article, we investigate the behavior of orbits in a time-independent axially symmetric galactic-type potential. This dynamical model can be considered to describe the motion in the central parts of a galaxy, for values of energies larger than the energy of escape. We use the classical surface-of-section method in order to visualize and interpret the structure of the phase space of the dynamical system. Moreover, the Lyapunov characteristic exponent is used in order to make an estimation of the degree of chaoticity of the orbits in our galactic model. Our numerical calculations suggest that in this galactic-type potential there are two kinds of orbits: (i) escaping orbits and (ii) trapped orbits, which do not escape at all. Furthermore, a large number of orbits of the dynamical system display chaotic motion. Among the chaotic orbits, there are orbits that escape quickly and also orbits that remain trapped for vast time intervals. When the value of a test particle's energy slightly exceeds the energy of escape, the number of trapped regular orbits increases as the value of the angular momentum increases. Therefore, the extent of the chaotic regions observed in the phase plane decreases as the energy value increases. Moreover, we calculate the average value of the escape period of chaotic orbits and try to correlate it with the value of the energy and also with the maximum value of the z component of the orbits. In addition, we find that the value of the Lyapunov characteristic exponent corresponding to each chaotic region for different values of energy increases exponentially as the energy increases. Some theoretical arguments are presented in order to support the numerically obtained outcomes.
Torque measurements reveal sequence-specific cooperative transitions in supercoiled DNA
Authors: Oberstrass Florian C. , Fernandes Louis E. , Bryant Zev
Published: April 2012

B-DNA becomes unstable under superhelical stress and is able to adopt a wide range of alternative conformations including strand-separated DNA and Z-DNA. Localized sequence-dependent structural transitions are important for the regulation of biological processes such as DNA replication and transcription. To directly probe the effect of sequence on structural transitions driven by torque, we have measured the torsional response of a panel of DNA sequences using single molecule assays that employ nanosphere rotational probes to achieve high torque resolution. The responses of Z-forming d(pGpC)

n

sequences match our predictions based on a theoretical treatment of cooperative transitions in helical polymers. “Bubble” templates containing 50–100 bp mismatch regions show cooperative structural transitions similar to B-DNA, although less torque is required to disrupt strand–strand interactions. Our mechanical measurements, including direct characterization of the torsional rigidity of strand-separated DNA, establish a framework for quantitative predictions of the complex torsional response of arbitrary sequences in their biological context.
Tissue-specific splicing of an
Ndufs6
gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy
Authors: Ke Bi-Xia , Pepe Salvatore , Grubb David R. , Komen Jasper C. , Laskowski Adrienne , Rodda Felicity A. , Hardman Belinda M. , Pitt James J. , Ryan Michael T. , Lazarou Michael , Koleff Jane , Cheung Michael M. H. , Smolich Joseph J. , Thorburn David R.
Published: April 2012

Mitochondrial complex I (CI) deficiency is the most common mitochondrial enzyme defect in humans. Treatment of mitochondrial disorders is currently inadequate, emphasizing the need for experimental models. In humans, mutations in the
NDUFS6
gene, encoding a CI subunit, cause severe CI deficiency and neonatal death. In this study, we generated a CI-deficient mouse model by knockdown of the
Ndufs6
gene using a gene-trap embryonic stem cell line.
Ndufs6
gt/gt
mice have essentially complete knockout of the Ndufs6 subunit in heart, resulting in marked CI deficiency. Small amounts of wild-type
Ndufs6
mRNA are present in other tissues, apparently due to tissue-specific mRNA splicing, resulting in milder CI defects.
Ndufs6
gt/gt
mice are born healthy, attain normal weight and maturity, and are fertile. However, after 4 mo in males and 8 mo in females,
Ndufs6
gt/gt
mice are at increased risk of cardiac failure and death. Before overt heart failure,
Ndufs6
gt/gt
hearts show decreased ATP synthesis, accumulation of hydroxyacylcarnitine, but not reactive oxygen species (ROS).
Ndufs6
gt/gt
mice develop biventricular enlargement by 1 mo, most pronounced in males, with scattered fibrosis and abnormal mitochondrial but normal myofibrillar ultrastructure.
Ndufs6
gt/gt
isolated working heart preparations show markedly reduced left ventricular systolic function, cardiac output, and functional work capacity. This reduced energetic and functional capacity is consistent with a known susceptibility of individuals with mitochondrial cardiomyopathy to metabolic crises precipitated by stresses. This model of CI deficiency will facilitate studies of pathogenesis, modifier genes, and testing of therapeutic approaches.
Mismatch repair-dependent mutagenesis in nondividing cells
Authors: Rodriguez Gina P. , Romanova Nina V. , Bao Gaobin , Rouf N. Cynthia , Kow Yoke Wah , Crouse Gray F.
Published: April 2012

Mismatch repair (MMR) is a major DNA repair pathway in cells from all branches of life that removes replication errors in a strand-specific manner, such that mismatched nucleotides are preferentially removed from the newly replicated strand of DNA. Here we demonstrate a role for MMR in helping create new phenotypes in nondividing cells. We show that mispairs in yeast that escape MMR during replication can later be subject to MMR activity in a replication strand-independent manner in nondividing cells, resulting in either fully wild-type or mutant DNA sequence. In one case, this activity is responsible for what appears to be adaptive mutation. This replication strand-independent MMR activity could contribute to the formation of tumors arising in nondividing cells and could also contribute to mutagenesis observed during somatic hypermutation of Ig genes.
Distinct neuropsychological subgroups in typically developing youth inform heterogeneity in children with ADHD
Authors: Fair Damien A. , Bathula Deepti , Nikolas Molly A. , Nigg Joel T.
Published: April 2012

Research and clinical investigations in psychiatry largely rely on the de facto assumption that the diagnostic categories identified in theDiagnostic and Statistical Manual(DSM) represent homogeneous syndromes. However, the mechanistic heterogeneity that potentially underlies the existing classification scheme might limit discovery of etiology for most developmental psychiatric disorders. Another, perhaps less palpable, reality may also be interfering with progress—heterogeneity in typically developing populations. In this report we attempt to clarify neuropsychological heterogeneity in a large dataset of typically developing youth and youth with attention deficit/hyperactivity disorder (ADHD), using graph theory and community detection. We sought to determine whether data-driven neuropsychological subtypes could be discerned in children with and without the disorder. Because individual classification is the sine qua non for eventual clinical translation, we also apply support vector machine-based multivariate pattern analysis to identify how well ADHD status in individual children can be identified as defined by the community detection delineated subtypes. The analysis yielded several unique, but similar subtypes acrossbothpopulations. Just as importantly, comparing typically developing children with ADHD children within each of these distinct subgroups increased diagnostic accuracy. Two important principles were identified that have the potential to advance our understanding of typical development and developmental neuropsychiatric disorders. The first tenet suggests that typically developing children can be classified into distinct neuropsychological subgroups with high precision. The second tenet proposes that some of the heterogeneity in individuals with ADHD might be “nested” in this normal variation.
Structure of p73 DNA-binding domain tetramer modulates p73 transactivation
Authors: Ethayathulla Abdul S. , Tse Pui-Wah , Monti Paola , Nguyen Sonha , Inga Alberto , Fronza Gilberto , Viadiu Hector
Published: April 2012

The transcription factor p73 triggers developmental pathways and overlaps stress-induced p53 transcriptional pathways. How p53-family response elements determine and regulate transcriptional specificity remains an unsolved problem. In this work, we have determined the first crystal structures of p73 DNA-binding domain tetramer bound to response elements with spacers of different length. The structure and function of the adaptable tetramer are determined by the distance between two half-sites. The structures with zero and one base-pair spacers show compact p73 DNA-binding domain tetramers with large tetramerization interfaces; a two base-pair spacer results in DNA unwinding and a smaller tetramerization interface, whereas a four base-pair spacer hinders tetramerization. Functionally, p73 is more sensitive to spacer length than p53, with one base-pair spacer reducing 90% of transactivation activity and longer spacers reducing transactivation to basal levels. Our results establish the quaternary structure of the p73 DNA-binding domain required as a scaffold to promote transactivation.
Heterochromatin protein 1 homologue Swi6 acts in concert with Ers1 to regulate RNAi-directed heterochromatin assembly
Authors: Hayashi Aki , Ishida Mayumi , Kawaguchi Rika , Urano Takeshi , Murakami Yota , Nakayama Jun-ichi
Published: April 2012

In fission yeast, the RNAi pathway is required for centromeric heterochromatin assembly. siRNAs derived from centromeric transcripts are incorporated into the RNA-induced transcriptional silencing (RITS) complex and direct it to nascent homologous transcripts. The RNA-induced transcriptional silencing-bound nascent transcripts further recruit the RNA-directed RNA polymerase complex (RDRC) to promote dsRNA synthesis and siRNA production. Heterochromatin coated with Swi6/Heterochromain Protein 1 is then formed following recruitment of chromatin modification machinery. Swi6 is also required for the upstream production of siRNA, although the mechanism for this has remained obscure. Here, we demonstrate that Swi6 recruits RDRC to heterochromatin through Ers1, an RNAi factor intermediate. An
ers1
+
mutant allele (
ers1-C62
) was identified in a genetic screen for mutants that alleviate centromeric silencing, and this phenotype was suppressed by overexpression of either the Hrr1 RDRC subunit or Clr4 histone H3-K9 methyltransferase. Ers1 physically interacts with Hrr1, and loss of Ers1 impairs RDRC centromeric localization. Although Ers1 failed to bind Clr4, a direct interaction with Swi6 was detected, and centromeric localization of Swi6 was enhanced by Clr4 overexpression in
ers1-C62
cells. Consistent with this, deletion of
swi6
+
reduced centromeric localization of Ers1 and RDRC. Moreover, tethering of Ers1 or Hrr1 to centromeric heterochromatin partially bypassed Swi6 function. These findings demonstrate an alternative mechanism for RDRC recruitment and explain the essential role of Swi6/Heterochromain Protein 1 in RNAi-directed heterochromatin assembly.
Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates
Authors: Santi Daniel V. , Schneider Eric L. , Reid Ralph , Robinson Louise , Ashley Gary W.
Published: April 2012

Conjugation to macromolecular carriers is a proven strategy for improving the pharmacokinetics of drugs, with many stable polyethylene glycol conjugates having reached the market. Stable conjugates suffer several limitations: loss of drug potency due to conjugation, confining the drug to the extracellular space, and the requirement for a circulating conjugate. Current research is directed toward overcoming such limitations through releasable conjugates in which the drug is covalently linked to the carrier through a cleavable linker. Satisfactory linkers that provide predictable cleavage rates tunable over a wide time range that are useful for both circulating and noncirculating conjugates are not yet available. We describe such conjugation linkers on the basis of a nonenzymatic β-elimination reaction with preprogrammed, highly tunable cleavage rates. A set of modular linkers is described that bears a succinimidyl carbonate group for attachment to an amine-containing drug or prodrug, an azido group for conjugation to the carrier, and a tunable modulator that controls the rate of β-eliminative cleavage. The linkers provide predictable, tunable release rates of ligands from macromolecular conjugates both in vitro and in vivo, with half-lives spanning from a range of hours to >1 y at physiological pH. A circulating PEG conjugate achieved a 56-fold half-life extension of the 39-aa peptide exenatide in rats, and a noncirculating s.c. hydrogel conjugate achieved a 150-fold extension. Using slow-cleaving linkers, the latter may provide a generic format for once-a-month dosage forms of potent drugs. The releasable linkers provide additional benefits that include lowering
C
max
and pharmacokinetic coordination of drug combinations.
Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a
Legionella
effector functioning in membrane trafficking
Authors: Ge Jianning , Gong Yi-Nan , Xu Ying , Shao Feng
Published: April 2012

Legionella pneumophila
, the causative agent of Legionnaires’ pneumonia, resides in a distinct vacuole structure called
Legionella
-containing vacuole (LCV). The LCV resists fusion with the lysosome and permits efficient bacterial replication in host macrophages, which requires a Dot/Icm type IVB secretion system. Dot/Icm-translocated effector SdhA is critical for
L. pneumophila
intracellular growth and functions to prevent host cell death. Here, we show that the absence of SdhA resulted in elevated caspase-1 activation and IL-1β secretion as well as macrophage pyroptosis during
Legionella
infection. These inflammasome activation phenotypes were independent of the established flagellin-NAIP5-NLRC4 axis, but relied on the DNA-sensing AIM2 inflammasome. We further demonstrate that
Legionella
DNA was released into macrophage cytosol, and this effect was significantly exaggerated by the absence of SdhA. SdhA bears a functional Golgi-targeting GRIP domain that is required for preventing AIM2 inflammasome activation. Ectopically expressed SdhA formed a unique ring-shape membrane structure, further indicating a role in membrane trafficking and maintaining LCV membrane integrity. Our data together suggest a possible link, mediated by the function of SdhA, between LCV trafficking/maturation and suppression of host innate immune detection.
Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk
Authors: Cohen Sheldon , Janicki-Deverts Denise , Doyle William J. , Miller Gregory E. , Frank Ellen , Rabin Bruce S. , Turner Ronald B.
Published: April 2012

We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.
De novo design of synthetic prion domains
Authors: Toombs James A. , Petri Michelina , Paul Kacy R. , Kan Grace Y. , Ben-Hur Asa , Ross Eric D.
Published: April 2012

Prions are important disease agents and epigenetic regulatory elements. Prion formation involves the structural conversion of proteins from a soluble form into an insoluble amyloid form. In many cases, this structural conversion is driven by a glutamine/asparagine (Q/N)-rich prion-forming domain. However, our understanding of the sequence requirements for prion formation and propagation by Q/N-rich domains has been insufficient for accurate prion propensity prediction or prion domain design. By focusing exclusively on amino acid composition, we have developed a prion aggregation prediction algorithm (PAPA), specifically designed to predict prion propensity of Q/N-rich proteins. Here, we show not only that this algorithm is far more effective than traditional amyloid prediction algorithms at predicting prion propensity of Q/N-rich proteins, but remarkably, also that PAPA is capable of rationally designing protein domains that function as prions in vivo.
Structural basis for negative cooperativity within agonist-bound TR:RXR heterodimers
Authors: Putcha Balananda-Dhurjati K. , Wright Edward , Brunzelle Joseph S. , Fernandez Elias J.
Published: April 2012

Thyroid hormones such as 3,3′,5 triiodo-
l
-thyronine (T3) control numerous aspects of mammalian development and metabolism. The actions of such hormones are mediated by specific thyroid hormone receptors (TRs). TR belongs to the nuclear receptor family of modular transcription factors that binds to specific DNA-response elements within target promoters. These receptors can function as homo- or heterodimers such as TR:9-
cis
retinoic acid receptor (RXR). Here, we present the atomic resolution structure of the TRα•T3:RXRα•9-
cis
retinoic acid (9c) ligand binding domain heterodimer complex at 2.95 Å along with T3 hormone binding and dissociation and coactivator binding studies. Our data provide a structural basis for allosteric communication between T3 and 9c and negative cooperativity between their binding pockets. In this structure, both TR and RXR are in the active state conformation for optimal binding to coactivator proteins. However, the structure of TR•T3 within TR•T3:RXR•9c is in a relative state of disorder, and the observed kinetics of binding show that T3 dissociates more rapidly from TR•T3:RXR•9c than from TR•T3:RXR. Also, coactivator binding studies with a steroid receptor coactivator-1 (receptor interaction domains 1–3) fragment show lower affinities (
K
a
) for TR•T3:RXR•9c than TR•T3:RXR. Our study corroborates previously reported observations from cell-based and binding studies and offers a structural mechanism for the repression of TR•T3:RXR transactivation by RXR agonists. Furthermore, the recent discoveries of multiple endogenous RXR agonists that mediate physiological tasks such as lipid biosynthesis underscore the pharmacological importance of negative cooperativity in ligand binding within TR:RXR heterodimers.
Morphine activates neuroinflammation in a manner parallel to endotoxin
Authors: Wang Xiaohui , Loram Lisa C. , Ramos Khara , de Jesus Armando J. , Thomas Jacob , Cheng Kui , Reddy Anireddy , Somogyi Andrew A. , Hutchinson Mark R. , Watkins Linda R. , Yin Hang
Published: April 2012

Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.
Viral-induced encephalitis initiates distinct and functional CD103
+
CD11b
+
brain dendritic cell populations within the olfactory bulb
Authors: D'Agostino Paul M. , Kwak Changsoo , Vecchiarelli Haley A. , Toth Judit Gal , Miller James M. , Masheeb Zahrah , McEwen Bruce S. , Bulloch Karen
Published: April 2012

Dendritic cells (DC) are antigen-presenting cells found in both lymphoid and nonlymphoid organs, including the brain (bDC) of
Cd11c/eyfp
transgenic C57BL/6 mice. Using an intranasal vesicular stomatitis virus infection, we demonstrated that EYFP
+
cells amass in areas associated with viral antigens, take on an activated morphology, and project their processes into infected neuronal tissue within the olfactory bulb. These bDC separated into three EYFP
+
CD45
+
CD11b
+
populations, all but one being able to functionally promote both T lymphocyte proliferation and T
H
1 cytokine production. One population was shown to emanate from the brain and a second population was peripherally derived. The third population was of indeterminate origin, being both radiosensitive and not replenished by donor bone marrow. Finally, each EYFP
+
population contained CD11b
+
CD103
+
subpopulations and could be distinguished in terms of CD115, Gr-1, and Ly-6C expression, highlighting mucosal and monocyte-derived DC lineages.
Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia
Authors: Lee Keunwook , Nam Ki Taek , Cho Sung Hoon , Gudapati Prathyusha , Hwang Yoonha , Park Do-Sim , Potter Ross , Chen Jin , Volanakis Emmanuel , Boothby Mark
Published: April 2012

Notch plays critical roles in both cell fate decisions and tumorigenesis. Notch receptor engagement initiates signaling cascades that include a phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway. Mammalian TOR (mTOR) participates in two distinct biochemical complexes, mTORC1 and mTORC2, and the relationship between mTORC2 and physiological outcomes dependent on Notch signaling is unknown. In this study, we report contributions of mTORC2 to thymic T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch. Conditional deletion of Rictor, an essential component of mTORC2, impaired Notch-driven proliferation and differentiation of pre-T cells. Furthermore, NF-κB activity depended on the integrity of mTORC2 in thymocytes. Active Akt restored NF-κB activation, a normal rate of proliferation, and differentiation of Rictor-deficient pre-T cells. Strikingly, mTORC2 depletion lowered CCR7 expression in thymocytes and leukemic cells, accompanied by decreased tissue invasion and delayed mortality in T-ALL driven by Notch. Collectively, these findings reveal roles for mTORC2 in promoting thymic T cell development and T-ALL and indicate that mTORC2 is crucial for Notch signaling to regulate Akt and NF-κB.
Low-temperature UV photoluminescence of ion beam synthesized Si nanoclusters embedded in Si
Authors: Sahu G , Lenka H P , Mahapatra D P , Rout B , Das M P
Published: April 2012

Ultraviolet (UV) photoluminescence (PL) data taken on a double Au implanted Si matrix are reported. This has been studied over a wide temperature range of 28–220 K. At low temperature, the spectrum shows four peaks corresponding to a zero-phonon line (ZPL) and three low-energy phonon-assisted lines. At 28 K the ZPL has an energy of 3.362 eV with a lifetime of ∼240 ps suggesting transitions across a direct gap. The temperature variation of the ZPL intensity indicates an activation energy ∼10 meV comparable to the binding energy of excitons in crystalline Si (c-Si). For T > 100 K, it shows a redshift which can be understood as coming from exciton–phonon interaction. At lower temperatures the corresponding line broadening shows evidence of interaction with low-energy phonons of average energy ∼7 meV as suggested earlier. All the above results indicate the emission to be coming from Si nanoclusters (NCs) embedded in the matrix.
Fabrication and surface-modification of implantable microprobes for neuroscience studies
Authors: Cao H , Nguyen C M , Chiao J C
Published: April 2012

In this work implantable micro-probes for central nervous system (CNS) studies were developed on silicon and polyimide substrates. The probes which contained micro-electrode arrays with different surface modifications were designed for implantation in the CNS. The electrode surfaces were modified with nano-scale structures that could greatly increase the active surface area in order to enhance the electrochemical current outputs while maintaining micro-scale dimensions of the electrodes and probes. The electrodes were made of gold or platinum, and designed with different sizes. The silicon probes were modified by silicon nanowires fabricated with the vapor–liquid–solid mechanism at high temperatures. With polyimide substrates, the nanostructure modification was carried out by applying concentrated gold or silver colloid solutions onto the micro-electrodes at room temperature. The surfaces of electrodes before and after modification were observed by scanning electron microscopy. The silicon nanowire-modified surface was characterized by cyclic voltammetry. Experiments were carried out to investigate the improvement in sensing performance. The modified electrodes were tested with H
2
O
2, electrochemical L-glutamate and dopamine. Comparisons between electrodes with and without nanostructure modification were conducted showing that the modifications have enhanced the signal outputs of the electrochemical neurotransmitter sensors.
Fabrication of micro accelerometer and magnetoresistive sensor directly on a ceramic substrate
Authors: Aoyagi Seiji
Published: April 2012

Micro-electro-mechanical systems (MEMS) sensors have movable parts: thus, it is difficult to handle them at fabrication because of the possibility of fracture. If a MEMS sensor could be fabricated not only on a silicon substrate but also on a ceramic substrate, which can be used for a package of the end product, the above-mentioned problem about handling would be solved, and its fabrication cost would be reduced. In this presentation, as demonstrations of the sensors directly fabricated on a ceramic package, an accelerometer and a magnetoresistive (MR) sensor are focused on. A micro accelerometer is proposed, which consists of a proof mass and ferroelectric substrate under it. A screen-printed barium titanate (BTO) film on an alumina substrate was employed as ferroelectrics. The sensitivity of the fabricated accelerometer was 0.1 pF 
g
−1. A triaxis MR sensor is proposed, which detects not only x- and y-axes’ magnetic field intensities but also that of the z-axis. Namely, not only azimuth but also angle of elevation of the sensor can be detected from triaxis components of the geomagnetic field. A permalloy (FeNi) plate is stood aside from the MR element. The plate distorts magnetic field and generates the x- (or y-) component from the originally z-directional field. A triaxis geomagnetic field was successfully detected by the fabricated sensor.
hOGG1 Ser326Cys polymorphism is associated with risk of bladder cancer in a Chinese population: A case‐control study
Authors: Ma Lan , Chu Haiyan , Wang Meilin , Shi Danni , Zhong Dongyan , Li Pu , Tong Na , Yin Changjun , Zhang Zhengdong
Published: April 2012

Human oxoguanine glycosylase 1 (hOGG1) is a DNA repair enzyme, which plays important roles in the base excision repair (BER) pathway. Several studies reported a common polymorphism Ser326Cys (rs1052133) in hOGG1, which conferred the susceptibility of bladder cancer. We hypothesized that the polymorphism is associated with risk of bladder cancer in a Chinese population. In a case‐control study of 1050 histologically confirmed bladder cancer patients and 1404 age and sex matched healthy controls, we genotyped the hOGG1 Ser326Cys polymorphism using TaqMan technology and assessed its association with bladder cancer risk. We found that the hOGG1 Ser/Cys + Ser/Ser genotypes were associated with a significantly increased risk of bladder cancer (adjusted odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.01–1.41), compared with the Cys/Cys genotype. Furthermore, the increased risk was more pronounced among subjects over age 65 years (OR = 1.31, 95% CI = 1.04–1.66), male subjects (OR = 1.21, 95% CI = 1.00–1.47), ever smokers (OR = 1.29, 95% CI = 1.00–1.68) and heavy smokers (>20 pack‐years) (OR = 1.45, 95% CI = 1.03–2.04). No significant association was observed in the stratification of tumor grade and tumor stage for bladder cancer. In conclusion, our results suggest that hOGG1 Ser326Cys polymorphism may contribute to the susceptibility to bladder cancer in a Chinese population. (Cancer Sci 2012; 103: 1215–1220)
The combined effect of very low nicotine content cigarettes, used as an adjunct to usual Quitline care (nicotine replacement therapy and behavioural support), on smoking cessation: a randomized controlled trial
Authors: Walker Natalie , Howe Colin , Bullen Chris , Grigg Michele , Glover Marewa , McRobbie Hayden , Laugesen Murray , Parag Varsha , Whittaker Robyn
Published: April 2012

Aim  To determine the combined effect of very low nicotine content (VLNC) cigarettes and usual Quitline care [nicotine replacement therapy (NRT) and behavioural support] on smoking abstinence, in smokers motivated to quit.

Design  Single‐blind, parallel randomized trial.

Setting  New Zealand.

Participants  Smokers who called the Quitline for quitting support were randomized to either VLNC cigarettes to use whenever they had an urge to smoke for up to 6 weeks after their quit date, in combination with usual Quitline care (8 weeks of NRT patches and/or gum or lozenges, plus behavioural support) or to usual Quitline care alone.

Measurements  The primary outcome was 7‐day point‐prevalence smoking abstinence 6 months after quit day. Secondary outcomes included continuous abstinence, cigarette consumption, withdrawal, self‐efficacy, alcohol use, serious adverse events and views on the use of the VLNC cigarettes at 3 and 6 weeks and 3 and 6 months.

Findings  A total of 1410 participants were randomized (705 in each arm), with a 24% loss to follow‐up at 6 months. Participants in the intervention group were more likely to have quit smoking at 6 months compared to the usual care group [7‐day point‐prevalence abstinence 33 versus 28%, relative risk (RR) = 1.18, 95% confidence interval (CI): 1.01, 1.39, P = 0.037; continuous abstinence 23 versus 15%, RR = 1.50, 95% CI: 1.20, 1.87, P = 0.0003]. The median time to relapse in the intervention group was 2 months compared to 2 weeks in the usual care group (P < 0.0001).

Conclusions  Addition of very low nicotine content cigarettes to standard Quitline smoking cessation support may help some smokers to become abstinent.
Pregnancy outcome after gestational exposure to erythromycin – a population‐based register study from Norway
Authors: Romøren Maria , Lindbæk Morten , Nordeng Hedvig
Published: April 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• It has generally been regarded as safe to take erythromycin during pregnancy. A recent study from Sweden found that erythromycin exposure in the first trimester was associated with congenital cardiovascular defects. The results led to warnings against using erythromycin in the first trimester from both the Swedish and Norwegian governments.

WHAT THIS STUDY ADDS

• This large, population‐based register study did not find that erythromycin or macrolide use in pregnancy was significantly associated with congenital malformations, cardiovascular malformations or any other specific malformation.

AIMS Erythromycin is a macrolide antibiotic indicated for respiratory tract infections, genital chlamydia and skin infections. It has recently been suggested that erythromycin use in the first trimester of pregnancy can increase the risk of congenital cardiovascular malformations. This study aimed to determine whether erythromycin exposure in the first trimester is associated with cardiovascular or other malformations.

METHODS We studied 180 120 women in Norway who were pregnant during 2004–2007. Data on all live births stillbirths and induced abortions after 12 gestational weeks from The Medical Birth Registry of Norway (MBRN) were linked to information from the Norwegian prescription database (NorPD). We compared the pregnancy outcomes of women who had taken erythromycin (n= 1786, 1.0%), penicillin V (n= 4921, 2.7%) or amoxicillin (n= 1599, 0.9%) in their first trimester with outcomes of women who had not taken any systemic antibiotics (n= 163 653, 90.9%) during this period.

RESULTS The risk of cardiovascular malformations was not significantly different with or without exposure to erythromycin in the first trimester (adjusted OR = 1.2 [95% CI 0.8, 1.8]) or in the most vulnerable period of heart formation (adjusted OR = 1.6 [95% CI 0.9–3.0]). Sub‐analyses showed that the risk for any specific malformations was not increased with erythromycin, macrolides, penicillin V or amoxicillin compared with no antibiotic use in first trimester.

CONCLUSIONS This large, population‐based register study did not find that exposure to erythromycin or macrolides in the first trimester of pregnancy was associated with fetal cardiovascular or other malformations. These results suggest that the risk of erythromycin use during early pregnancy, if any, is low.