bluuebunny/crossref_metadata_2025 huggingface dataset:
Similar biological medicinal products: lessons learned and challenges ahead
Authors: Ruiz Sol , Calvo Gonzalo
Published: April 2011

The first similar biological medicinal products (or biosimilars) were approved in the European Union (EU) in 2006 in accordance to a regulatory framework published by the European Commission in 2003 and 2004. The term ‘similar biological’ or biosimilar was preferred instead of the term ‘biogeneric’ as, in contrast to small molecules in chemical drugs, due to the size and complexity of biological products, additional safety and efficacy studies would be needed to establish comparability to a reference product. Several product-specific guidelines have already been developed by the European Medicines Agency describing the requirements to establish comparability on quality, safety and efficacy to the reference product and some others are currently under development. Even though the harmonized European regulatory framework for biosimilars there appear to be marked differences among the EU countries in the perception of the value and use of biosimilars. Several factors have been considered as challenges to their wide use such as concerns about their safety and efficacy, pharmacovigilance, interchangeability and substitution, market competition, and extrapolation of indications. A proper knowledge of these issues is required to ensure an appropriate place on the market for these products.
Toward Smarter Health and Well-Being: An Implicit Role for Networking and Information Technology
Authors: Gianchandani Erwin P
Published: April 2011

The number of people afflicted with chronic illnesses such as obesity, cancer, and diabetes has soared in recent years, generating new kinds of disparate medical challenges. In turn, these challenges have resulted in skyrocketing costs, preventable deaths, and medical malpractice claims. For example, studies have found nearly half of all US patients receive inadequate care each year, over 2 million are harmed by hospital-acquired infections, and over 1 million suffer disabling complications during surgery – even though half of these are thought to be avoidable. These challenges have catalyzed the beginning of a transformation in care delivery, from a health-care system that focuses on disease to one that must look after patients – including individuals and communities. To provide proper treatment to those who are chronically ill, the health-care system has to support improved individuals’ health-related practices prior to the manifestation of disease; ensure that a range of practitioners can deliver quality clinical care during the onset of an illness; and facilitate patient-provider-family partnerships during post-disease wellness care. As we describe in this review, key advances in networking and information technologies – spanning patient monitoring, data visualization and decision making, robotics and computer vision for diagnosis and surgery, social networking for fostering community-based support systems, and so on – stand to drive forward these changes. Together with social scientists, systems engineers, medical practitioners, and computer scientists, information systems scholars can help alter the nature of care delivery well into the twenty-first century, ultimately contributing to a system that is much more safe, effective, reliable, and timely than it is today.
On the topological sensitivity of cellular automata
Authors: Baetens Jan M. , De Baets Bernard
Published: April 2011

Ever since the conceptualization of cellular automata (CA), much attention has been paid to the dynamical properties of these discrete dynamical systems, and, more in particular, to their sensitivity to the initial condition from which they are evolved. Yet, the sensitivity of CA to the topology upon which they are based has received only minor attention, such that a clear insight in this dependence is still lacking and, furthermore, a quantification of this so-called topological sensitivity has not yet been proposed. The lack of attention for this issue is rather surprising since CA are spatially explicit, which means that their dynamics is directly affected by their topology. To overcome these shortcomings, we propose topological Lyapunov exponents that measure the divergence of two close trajectories in phase space originating from a topological perturbation, and we relate them to a measure grasping the sensitivity of CA to their topology that relies on the concept of topological derivatives, which is introduced in this paper. The validity of the proposed methodology is illustrated for the 256 elementary CA and for a family of two-state irregular totalistic CA.
High magnetic-field-induced phase transitions and refined magnetic phase diagram of Gd5Ge4
Authors: Wu Y. Y. , Xia Z. C. , Ouyang Z. W. , Huang Y. , Li L.
Published: April 2011

We have performed magnetization measurements of Gd5Ge4 with little or no ferromagnetic (FM) impurities under a pulsed magnetic field up to 40 T. The results reveal previously undetected transitions between 85 and 105 K, that is, a distinct second-order antiferromagnetic (AFM)-paramagnetic (PM) transition, followed by a first-order PM-ferromagnetic (FM) transition. The distinct variation of the slope of the M(H) curves is observed around the AFM-PM transition. Combining our high-field data and those reported earlier, a new magnetic field-temperature phase diagram, in which the AFM, PM, and FM states are well separated, is constructed.
Inverse four-domain twisted nematic liquid crystal display fabricated by the enhancement of azimuthal anchoring energy
Authors: Jo Soo In , Choi Sang-Woong , Lee You-Jin , Moon Yeon-Kyu , Yang Young-Cheol , Yu Chang-Jae , Kim Jae-Hoon
Published: April 2011

An inverse four-domain twisted nematic (IFDTN) liquid crystal (LC) display was fabricated by enhancing the azimuthal anchoring energy of the alignment layers. By stacking a vertical alignment layer onto a planar alignment layer, we increased the azimuthal anchoring energy by approximately 17-fold times compared to that with vertical alignment only. Due to the enhanced azimuthal anchoring energy, we were able to achieve a four-domain twisted nematic LC structure without dopant via the application of an external voltage. A simulation of the LC molecular orientation with respect to the azimuthal anchoring energy, the viewing angle characteristics, and the switching behavior of the IFDTN LC are presented.
An atomistic study into the defect chemistry of hexagonal barium titanate
Authors: Dawson J. A. , Freeman C. L. , Ben L.-B. , Harding J. H. , Sinclair D. C.
Published: April 2011

Using a recently established BaTiO3 potential model specifically designed for the calculation of defect energetics, atomistic simulations have been carried out on the intrinsic defect chemistry and Rare Earth (RE3+) doping of hexagonal barium titanate (h-BaTiO3). Five charge compensation schemes have been considered as well as potential cluster binding energies. The results show that ion size arguments are obeyed. In the dilute concentration limit, large RE3+ cations dope at the Ba-site via a titanium vacancy mechanism and mid sized RE3+ cations dope at the Ba and Ti sites simultaneously via a self compensation mechanism. In contrast, small RE3+ cations dope exclusively on the Ti-site via an oxygen vacancy compensation scheme. Comparisons between the hexagonal and cubic phases of BaTiO3 have also been drawn. It is suggested that Ba-site doping is less favorable and that Ti-site doping is considerably more favorable in h-BaTiO3 and that different defect configurations have a significant effect on the binding energies between such defects, leading to some mechanisms becoming more or less energetically favorable as a result.
Kerr nonlinearity in a driven two-subband system in a semiconductor quantum well
Authors: Kosionis S. G. , Terzis A. F. , Paspalakis E.
Published: April 2011

We study theoretically the Kerr nonlinearity of a probe field in the presence of a near resonant pump field in a two-subband system in a semiconductor quantum well structure. In our study we take into account the effects of electron–electron interactions and consider the interaction of the two-subband system with rectangular electromagnetic fields. For the description of the system dynamics we use the nonlinear differential equations of the density matrix elements for the several nonlinear optical processes, under the rotating wave approximation. These equations are solved numerically for a GaAs/AlGaAs quantum well structure. We show that the Kerr nonlinearity of a driven two-subband system can be significantly dependent on the frequency and the intensity of the pump field and on electron sheet density.
A photosensitive Cr3+ center in photorefractive Bi12SiO20 crystals co-doped with chromium and phosphorus
Authors: Ahmad Ijaz , Marinova Vera , Vrielinck Henk , Callens Freddy , Goovaerts Etienne
Published: April 2011

A trigonal Cr3+ (3d3) defect in sillenite type Bi12SiO20 crystals co-doped with chromium and phosphorus has been identified by means of multi-frequency X-band (9.4 GHz), Q-band (35 GHz) and W-band (94 GHz) electron paramagnetic resonance (EPR). A consistent analysis of the observed spectra and their angular dependence was reached using an S = 3/2 spin Hamiltonian with axial symmetry around a 〈111〉 crystallographic direction, an isotropic g-value g = 1.983, and a zero field splitting parameter B20 = 0.1950 cm−1. The spectra are attributed to a chromium ion in the unusual Cr3+ valence replacing a substitutional Si4+ in tetrahedral oxygen coordination. Evidence is found that the symmetry lowering from tetrahedral to trigonal is not spontaneous but induced by an associated defect, for which a P5+ ion in a nearest-neighbor Si4+ site is the most plausible candidate. Optical excitation results in a reversible charge transfer process directly correlated with a photochromic effect: near-UV light leads to a strong reduction of the Cr3+ EPR signals, and induces a broad band at 675 nm in the absorption spectrum, and both effects are reversed under red light excitation.
Effect of high pressure on acoustic properties of several polymers: Use of impulsive stimulated light scattering method
Authors: Dreger Z. A. , Zhou J. , Dang N. C. , Gupta Y. M.
Published: April 2011

The acoustic properties of four polymers compressed to high pressures in a diamond anvil cell were determined using the impulsive stimulated light scattering (ISLS) method. Despite the weak scattering efficiency of these polymers, good signal quality was obtained by using a continuous wave probe and an optical heterodyne detection. We provide, for the first time, longitudinal acoustic velocities up to 5 GPa for two thermoplasts: poly(methyl-methacrylate) and poly(styrene), and two elastomers: poly(butadiene) and triblock copolymer of polystyrene-block-polybutadiene-block-polystyrene. The longitudinal acoustic velocities for all of these polymers displayed nonlinear pressure dependence. Despite the significant differences in the initial acoustic velocities these velocities converged above 2.5 GPa. This convergence is associated with the ultimate reduction of free volume in the studied polymers. We explored the possibility of measuring shear acoustic waves in these polymers using ISLS in a depolarized geometry. The data obtained here are important for modeling the response of polymers at extreme conditions.
Er2Fe14B single crystal as magnetic refrigerant at the spin reorientation transition
Authors: Basso Vittorio , Sasso Carlo P. , Küpferling Michaela , Skokov Konstantin P. , Gutfleisch Oliver
Published: April 2011

In this paper we study the specific heat under magnetic field cp(Ha,T) and the magnetic field induced isothermal entropy change Δs(Ha,T) of Er2Fe14B by direct calorimetry and magnetic measurements. We find that the spin reorientation temperature is TSR=322.8±0.1 K and the entropy change is Δs=0.735±0.005Jkg-1K-1. The measured data are interpreted by a model of the magnetization process taking into account a temperature-dependent uniaxial anisotropy constant K1(T), the magnetic field energy, and the effect of the demagnetizing field. The model is able to describe the essential features of the measured Δs(Ha,T) in terms of reversible rotation of the magnetization induced by the magnetic field. From the model we find that the entropy change has a magnetic field independent saturation value: ΔsK(T)=0.735-5.5×10-3(T-TSR) and that the magnetic field amplitude increases the temperature range over which the effect is observed as ΔT=βμ0H with β=54 KT-1.
Correlated barrier hopping in CdS nanoparticles and nanowires
Authors: Chandran Anoop , Samuel M Soosen , Koshy Jiji , George K C
Published: April 2011

The ac conduction in CdS nanoparticles and nanowires was investigated in the frequency range 102 to 106 Hz and in the temperature range 303–573K. The behavior of ac conductivity was found to agree with that reported for amorphous materials and doped semiconductors. The values of ac conductivities were found to be higher than those reported for bulk CdS. The experimental results were analyzed with the CBH model proposed by Elliott. This model provided reasonable values for the maximum barrier height and characteristic relaxation time. The electrical properties of CdS nanowires and nanoparticles were compared. It was also found that the concentration of charged defect centers was large in nanowires and nanoparticles and it tended to decrease with an increase in temperature. The density of neutral defect, formed by the conversion of charged defects was also calculated. The defects in both types of nanostructures were studied by photoluminescence spectroscopy. It was found that nanoparticles possessed higher defect density than nanowires.
A molecular dynamics and ab initio analysis of the electronic structure of single-walled carbon nanotubes adhered to a substrate
Authors: Van Der Geest A. G. , Lu Z. , Lusk M. T. , Dunn M. L.
Published: April 2011

Single-wall nanotubes can adhere to planar surfaces via van der Waals forces, and this causes the tubes to deform. We use classical molecular dynamics to estimate this deformation and density functional theory to quantify its impact on electronic band structure. For (n,0) tubes, adhesion causes the maximum bandgap to rise more rapidly with diameter, but the value of the maximum is not affected. The influence of adhesion forces on bandgap was found to correlate with that associated with lateral, uniaxial compression for moderate values of adhesion energy and compressive distortion.
Tuning random lasers by engineered absorption
Authors: El-Dardiry Ramy G. S. , Lagendijk Ad
Published: April 2011

We achieve control over the emission wavelength of a random laser experimentally by adjusting the amount of absorption of emission light. The random laser consists of elastic scatterers in a high quantum efficiency gain medium to which a nonfluorescent dye is added. This nonfluorescent dye shifts the net gain curve and thereby the emission peak of the random laser. Mode competition effects are observed and explained. We interpret our results using a theoretical model that describes the spectral response of the system as a function of the effective cavity decay time and (re)absorption processes.
Alternating current Josephson effect in superconductor–graphene–superconductor junctions
Authors: Xu G. J. , Wu B. H. , Cao J. C.
Published: April 2011

We investigate the ac Josephson effect in superconductor–graphene–superconductor (SGS) junctions by using the Floquet–Green’s function formalism to solve the Dirac–Bogoliubov–de Gennes equation. The numerical results show rich subharmonic gap structures such as the negative differential conductance (NDC) in the dc current. The tunability of the current magnitude can be controlled by the gate voltage, which determines the carriers’ densities in graphene. With increasing bias, the ac components decay in an oscillatory manner as in superconductor–normal–superconductor junctions. It is found that the higher-order components have an explicit contribution to the total current under a low bias, which leads to the deviation from a simple sine-like dependence on time for the total current. The NDC characteristics and the tunable current magnitude are excellent hints for the potential application of SGS junctions.
Asymptotic evolution of quantum walks with random coin
Authors: Ahlbrecht A. , Vogts H. , Werner A. H. , Werner R. F.
Published: April 2011

We study the asymptotic position distribution of general quantum walks on a lattice, including walks with a random coin, which is chosen from step to step by a general Markov chain. In the unitary (i.e., nonrandom) case, we allow any unitary operator which commutes with translations and couples only sites at a finite distance from each other. For example, a single step of the walk could be composed of any finite succession of different shift and coin operations in the usual sense, with any lattice dimension and coin dimension. We find ballistic scaling and establish a direct method for computing the asymptotic distribution of position divided by time, namely as the distribution of the discrete time analog of the group velocity. In the random case, we let a Markov chain (control process) pick in each step one of finitely many unitary walks, in the sense described above. In ballistic order, we find a nonrandom drift which depends only on the mean of the control process and not on the initial state. In diffusive scaling, the limiting distribution is asymptotically Gaussian, with a covariance matrix (diffusion matrix) depending on momentum. The diffusion matrix depends not only on the mean but also on the transition rates of the control process. In the nonrandom limit, i.e., when the coins chosen are all very close or the transition rates of the control process are small, leading to long intervals of ballistic evolution, the diffusion matrix diverges. Our method is based on spatial Fourier transforms, and the first and second order perturbation theory of the eigenvalue 1 of the transition operator for each value of the momentum.
Low-voltage gallium–indium–zinc–oxide thin film transistors based logic circuits on thin plastic foil: Building blocks for radio frequency identification application
Authors: Tripathi A. K. , Smits E. C. P , van der Putten J. B. P. H. , van Neer M. , Myny K. , Nag M. , Steudel S. , Vicca P. , O’Neill K. , van Veenendaal E. , Genoe J. , Heremans P. , Gelinck G. H.
Published: April 2011

In this work a technology to fabricate low-voltage amorphous gallium–indium–zinc oxide thin film transistors (TFTs) based integrated circuits on 25 μm foils is presented. High performance TFTs were fabricated at low processing temperatures (<150 °C) with field effect mobility around 17 cm2/V s. The technology is demonstrated with circuit building blocks relevant for radio frequency identification applications such as high-frequency functional code generators and efficient rectifiers. The integration level is about 300 transistors.
Spectroscopic evidence for nonradiative energy transfer between colloidal CdSe/ZnS nanocrystals and functionalized silicon substrates
Authors: Nguyen H. M. , Seitz O. , Aureau D. , Sra A. , Nijem N. , Gartstein Yu. N. , Chabal Y. J. , Malko A. V.
Published: April 2011

We present the fabrication and properties of hybrid structures consisting of a monolayer of colloidal CdSe nanocrystals grafted on hydrogenated Si surfaces via amine modified carboxy-alkyl chain linkers. The wet chemical preparation ensures that Si surfaces are fully passivated with a negligible number of nonradiative surface state defects and that the separation between nanocrystals and Si is tightly controlled. An eightfold decrease in photoluminescence lifetime of nanocrystals on Si is observed as compared to glass. A quantitative analysis reveals that the nonradiative transfer from nanocrystals to Si is 65% efficient, demonstrating the potential of such hybrids for practical photovoltaic devices.
Remote estimation of chlorophyll on two wheat cultivars in two rainfed environments
Authors: Cammarano Davide , Fitzgerald Glenn , Basso Bruno , Chen Deli , Grace Peter , O'Leary Garry
Published: April 2011

For this study we hypothesise that the use of canopy chlorophyll content index (CCCI) and crop greenness will be useful in assessing crop nutritional status and provide a robust management tool by growth stage DC30 for fertiliser application across multiple sites without being confounded by soil and biomass differences. The objectives of this study were: (i) to study the robustness of the CCCI and greenness as a measure of crop N content at two different locations, and (ii) to validate the model developed for crop nitrogen (N) determination. Data were collected from two rain-fed field sites cropped to wheat, one in Southern Italy (Foggia) and the other in the south-eastern wheat belt of Australia (Horsham). Data collection was conducted during the growing season in 2006–07 (December–June) for the Italian site and during the 2006 and 2007 (June–December) growing seasons for the Australian site. Measurements included crop biophysical properties (leaf area index (LAI), biomass, crop N concentration), hyperspectral remote sensing data, and SPAD (chlorophyll meter) determination. An independent dataset including SPAD, biomass, and remotely sensed data from Horsham (Australia) was used to test the validity of the model developed. Results showed that there is good correlation between SPAD and crop N content. The relationship between greenness (measured as LAI*SPAD) and CCCI was fitted with an exponential model and was not affected by biomass accumulation or soil reflectance (r2 = 0.85; y = 15.1e4.5424x; P < 0.001). When this model was tested on the independent dataset it yielded good results for the estimation of greenness (y = 1.22x − 54.87; r2 = 0.90; P < 0.001; root mean square error 32.2; relative error 15%). In conclusion, SPAD measurements combined with LAI could be used as a crop nutritional management tool by DC30 for fertiliser application across multiple sites.
Diagnosis and simulation: a suitable combination to support farming systems design
Authors: Martin Guillaume , Theau Jean-Pierre , Therond Olivier , Martin-Clouaire Roger , Duru Michel
Published: April 2011

Designing or improving farming systems requires understanding their dynamics so as to predict their behaviour in response to management. Simulation tools can potentially support the process by which farmers and scientists might obtain such an encompassing understanding. The usability of these tools is, however, partially inhibited by the inherent complexity of the interactions at work in farm-scale models. Whereas such models are generally used in isolation, here we present an approach in which a field-scale diagnosis method complements a farm-scale simulation model. This diagnosis method lends itself easily to an intelligible presentation of field-specific knowledge that can be fed to the simulation tool for more encompassing considerations. Our approach is used to support the design of novel management strategies in grassland-based beef systems and proved to be effective when applied to two farms in the French Pyrenees. Thanks to the integrative representation of the various processes, including the management ones, simulation contributed to deeper learning of both scientists and farmers about room for manoeuvre for increasing self-sufficiency for forage. The diagnosis phase enhanced the learning process by providing a simpler framework in which elementary problems at field scale could be considered separately before being examined concurrently at farm scale in the simulation phase.
Managing ecological thresholds in coupled environmental–human systems
Authors: Horan Richard D. , Fenichel Eli P. , Drury Kevin L. S. , Lodge David M.
Published: April 2011

Many ecosystems appear subject to regime shifts—abrupt changes from one state to another after crossing a threshold or tipping point. Thresholds and their associated stability landscapes are determined within a coupled socioeconomic–ecological system (SES) where human choices, including those of managers, are feedback responses. Prior work has made one of two assumptions about managers: that they face no institutional constraints, in which case the SES may be managed to be fairly robust to shocks and tipping points are of little importance, or that managers are rigidly constrained with no flexibility to adapt, in which case the inferred thresholds may poorly reflect actual managerial flexibility. We model a multidimensional SES to investigate how alternative institutions affect SES stability landscapes and alter tipping points. With institutionally dependent human feedbacks, the stability landscape depends on institutional arrangements. Strong institutions that account for feedback responses create the possibility for desirable states of the world and can cause undesirable states to cease to exist. Intermediate institutions interact with ecological relationships to determine the existence and nature of tipping points. Finally, weak institutions can eliminate tipping points so that only undesirable states of the world remain.
Defining the origins of Ras/p53-mediated squamous cell carcinoma
Authors: White Andrew C. , Tran Kathy , Khuu Joan , Dang Christine , Cui Yongyan , Binder Scott W. , Lowry William E.
Published: April 2011

The precise identity of cancer cells of origin and the molecular events of tumor initiation in epidermal squamous cell carcinoma (SCC) are unknown. Here we show that malignancy potential is related to the developmental capacity of the initiating cancer cell in a genetically defined, intact, and inducible in vivo model. Specifically, these data demonstrate that SCCs can originate from inside the hair follicle stem cell (SC) niche or from immediate progenitors, whereas more developmentally restricted progeny, the transit amplifying (TA) cells, are unable to generate even benign tumors in the same genetic context. Using a temporal model of tumorigenesis in situ, we highlight the phenotypes of cancer progression from the hair follicle SC niche, including hyperplasia, epithelial to mesenchymal transition, and SCC formation. Furthermore, we provide insights into the inability of hair follicle TA cells to respond to tumorigenic stimuli.
Identifying the cellular origin of squamous skin tumors
Authors: Lapouge Gaëlle , Youssef Khalil Kass , Vokaer Benoit , Achouri Younes , Michaux Cindy , Sotiropoulou Panagiota A. , Blanpain Cédric
Published: April 2011

Squamous cell carcinoma (SCC) is the second most frequent skin cancer. The cellular origin of SCC remains controversial. Here, we used mouse genetics to determine the epidermal cell lineages at the origin of SCC. Using mice conditionally expressing a constitutively active KRas mutant (G12D) and an inducible CRE recombinase in different epidermal lineages, we activated Ras signaling in different cellular compartments of the skin epidermis and determined from which epidermal compartments Ras activation induces squamous tumor formation. Expression of mutant KRas in hair follicle bulge stem cells (SCs) and their immediate progeny (hair germ and outer root sheath), but not in their transient amplifying matrix cells, led to benign squamous skin tumor (papilloma). Expression of KRas
G12D
in interfollicular epidermis also led to papilloma formation, demonstrating that squamous tumor initiation is not restricted to the hair follicle lineages. Whereas no malignant tumor was observed after KRas
G12D
expression alone, expression of KRas
G12D
combined with the loss of p53 induced invasive SCC. Our studies demonstrate that different epidermal lineages including bulge SC are competent to initiate papilloma formation and that multiple genetic hits in the context of oncogenic KRas are required for the development of invasive SCC.
Structural analysis of human Orc6 protein reveals a homology with transcription factor TFIIB
Authors: Liu Shixuan , Balasov Maxim , Wang Hongfei , Wu Lijie , Chesnokov Igor N. , Liu Yingfang
Published: April 2011

The Origin Recognition Complex (ORC) is a six-subunit protein important for the initiation of DNA replication in eukaryotic cells. Orc6 is the smallest and the least conserved among ORC subunits. It is required for the DNA replication but also has a function in cytokinesis in metazoan species, however, the mechanisms of Orc6 action in these processes are not clear. Here we report a structure of the middle domain of human Orc6. This domain has an overall fold similar to the corresponding helical domain of transcription factor TFIIB. Based on these findings, a model of Orc6 binding to DNA is produced. We have identified amino acids of Orc6 which are directly involved in DNA binding. Alterations of these amino acids abolish DNA binding ability of Orc6 and also result in reduced levels of DNA replication in vitro and in cultured cells. Our data indicate that Orc6 is one of the DNA binding subunits of ORC in metazoan species. We propose that Orc6 may participate in positioning of ORC at the origins of DNA replication similar to the role of TFIIB in positioning transcription preinitiation complex at the promoter.
Measuring steady-state and dynamic endoplasmic reticulum and Golgi Zn
2+
with genetically encoded sensors
Authors: Qin Yan , Dittmer Philip J. , Park J. Genevieve , Jansen Katarina B. , Palmer Amy E.
Published: April 2011

Zn
2+
plays essential roles in biology, and cells have adopted exquisite mechanisms for regulating steady-state Zn
2+
levels. Although much is known about total Zn
2+
in cells, very little is known about its subcellular distribution. Yet defining the location of Zn
2+
and how it changes with signaling events is essential for elucidating how cells regulate this essential ion. Here we create fluorescent sensors genetically targeted to the endoplasmic reticulum (ER) and Golgi to monitor steady-state Zn
2+
levels as well as flux of Zn
2+
into and out of these organelles. These studies reveal that ER and Golgi contain a concentration of free Zn
2+
that is 100 times lower than the cytosol. Both organelles take up Zn
2+
when cytosolic levels are elevated, suggesting that the ER and Golgi can sequester elevated cytosolic Zn
2+
and thus have the potential to play a role in influencing Zn
2+
toxicity. ER Zn
2+
homeostasis is perturbed by small molecule antagonists of Ca
2+
homeostasis and ER Zn
2+
is released upon elevation of cytosolic Ca
2+
pointing to potential exchange of these two ions across the ER. This study provides direct evidence that Ca
2+
signaling can influence Zn
2+
homeostasis and vice versa, that Zn
2+
dynamics may modulate Ca
2+
signaling.
How simple rules determine pedestrian behavior and crowd disasters
Authors: Moussaïd Mehdi , Helbing Dirk , Theraulaz Guy
Published: April 2011

With the increasing size and frequency of mass events, the study of crowd disasters and the simulation of pedestrian flows have become important research areas. However, even successful modeling approaches such as those inspired by Newtonian force models are still not fully consistent with empirical observations and are sometimes hard to calibrate. Here, a cognitive science approach is proposed, which is based on behavioral heuristics. We suggest that, guided by visual information, namely the distance of obstructions in candidate lines of sight, pedestrians apply two simple cognitive procedures to adapt their walking speeds and directions. Although simpler than previous approaches, this model predicts individual trajectories and collective patterns of motion in good quantitative agreement with a large variety of empirical and experimental data. This model predicts the emergence of self-organization phenomena, such as the spontaneous formation of unidirectional lanes or stop-and-go waves. Moreover, the combination of pedestrian heuristics with body collisions generates crowd turbulence at extreme densities—a phenomenon that has been observed during recent crowd disasters. By proposing an integrated treatment of simultaneous interactions between multiple individuals, our approach overcomes limitations of current physics-inspired pair interaction models. Understanding crowd dynamics through cognitive heuristics is therefore not only crucial for a better preparation of safe mass events. It also clears the way for a more realistic modeling of collective social behaviors, in particular of human crowds and biological swarms. Furthermore, our behavioral heuristics may serve to improve the navigation of autonomous robots.
Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)
Authors: Bonavia Aurelio , Franti Michael , Pusateri Keaney Erin , Kuhen Kelli , Seepersaud Mohindra , Radetich Branko , Shao Jian , Honda Ayako , Dewhurst Janetta , Balabanis Kara , Monroe James , Wolff Karen , Osborne Colin , Lanieri Leanne , Hoffmaster Keith , Amin Jakal , Markovits Judit , Broome Michelle , Skuba Elizabeth , Cornella-Taracido Ivan , Joberty Gerard , Bouwmeester Tewis , Hamann Lawrence , Tallarico John A. , Tommasi Ruben , Compton Teresa , Bushell Simon M.
Published: April 2011

The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.
Adenovirus type-35 vectors block human CD4
+
T-cell activation via CD46 ligation
Authors: Adams William C. , Gujer Cornelia , McInerney Gerald , Gall Jason G. D. , Petrovas Constantinos , Hedestam Gunilla B. Karlsson , Koup Richard A. , Loré Karin
Published: April 2011

Recombinant adenoviruses (rAds) based on types 5 (rAd5) and 35 (rAd35) have emerged as important vaccine delivery vectors in clinical testing for a variety of pathogens. A major difference between these vectors is their binding to cellular receptors used for infection. Whereas rAd5 binds coxsackie-adenovirus receptor (CAR), rAd35 binds the complement regulatory protein CD46. Although rAd35 infected and phenotypically matured human blood dendritic cells (DCs) more efficiently than rAd5, we show here that rAd35 markedly suppressed DC-induced activation of naive CD4
+
T cells. rAd35 specifically blocked both DCs and anti-CD3/CD28 mAb-induced naive T-cell proliferation and IL-2 production. This effect was also observed in CD4
+
memory T cells but to a lesser extent. The suppression occurred by rAd35 binding to CD46 on T cells and was independent of infection. CD46 engagement with mAb mimicked the effects of rAd35 and also led to deficient NF-κB nuclear translocation. In contrast, rAd5 and rAd35 vectors with ablated CD46 binding did not inhibit T-cell activation. Our findings provide insights into the basic biology of adenoviruses and indicate that CD46 binding may have an impact on the generation of primary CD4
+
T-cell responses by Ad35.
Histone demethylase JMJD2B coordinates H3K4/H3K9 methylation and promotes hormonally responsive breast carcinogenesis
Authors: Shi Lei , Sun Luyang , Li Qian , Liang Jing , Yu Wenhua , Yi Xia , Yang Xiaohan , Li Yanyan , Han Xiao , Zhang Yu , Xuan Chenghao , Yao Zhi , Shang Yongfeng
Published: April 2011

It is well-documented that the methylation of histone H3 lysine 4 (H3K4) and of H3K9 are mutually exclusive, an epigenetic phenomenon conserved from yeast to humans. How this opposed methylation modification is accomplished and coordinated in mammalian cells is poorly understood. Here we report that the H3K9 trimethyl demethylase JMJD2B is an integral component of the H3K4-specific methyltransferase, the mixed-lineage leukemia (MLL) 2 complex. We show that the JMJD2B/MLL2 complex is copurified with estrogen receptor α (ERα) and is required for ERα-regulated transcription. We demonstrate that H3K9 demethylation and H3K4 methylation are coordinated in ERα-activated transcription such that H3K9 demethylation is a prerequisite for H3K4 methylation. Significantly, depletion of JMJD2B impairs the estrogen-induced G
1
/S transition of the cell cycle in vitro and inhibits breast tumorigenesis in vivo. Interestingly,
JMJD2B
itself is an ERα target gene, and forms a feed-forward regulatory loop in regulation of the hormone response. Our results provide a molecular basis for the coordinated H3K4 methylation/H3K9 demethylation in transcription activation, link the trimethyl demethylase JMJD2B to euchromatin functions, and provide a mechanism for JMJD2B in breast carcinogenesis.
Regulatory T cells control tolerogenic versus autoimmune response to sperm in vasectomy
Authors: Wheeler Karen , Tardif Steve , Rival Claudia , Luu Brian , Bui Elise , del Rio Roxana , Teuscher Cory , Sparwasser Tim , Hardy Daniel , Tung Kenneth S. K.
Published: April 2011

Vasectomy is a well accepted global contraceptive approach frequently associated with epididymal granuloma and sperm autoantibody formation. To understand the long-term sequelae of vasectomy, we investigated the early immune response in vasectomized mice. Vasectomy leads to rapid epithelial cell apoptosis and necrosis, persistent inflammation, and sperm granuloma formation in the epididymis. Vasectomized B6AF1 mice did not mount autoimmune response but instead developed sperm antigen-specific tolerance, documented as resistance to immunization-induced experimental autoimmune orchitis (EAO) but not experimental autoimmune encephalomyelitis. Strikingly, tolerance switches over to pathologic autoimmune state following concomitant CD4+CD25+Foxp3+regulatory T cell (Treg) depletion: unilaterally vasectomized mice produce dominant autoantibodies to an orchitogenic antigen (zonadhesin), and develop CD4 T-cell– and antibody-dependent bilateral autoimmune orchitis. Therefore, (i) Treg normally prevents spontaneous organ-specific autoimmunity induction by persistent endogenous danger signal, and (ii) autoantigenic stimulation with sterile autoinflammation can lead to tolerance. Finally, postvasectomy tolerance occurs in B6AF1, C57BL/6, and A/J strains. However, C57BL/6 mice resisted EAO after 60% Treg depletion, but developed EAO after 97% Treg reduction. Therefore, variance in intrinsic Treg function—a possible genetic trait—can influence the divergent tolerogenic versus autoimmune response to vasectomy.
Protein induced fluorescence enhancement as a single molecule assay with short distance sensitivity
Authors: Hwang Helen , Kim Hajin , Myong Sua
Published: April 2011

Single-molecule FRET has been widely used for monitoring protein–nucleic acids interactions. Direct visualization of the interactions, however, often requires a site-specific labeling of the protein, which can be circuitous and inefficient. In addition, FRET is insensitive to distance changes in the 0–3-nm range. Here, we report a systematic calibration of a single molecule fluorescence assay termed protein induced fluorescence enhancement. This method circumvents protein labeling and displays a marked distance dependence below the 4-nm distance range. The enhancement of fluorescence is based on the photophysical phenomenon whereby the intensity of a fluorophore increases upon proximal binding of a protein. Our data reveals that the method can resolve as small as a single base pair distance at the extreme vicinity of the fluorophore, where the enhancement is maximized. We demonstrate the general applicability and distance sensitivity using (a) a finely spaced DNA ladder carrying a restriction site for BamHI, (b) RNA translocation by DExH enzyme RIG‐I, and (c) filament dynamics of RecA on single-stranded DNA. The high spatio-temporal resolution data and sensitivity to short distances combined with the ability to bypass protein labeling makes this assay an effective alternative or a complement to FRET.
Single-molecule analysis reveals the molecular bearing mechanism of DNA strand exchange by a serine recombinase
Authors: Bai Hua , Sun Mingxuan , Ghosh Pallavi , Hatfull Graham F. , Grindley Nigel D. F. , Marko John F.
Published: April 2011

Structural and topological data suggest that serine site-specific DNA recombinases exchange duplex DNAs by rigid-body relative rotation of the two halves of the synapse, mediated by a flat protein-protein interaction surface. We present evidence for this rotational motion for a simple serine recombinase, the Bxb1 phage integrase, from a single-DNA-based supercoil-release assay that allows us to follow crossover site cleavage, rotation, religation, and product release in real time. We have also used a two-DNA braiding-relaxation experiment to observe the effect of synapse rotation in reactions on two long molecules. Relaxation and unbraiding are rapid (averaging 54 and 70 turns/s, respectively) and complete, with no discernible pauses. Nevertheless, the molecular friction associated with rotation is larger than that of type-I topoisomerases in a similar assay. Surprisingly we find that the synapse can stay rotationally “open” for many minutes.
Discovery of epoxyqueuosine (oQ) reductase reveals parallels between halorespiration and tRNA modification
Authors: Miles Zachary D. , McCarty Reid M. , Molnar Gabriella , Bandarian Vahe
Published: April 2011

Transfer RNA is one of the most richly modified biological molecules. Biosynthetic pathways that introduce these modifications are underexplored, largely because their absence does not lead to obvious phenotypes under normal growth conditions. Queuosine (Q) is a hypermodified base found in the wobble positions of tRNA Asp, Asn, His, and Tyr from bacteria to mankind. Using liquid chromatography MS methods, we have screened 1,755 single gene knockouts of
Escherichia coli
and have identified the key final step in the biosynthesis of Q. The protein is homologous to B
12
-dependent iron-sulfur proteins involved in halorespiration. The recombinant
Bacillus subtilis
epoxyqueuosine (oQ) reductase catalyzes the conversion of oQ to Q in a synthetic substrate, as well as undermodified RNA isolated from an oQ reductase knockout strain. The activity requires inclusion of a reductant and a redox mediator. Finally, exogenously supplied cobalamin stimulates the activity. This work provides the framework for studies of the biosynthesis of other modified RNA components, where lack of accessible phenotype or obvious gene clustering has impeded discovery. Moreover, discovery of the elusive oQ reductase protein completes the biosynthetic pathway of Q.
Dynamic reconfiguration of human brain networks during learning
Authors: Bassett Danielle S. , Wymbs Nicholas F. , Porter Mason A. , Mucha Peter J. , Carlson Jean M. , Grafton Scott T.
Published: April 2011

Human learning is a complex phenomenon requiring flexibility to adapt existing brain function and precision in selecting new neurophysiological activities to drive desired behavior. These two attributes—flexibility and selection—must operate over multiple temporal scales as performance of a skill changes from being slow and challenging to being fast and automatic. Such selective adaptability is naturally provided by modular structure, which plays a critical role in evolution, development, and optimal network function. Using functional connectivity measurements of brain activity acquired from initial training through mastery of a simple motor skill, we investigate the role of modularity in human learning by identifying dynamic changes of modular organization spanning multiple temporal scales. Our results indicate that flexibility, which we measure by the allegiance of nodes to modules, in one experimental session predicts the relative amount of learning in a future session. We also develop a general statistical framework for the identification of modular architectures in evolving systems, which is broadly applicable to disciplines where network adaptability is crucial to the understanding of system performance.
Distinct contributions of nicotinic acetylcholine receptor subunit α4 and subunit α6 to the reinforcing effects of nicotine
Authors: Exley Richard , Maubourguet Nicolas , David Vincent , Eddine Raphaël , Evrard Alexis , Pons Stéphanie , Marti Fabio , Threlfell Sarah , Cazala Pierre , McIntosh J. Michael , Changeux Jean-Pierre , Maskos Uwe , Cragg Stephanie J. , Faure Philippe
Published: April 2011

Nicotine is the primary psychoactive component of tobacco. Its reinforcing and addictive properties depend on nicotinic acetylcholine receptors (nAChRs) located within the mesolimbic axis originating in the ventral tegmental area (VTA). The roles and oligomeric assembly of subunit α4- and subunit α6-containing nAChRs in dopaminergic (DAergic) neurons are much debated. Using subunit-specific knockout mice and targeted lentiviral re-expression, we have determined the subunit dependence of intracranial nicotine self-administration (ICSA) into the VTA and the effects of nicotine on dopamine (DA) neuron excitability in the VTA and on DA transmission in the nucleus accumbens (NAc). We show that the α4 subunit, but not the α6 subunit, is necessary for ICSA and nicotine-induced bursting of VTA DAergic neurons, whereas subunits α4 and α6 together regulate the activity dependence of DA transmission in the NAc. These data suggest that α4-dominated enhancement of burst firing in DA neurons, relayed by DA transmission in NAc that is gated by nAChRs containing α4 and α6 subunits, underlies nicotine self-administration and its long-term maintenance.
MHCII glycosylation modulates Bacteroides fragilis carbohydrate antigen presentation
Authors: Ryan Sean O. , Bonomo Jason A. , Zhao Fan , Cobb Brian A.
Published: April 2011

N-linked glycans are thought to protect class II major histocompatibility complex (MHC) molecules (MHCII) from proteolytic cleavage and assist in arranging proteins within the immune synapse, but were not thought to directly participate in antigen presentation. Here, we report that antigen-presenting cells (APCs) lacking native complex N-glycans showed reduced MHCII binding and presentation of the T cell activating glycoantigen (GlyAg) polysaccharide A from Bacteroides fragilis but not conventional peptides. APCs lacking native N-glycans also failed to mediate GlyAg-driven T cell activation but activated T cells normally with protein antigen. Mice treated with the mannosidase inhibitor kifunensine to prevent the formation of complex N-glycans were unable to expand GlyAg-specific T cells in vivo upon immunization, yet adoptive transfer of normally glycosylated APCs into these animals overcame this defect. Our findings reveal that MHCII N-glycosylation directly impacts binding and presentation of at least one class of T cell–dependent antigen.