bluuebunny/crossref_metadata_2025 huggingface dataset:
A robust dual reporter system to visualize and quantify gene expression mediated by transcription activator-like effectors
Authors: Uhde-Stone Claudia , Huang Joseph , Lu Biao
Published: August 2012

Background

Transcription activator-like effectors (TALEs) are a class of naturally occurring transcription effectors that recognize specific DNA sequences and modulate gene expression. The modularity of TALEs DNA binding domain enables sequence-specific perturbation and offers broad applications in genetic and epigenetic studies. Although the efficient construction of TALEs has been established, robust functional tools to assess their functions remain lacking.

Results

We established a dual reporter system that was specifically designed for real-time monitoring and quantifying gene expression mediated by TALEs. We validated both sensitivity and specificity of this dual-reporter system in mammalian cells, and demonstrated that this dual reporter system is robust and potentially amenable to high throughput (HTP) applications.

Conclusion

We have designed, constructed and validated a novel dual reporter system for assessing TALE mediated gene regulations. This system offers a robust and easy-to- use tool for real-time monitoring and quantifying gene expression in mammalian cells.
Cytotoxic effects of ZnO hierarchical architectures on RSC96 Schwann cells
Authors: Yin Yixia , Lin Qiang , Sun Haiming , Chen Dan , Wu Qingzhi , Chen Xiaohui , Li Shipu
Published: August 2012

The alteration in intracellular Zn2+ homeostasis is attributed to the generation of intracellular reactive oxygen species, which subsequently results in oxidative damage of organelles and cell apoptosis. In this work, the neurotoxic effects of ZnO hierarchical architectures (nanoparticles and microspheres, the prism-like and flower-like structures) were evaluated through the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay using RSC96 Schwann cells as the model. Cell apoptosis and cell cycle were detected using flow cytometry. The concentration of Zn2+ in the culture media was monitored using atomic absorption spectrometry. The results show that ZnO nanoparticles and microspheres displayed significant cytotoxic effects on RSC96 Schwann cells in dose- and time-dependent manners, whereas no or low cytotoxic effect was observed when the cells were treated with the prism-like and flower-like ZnO. A remarkable cell apoptosis and G2/M cell cycle arrest were observed when RSC96 Schwann cells were exposed to ZnO nanoparticles and microspheres at a dose of 80 μg/mL for 12 h. The time-dependent increase of Zn2+ concentration in the culture media suggests that the cytotoxic effects were associated with the decomposition of ZnO hierarchical architecture and the subsequent release of Zn2+. These results provide new insights into the cytotoxic effects of complex ZnO architectures, which could be prominently dominated by nanoscale building blocks.
DNA-directed immobilization of horseradish peroxidase onto porous SiO2 optical transducers
Authors: Shtenberg Giorgi , Massad-Ivanir Naama , Engin Sinem , Sharon Michal , Fruk Ljiljana , Segal Ester
Published: August 2012

Multifunctional porous Si nanostructure is designed to optically monitor enzymatic activity of horseradish peroxidase. First, an oxidized PSi optical nanostructure, a Fabry-Pérot thin film, is synthesized and is used as the optical transducer element. Immobilization of the enzyme onto the nanostructure is performed through DNA-directed immobilization. Preliminary studies demonstrate high enzymatic activity levels of the immobilized horseradish peroxidase, while maintaining its specificity. The catalytic activity of the enzymes immobilized within the porous nanostructure is monitored in real time by reflective interferometric Fourier transform spectroscopy. We show that we can easily regenerate the surface for consecutive biosensing analysis by mild dehybridization conditions.
Purification of silicon powder by the formation of thin porous layer followed byphoto-thermal annealing
Authors: Khalifa Marouan , Hajji Messaoud , Ezzaouia Hatem
Published: August 2012

Porous silicon has been prepared using a vapor-etching based technique on a commercial silicon powder. Strong visible emission was observed in all samples. Obtained silicon powder with a thin porous layer at the surface was subjected to a photo-thermal annealing at different temperatures under oxygen atmosphere followed by a chemical treatment. Inductively coupled plasma atomic emission spectrometry results indicate that silicon purity is improved from 99.1% to 99.994% after annealing at 900°C.
Intranasal fentanyl versus intravenous morphine in the emergency department treatment of severe painful sickle cell crises in children: Study protocol for a randomised controlled trial
Authors: Barrett Michael Joseph , Cronin John , Murphy Adrian , McCoy Siobhan , Hayden John , an Fhailí SinéadNic , Grant Tim , Wakai Abel , McMahon Corrina , Walsh Sean , O’Sullivan Ronan
Published: August 2012

Background

Children with sickle cell disease (SCD) frequently and unpredictably present to the emergency department (ED) with pain. The painful event is the hallmark acute clinical manifestation of SCD, characterised by sudden onset and is usually bony in origin. This study aims to establish if 1.5mcg/kg of intranasal fentanyl (INF; administered via a Mucosal Atomiser Device, MAD™) is non-inferior to intravenous morphine 0.1 mg/kg in severe SCD-associated pain.

Methods/design

This study is a randomised,double-blind, double-dummy active control trial of children (weighing more than 10 kg) between 1 year and 21 years of age with severe painful sickle cell crisis. Severe pain is defined as rated seven or greater on a 0 to 10 age-appropriate numeric pain scale or equivalent. The trial will be conducted in a single tertiary urban paediatric ED in Dublin, Ireland. Each patient will receive a single active agent and a single placebo via the intravenous and intranasal routes. All clinical and research staff, patients and parents will be blinded to the treatment allocation. The primary endpoint is severity of pain scored at 10 min from administration of the study medications. Secondary endpoints include pain severity measured at 0, 5, 15, 20, 30, 60 and 120 min after the administration of analgesia, proportion of patients requiring rescue analgesia and incidence of adverse events. The trial ends at 120 min after the administration of the study drugs. A clinically meaningful difference in validated pain scores has been defined as 13 mm. Setting the permitted threshold to 50% of this limit (6 mm) and assuming both treatments are on average equal, a sample size of 30 patients (15 per group) will provide at least 80% power to demonstrate that INF is non-inferior to IV morphine with a level of significance of 0.05.

Discussion

This clinical trial will inform of the role of INF 1.5mcg/kg via MAD in the acute treatment of severe painful sickle cell crisis in children in the ED setting.

Trial registration

Current Controlled Trials ISRCTN67469672 and EudraCT no. 2011-005161-20
Microwave synthesis and thermal properties of polyacrylate derivatives containing itaconic anhydride moieties
Authors: Osman Sameh M , El-Newehy Mohamed H , Al-Deyab Salem S , El-Faham Ayman
Published: August 2012

Background

Microwave irradiation as an alternative heat source is now a well-known method in synthetic chemistry. Microwave heating has emerged as a powerful technique to promote a variety of chemical reactions, offering reduced pollution, low cost and offer high yields together with simplicity in processing and handling. On the other hand, copolymers containing both hydrophilic and hydrophobic segments are drawing considerable attention because of their possible use in biological systems. Various copolymer compositions can produce a very large number of different arrangements, producing materials of varying chemical and physical properties. Thus, the hydrophilicity of copolymers can be modified by changing the amount of incorporated itaconic anhydride.

Results

A series of methyl methacrylate (MMA) and acrylamide (AA) copolymers containing itaconic anhydride (ITA) were synthesized by microwave irradiation employing a multimode reactor (Synthos 3000 Aton Paar, GmbH, 1400 W maximum magnetron) as well as conventional method. The thermal properties of the copolymers were evaluated by different techniques. Structure-thermal property correlation based on changing the itaconic anhydride ratio was demonstrated. Results revealed that the incorporation of itaconic anhydride into the polymeric backbone of all series affect the thermal stability of copolymers. In addition, the use of the microwave method offers high molecular weight copolymers which lead eventually to an increase in thermal stability.

Conclusions

Microwave irradiation method showed advantages for the produced copolymers compared to that prepared by conventional method, where it can offer a copolymer in short time, high yield, more pure compounds and more thermally stable copolymers, rather than conventional method. Also, microwave irradiation method gives higher molecular weight due to prevention of the chain transfer. Moreover, as the itaconic anhydride content increases the thermal stability and T

g
increase due to the decrease in the crystallinity.
Best-bet integrated strategies for containing drug-resistant trypanosomes in cattle
Authors: Mungube Erick O , Diall Oumar , Baumann Maximilian PO , Hoppenheit Antje , Hinney Barbara , Bauer Burkhard , Sanogo Yousouf , Maiga Brehima , Zessin Karl-Hans , Randolph Thomas F , Clausen Peter-Henning
Published: August 2012

Background

African animal trypanosomosis is a major constraint to the rearing of productive livestock in the sub-humid Sudan-Sahel zone of West Africa where cotton is grown. Trypanosomosis is mainly controlled using trypanocidal drugs, but the effective use of drugs is threatened by the development of widespread resistance. This study tested integrated best-bet strategies for containment and/ or reversal of trypanocide resistance in villages in south-east Mali where resistance has been reported.

Methods

Four sentinel villages each from an intervention area (along the road from Mali to Burkina Faso) and a control area (along the road from Mali to Côte d’Ivoire) were selected for the study. Tsetse control was based on deltamethrin-treated stationary attractive devices and targeted cattle spraying between March 2008 and November 2009. Trypanosome-positive cattle were selectively treated with 3.5 mg/kg diminazene aceturate. Strategic helminth control using 10 mg/kg albendazole was also undertaken. During the intervention, tsetse densities along drainage lines, trypanosome infections and faecal egg counts in risk cattle (3 to 12 months of age) were monitored.

Results

Catch reductions of 66.5 % in Glossina palpalis gambiensis and 90 % in G. tachinoides were observed in the intervention area. Trypanosome prevalence was significantly (p < 0.05) lower in the intervention area (2.3 %; 1.3-3.6 %) compared to the control area (17.3 %; 14.8-20.1 %). Albendazole treatment resulted in a faecal egg count reduction of 55.6 % and reduced trypanosome infection risk (2.9 times lower than in the placebo group) although not significantly (p > 0.05). Further studies are required before confirming the existence of albendazole resistant strongyles in the study area.

Conclusion

Integration of best-bet strategies in areas of multiple drug-resistance is expected to reduce trypanosome infection risk thus contributing to containment of trypanocidal drug resistance. Integrated best-bet strategies could therefore be considered a viable trypanosomosis control option especially in areas where multiple drug-resistance has been reported.
Squamous cell carcinoma of the oral cavity and the oropharynx in patients less than 40 years of age: a 20-year analysis
Authors: Udeabor Samuel E , Rana Majeed , Wegener Gerd , Gellrich Nils-Claudius , Eckardt André M
Published: August 2012

Background

Squamous cell carcinoma mainly afflicts patients older than 40 years of age however, few cases are seen in younger patients. The aim of this study therefore was to determine the incidence of squamous cell carcinoma of the oral cavity and oropharynx in patients less than 40 years of age with a view to assessing the prognosis over a period of time.

Methods

This was a 20 years retrospective review of patients who were histologically diagnosed with squamous cell carcinoma of the oral cavity and the oropharynx at the Department of Cranio-Maxillo-Facial Surgery of the Hannover Medical School, Germany and had not received treatment anywhere else. Records of these patients were analysed for age and sex distribution, tumour staging and differentiation, location, treatment given, recurrences and metastasis, time between diagnosis and death or last contact with patient, and possible cause of death. Comparisons were also made with patients older than 40 years of age.

Results and discussion

A total of 977 patients treated for squamous cell carcinoma of the oral cavity and the oropharynx in the 20-year period of this study were included. Thirty eight (3.9 %) of the overall patient population were under 40 years of age. Among these, 30 (78.9%) were males and 8 (21.1%) were females. The incidence was highest in the 30–39 year age group accounting for 31 (81.6%) of the 38 patients. The moderately differentiated carcinoma was commonest (24; 63.2%). The floor of the mouth had the highest number of tumours (15; 39.5%), but none was seen in the oropharynx. Surgery alone was the main stay of treatment given to 26 (68.4%) patients. At the end of the study period, 13 (34.2%) patients had died of the tumour and the 5-year survival rate was 66.2%. In the older patient group (>40 years), 42.7% died from the tumour and the 5-year survival rate was 57.6%.

Conclusion

The results from the present study showed that young adults may have a better prognosis especially in terms of long term overall survival from oral and oropharyngeal carcinoma.
Constrained least-squares spectral analysis: Application to seismic data
Authors: Puryear Charles I. , Portniaguine Oleg N. , Cobos Carlos M. , Castagna John P.
Published: August 2012

An inversion-based algorithm for computing the time-frequency analysis of reflection seismograms using constrained least-squares spectral analysis is formulated and applied to modeled seismic waveforms and real seismic data. The Fourier series coefficients are computed as a function of time directly by inverting a basis of truncated sinusoidal kernels for a moving time window. The method resulted in spectra that have reduced window smearing for a given window length relative to the discrete Fourier transform irrespective of window shape, and a time-frequency analysis with a combination of time and frequency resolution that is superior to the short time Fourier transform and the continuous wavelet transform. The reduction in spectral smoothing enables better determination of the spectral characteristics of interfering reflections within a short window. The degree of resolution improvement relative to the short time Fourier transform increases as window length decreases. As compared with the continuous wavelet transform, the method has greatly improved temporal resolution, particularly at low frequencies.
Laplace-domain full-waveform inversion of seismic data lacking low-frequency information
Authors: Ha Wansoo , Shin Changsoo
Published: August 2012

The lack of the low-frequency information in field data prohibits the time- or frequency-domain waveform inversions from recovering large-scale background velocity models. On the other hand, Laplace-domain waveform inversion is less sensitive to the lack of the low frequencies than conventional inversions. In theory, frequency filtering of the seismic signal in the time domain is equivalent to a constant multiplication of the wavefield in the Laplace domain. Because the constant can be retrieved using the source estimation process, the frequency content of the seismic data does not affect the gradient direction of the Laplace-domain waveform inversion. We obtained inversion results of the frequency-filtered field data acquired in the Gulf of Mexico and two synthetic data sets obtained using a first-derivative Gaussian source wavelet and a single-frequency causal sine function. They demonstrated that Laplace-domain inversion yielded consistent results regardless of the frequency content within the seismic data.
Modeling compaction effects on the elastic properties of clay-water composites
Authors: Moyano Bernardo , Spikes Kyle T. , Johansen Tor Arne , Mondol Nazmul Haque
Published: August 2012

Modeling the elastic properties of clay-bearing rocks (shales) requires thorough knowledge of the mineral constituents, their elastic properties, pore space microstructure, and orientations of clay platelets. Information about these variables and their complex interrelationships is rarely available for real rocks. We theoretically modeled the elastic properties of synthetic clay-water composites compacted in the laboratory, including estimates of pore space topology and percolation behavior. The mineralogy of the samples was known exactly, and the focus was on two monomineralic samples comprised of kaolinite and smectite. We used differential effective medium theory (DEM) and analysis of scanning electron microscope (SEM) images of the compacted kaolinite and smectite samples. Percolation behavior was included through calculations of critical porosities from measurements of the liquid limits of the individual clay powders. Quantitative analysis of the SEM images showed that the large scale ([Formula: see text]) pore space of the smectite composite had more rounded pores (mean aspect ratio [Formula: see text]) than the kaolinite composite (mean pore’s aspect ratio [Formula: see text]). However, models that used only these large-scale pore shapes could not explain the compressional and shear velocity measurements. DEM simulations with a single pore aspect ratio showed that bulk and shear moduli are controlled by different pore shapes. Conversely, modeling results that combined critical porosity and dual porosity models into DEM theory compared well with the measured bulk and shear moduli of compacting kaolinite and smectite composites. The methods and results we used could be used to model unconsolidated clay-bearing rocks of more complex mineralogy.
3D CSEM modeling and time-lapse sensitivity analysis for subsurface CO2 storage
Authors: Bhuyian Anwar H. , Landrø Martin , Johansen Ståle E.
Published: August 2012

Monitoring a time-lapse geophysical anomaly due to variation in the pore-fluid contents of a subsurface reservoir is critical for further development and management. However, it may be difficult to detect the changes in P-wave responses beyond a certain level of saturation. A comprehensive 3D finite-difference time domain (FDTD) forward modeling, based on idealized subsurface resistivity structures, demonstrates the possibility of marine controlled-source electromagnetic (CSEM) surveying to monitor the movement of subsurface [Formula: see text] storage. We focused on CSEM sensitivity studies with respect to variations in geometry and/or saturation of [Formula: see text] storage, evaluation of the effects of reservoir depths and lithology, and detection of [Formula: see text] leakage from the main storage. A 100% lateral expansion from the initial diameter (1500 m) of a typical [Formula: see text] plume with thickness and resistivity of 100 m and 80 Ωm, respectively, at 850 m below seafloor, results in 41% electric field (E-field) magnitude increase at 2500 m source-receiver offset for 0.5 Hz source frequency. In comparison, a 300% vertical expansion of a 50 m thick plume with diameter and resistivity of 2500 m and 80 Ωm, respectively, gives only a 7% E-field magnitude anomaly. An increase of the aspect ratio of a [Formula: see text] plume with diameter and thickness of 1750 and 130 m, respectively, by 110%, without volumetric change, results in a 20% E-field magnitude increase. The E-field magnitude differences due to [Formula: see text] saturation change by 20% in clay-rich (10% clay) and clean reservoirs are almost identical; thus, a time-lapse anomaly in a clay-rich reservoir might be detectable. A gradual inverse variation of offset and frequency can differentiate the responses of a 50 m thick shallow [Formula: see text] accumulation, 200 m below the seafloor, from the main [Formula: see text] plume at 850 m below the seafloor and allow for early warning of [Formula: see text] leakage.
Induced polarization in airborne EM
Authors: Kratzer Terence , Macnae James C.
Published: August 2012

A major impediment in the path toward airborne induced polarization (IP) is an effective method to quantify data from inductive sources, such as those used in airborne electromagnetic systems. We modeled inductive IP using a combination of Warburg and exponential decay models as a basis for fitting electromagnetic data from ground time-domain electromagnetic (TEM) and airborne versatile TEM (VTEM) surveys. Observed decays were deconvolved into electromagnetic and IP constituents by constrained least-squares fitting of basis functions modified to account for transmitter waveforms. The method was confirmed through synthetic modeling of 2D and 3D structures, and when applied to ground TEM or airborne TEM data, obtained an estimate of apparent chargeability at each station or fiducial. In the case of a VTEM survey in Africa, the apparent chargeabilities mapped graphitic sediments and provided spatially consistent indications of clay concentrations. A limitation on this airborne IP for airborne applications is motion noise, which places a lower limit on usable base frequency and begins to significantly affect the signal at the later delay times, when IP effects are most visible.
Quasi-Newton full-waveform inversion with a projected Hessian matrix
Authors: Ma Yong , Hale Dave
Published: August 2012

We present a method, in realistic-size full-waveform inversion (FWI), to explicitly construct a projected Hessian matrix and its inverse matrix, which we subsequently used to solve FWI with a quasi-Newton method. Newton’s method is practically unfeasible in solving realistic-size FWI problems because of the prohibitive cost (computing time and memory consumption) of calculating the Hessian matrix and the inverse Hessian. Therefore, the Gauss-Newton method and various quasi-Newton methods are proposed to approximate a Hessian matrix. Particularly, current quasi-Newton FWI (QNFWI) commonly uses the limited-memory BFGS (L-BFGS) method, which, however, only implicitly approximates an inverse Hessian. We repose FWI as a sparse optimization problem in a sparse model space, which contains substantially fewer model parameters that are constrained by structures of the model. With respect to fewer parameters in the sparse model, we can avoid the “limited-memory” approximation and are able to explicitly compute and store a projected Hessian matrix that saves the computational time and required memory. We constructed such a projected Hessian matrix by adapting the classic BFGS method to a projected BFGS (P-BFGS) method in the sparse space. Using the projected Hessian matrix and its inverse, we can apply the P-BFGS method to solve FWI with a quasi-Newton method. In QNFWI with P-BFGS because we invert for a sparse model with much fewer parameters, the memory required to compute the projected Hessian is negligible compared to either forward modeling or gradient calculation. QNFWI with P-BFGS converges in fewer iterations than conjugate-gradient based methods and QNFWI with L-BFGS.
Locomotory activity and feeding strategy of the hadal munnopsid isopod Rectisura cf. herculea (Crustacea: Asellota) in the Japan Trench
Authors: Jamieson Alan J. , Fujii Toyonobu , Priede Imants G.
Published: August 2012

Benthic fauna in the hadal zone (6500-11,000 m) rely on maintaining sufficient locomotory activity to exploit a low, patchy and uniquely distributed food supply while exposed to high pressure, low temperatures and responding to predator-prey interactions. Very little is currently known about the locomotory capabilities of hadal fauna. In situ video footage of the isopod Rectisura cf. herculea (Birstein 1957) (Asellota, Munnopsidae) was obtained from 6945 and 7703 m deep in the Japan Trench (NW Pacific Ocean). Measurements of locomotion revealed routine walking speeds of 0.19±0.04 BL s-1 (mean ± s.d.), increasing to 0.33±0.04 BL s-1 if naturally perturbed by larger organisms. When immediately threatened by the presence of predators (decapod crustaceans), the isopods are capable of eliciting backward escape jumps and burst swimming escape responses of 2.6±1.5 BL s-1 and 4.63±0.9 BL s-1, respectively. These data suggest no significant reduction in locomotory capability despite the extreme depths in which they inhabit. These observations also revealed the isopod to be a bait-attending and aggregative species and suggest that it may not be obligatorily selecting infaunal food sources as previously thought.
New model for gain control of signal intensity to object distance in echolocating bats
Authors: Nørum Ulrik , Brinkløv Signe , Surlykke Annemarie
Published: August 2012

Echolocating bats emit ultrasonic calls and listen for the returning echoes to orient and localize prey in darkness. The emitted source level, SL (estimated signal intensity 10 cm from the mouth), is adjusted dynamically from call to call in response to sensory feedback as bats approach objects. A logarithmic relationship of SL=20log10(x), i.e. 6 dB output reduction per halving of distance, x, has been proposed as a model for the relationship between emitted intensity and object distance, not only for bats but also for echolocating toothed whales. This logarithmic model suggests that the approaching echolocator maintains a constant intensity impinging upon the object, but it also implies ever-increasing source levels with distance, a physical and biological impossibility. We developed a new model for intensity compensation with an exponential rise to the maximum source level: SL=SLmax–ae–bx. In addition to providing a method for estimating maximum output, the new model also offers a tool for estimating a minimum detection distance where intensity compensation starts. We tested the new exponential model against the ‘conventional’ logarithmic model on data from five bat species. The new model performed better in 77% of the trials and as good as the conventional model in the rest (23%). We found much steeper rates of compensation when fitting the model to individual rather than pooled data, with slopes often steeper than –20 dB per halving of distance. This emphasizes the importance of analyzing individual events. The results are discussed in light of habitat constraints and the interaction between bats and their eared prey.
The effect of surface water and wetting on gecko adhesion
Authors: Stark Alyssa Y. , Sullivan Timothy W. , Niewiarowski Peter H.
Published: August 2012

Despite profound interest in the mechanics and performance of the gecko adhesive system, relatively few studies have focused on performance under conditions that are ecologically relevant to the natural habitats of geckos. Because geckos are likely to encounter surfaces that are wet, we used shear force adhesion measurements to examine the effect of surface water and toe pad wetting on the whole-animal performance of a tropical-dwelling gecko (Gekko gecko). To test the effect of surface wetting, we measured the shear adhesive force of geckos on three substrate conditions: dry glass, glass misted with water droplets and glass fully submerged in water. We also investigated the effect of wetting on the adhesive toe pad by soaking the toe pads prior to testing. Finally, we tested for repeatability of the adhesive system in each wetting condition by measuring shear adhesion after each step a gecko made under treatment conditions. Wetted toe pads had significantly lower shear adhesive force in all treatments (0.86±0.09 N) than the control (17.96±3.42 N), as did full immersion in water (0.44±0.03 N). Treatments with droplets of water distributed across the surface were more variable and did not differ from treatments where the surface was dry (4.72±1.59 N misted glass; 9.76±2.81 N dry glass), except after the gecko took multiple steps. These findings suggest that surface water and the wetting of a gecko's adhesive toe pads may have significant consequences for the ecology and behavior of geckos living in tropical environments.
A model based on oscillatory threshold and build-up of a developmental substance explains gating of adult emergence inDrosophila melanogaster
Authors: Mukherjee Narendra , Kannan Nisha N. , Yadav Pankaj , Sharma Vijay Kumar
Published: August 2012

Adult emergence (eclosion) of fruit flies Drosophila melanogaster under constant laboratory conditions follows a circadian pattern with bouts of eclosion recurring at approximately 24 h intervals. Under periodic light:dark (LD) cycles, adults emerge only during a specific time of the day followed by little or no emergence for the rest of the day. This phenomenon is therefore equated to a gate of emergence that, when open, allows adults to emerge and when closed, no emergence takes place. In this study, we attempt to understand the mechanism underlying adult emergence rhythm in D. melanogaster using a model based on interplay between developmental and circadian clock systems. The model is composed of an oscillatory threshold of a substance that builds up during pre-adult development. Computer simulations based on this model enabled us to make specific predictions about the ‘gate width’ of the adult emergence rhythm under conditions of fast/slow pre-adult development and short/long circadian periods, which we subsequently tested empirically. The main predictions from the simulations are: (1) flies with faster development have greater gate width and vice versa, and (2) flies with faster circadian clocks have shorter gate width and vice versa. To empirically validate these predictions, we carried out experiments on D. melanogaster populations known to have fast/slow pre-adult development, short/long circadian periods and narrow/wide gate width. Additionally, we manipulated the rate of pre-adult development of the above flies by increasing/decreasing ambient temperature to further examine the influence of developmental rates on gate width of adult emergence rhythm by a complementary approach. The results show that gate width is greatly influenced by the duration of pre-adult development and the length of circadian cycles. This suggests that the adult emergence rhythm of D. melanogaster may be based on mechanisms involving oscillatory threshold and build-up of a developmental substance.
Overview: resisting welfare state restructuring in the UK
Authors: Taylor-Gooby Peter
Published: August 2012

The UK Coalition government's cut-backs and restructuring of the welfare state imply considerable risks for citizens and for its own economic legacy and re-election prospects. They form part of a larger strategy to set the UK political economy on an entirely new path. This article reviews current proposals and shows that any viable alternative programme must be eclectic and must accept that some parts of a good welfare state cannot be justified on practical economic or human capital grounds, but must be included because they are good in themselves.
Varieties of crisis, varieties of austerity: social policy in challenging times
Authors: Farnsworth Kevin , Irving Zoë
Published: August 2012

In the period since 2008 it has become clear that the financial collapse and its ensuing crises have affected countries differently. However, a new ‘austerity consensus’ appears to have developed which is threatening the welfare gains established since the 1930s. By considering in comparative perspective the extent of austerity measures and the ways in which the normalisation of the ‘new age’ is being resisted, this article reflects on whether we are now facing the ‘end of history’ for welfare states given the widespread regression of social provision and the view that welfare states have become ‘unaffordable’.
The ability of public library staff to help homeless people in the United States: exploring relationships, roles and potential
Authors: Anderson Keith A. , Simpson Chaniqua D. , Fisher Lynette G.
Published: August 2012

For public library staff, helping homeless service users can be challenging as they present a range of needs and concerns. In this exploratory study, library staff in the United States completed postal surveys focusing on their relationships with and abilities to help homeless library service patrons. Findings indicated that library staff may be in a position to help, yet they are not well trained to address the specific and often complex needs of homeless people. In the future, additional training may enable library staff to serve in a gatekeeper capacity to link homeless patrons with formal social service providers.
‘Back on the brew [benefits] again’ why so many transitions from welfare into work are not sustained
Authors: McCollum David
Published: August 2012

Employment policies have conventionally focused on the transition from welfare to work. However, many of those who leave out-of-work benefits for employment return to them again relatively quickly, meaning that some people cycle between work and welfare for much of their working lives. This article draws on 130 semi-structured interviews with work-welfare ‘cyclers’, service providers and employers in Glasgow and Dundee, Scotland, to investigate the causes of these detrimental transitions. An argument is developed which contends that ‘bad’ attitudes to paid work and ‘bad’ types of such work to varying degrees lie behind this form of labour market disadvantage.
Formation of Golgi-Derived Active Zone Precursor Vesicles
Authors: Maas Christoph , Torres Viviana I. , Altrock Wilko D. , Leal-Ortiz Sergio , Wagh Dhananjay , Terry-Lorenzo Ryan T. , Fejtova Anna , Gundelfinger Eckart D. , Ziv Noam E. , Garner Craig C.
Published: August 2012

Vesicular trafficking of presynaptic and postsynaptic components is emerging as a general cellular mechanism for the delivery of scaffold proteins, ion channels, and receptors to nascent and mature synapses. However, the molecular mechanisms leading to the selection of cargos and their differential transport to subneuronal compartments are not well understood, in part because of the mixing of cargos at the plasma membrane and/or within endosomal compartments. In the present study, we have explored the cellular mechanisms of active zone precursor vesicle assembly at the Golgi in dissociated hippocampal neurons ofRattus norvegicus. Our studies show that Piccolo, Bassoon, and ELKS2/CAST exit thetrans-Golgi network on a common vesicle that requires Piccolo and Bassoon for its proper assembly. In contrast, Munc13 and synaptic vesicle proteins use distinct sets of Golgi-derived transport vesicles, while RIM1α associates with vesicular membranes in a post-Golgi compartment. Furthermore, Piccolo and Bassoon are necessary for ELKS2/CAST to leave the Golgi in association with vesicles, and a core domain of Bassoon is sufficient to facilitate formation of these vesicles. While these findings support emerging principles regarding active zone differentiation, the cellular and molecular analyses reported here also indicate that the Piccolo-Bassoon transport vesicles leaving the Golgi may undergo further changes in protein composition before arriving at synaptic sites.
Sodium Channel Nav1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury
Authors: Shields Shannon D. , Cheng Xiaoyang , Üçeyler Nurcan , Sommer Claudia , Dib-Hajj Sulayman D. , Waxman Stephen G.
Published: August 2012

Marked hypersensitivity to heat and mechanical (pressure) stimuli develop after a burn injury, but the neural mechanisms underlying these effects are poorly understood. In this study, we establish a new mouse model of focal second-degree burn injury to investigate the molecular and cellular basis for burn injury-induced pain. This model features robust injury-induced behavioral effects and tissue-specific altered cytokine profile, but absence of glial activation in spinal dorsal horn. Three voltage-gated sodium channels, Nav1.7, Nav1.8, and Nav1.9, are preferentially expressed in peripheral somatosensory neurons of the dorsal root ganglia (DRGs) and have been implicated in injury-induced neuronal hyperexcitability. Using knock-out mice, we provide evidence that Nav1.7 selectively contributes to burn-induced hypersensitivity to heat, but not mechanical, stimuli. After burn model injury, wild-type mice display increased sensitivity to heat stimuli, and a normally non-noxious warm stimulus induces activity-dependent Fos expression in spinal dorsal horn neurons. Strikingly, both effects are absent in Nav1.7 conditional knock-out (cKO) mice. Furthermore, burn injury increases density and shifts activation of tetrodotoxin-sensitive currents in a hyperpolarized direction, both pro-excitatory properties, in DRG neurons from wild-type but not Nav1.7 cKO mice. We propose that, in sensory neurons damaged by burn injury to the hindpaw, Nav1.7 currents contribute to the hyperexcitability of sensory neurons, their communication with postsynaptic spinal pain pathways, and behavioral thresholds to heat stimuli. Our results offer insights into the molecular and cellular mechanisms of modality-specific pain signaling, and suggest Nav1.7-blocking drugs may be effective in burn patients.
Methylene Blue Modulates Huntingtin Aggregation Intermediates and Is Protective in Huntington's Disease Models
Authors: Sontag Emily Mitchell , Lotz Gregor P. , Agrawal Namita , Tran Andrew , Aron Rebecca , Yang Guocheng , Necula Mihaela , Lau Alice , Finkbeiner Steven , Glabe Charles , Marsh J. Lawrence , Muchowski Paul J. , Thompson Leslie M.
Published: August 2012

Huntington's disease (HD) is a devastating neurodegenerative disorder with no disease-modifying treatments available. The disease is caused by expansion of a CAG trinucleotide repeat and manifests with progressive motor abnormalities, psychiatric symptoms, and cognitive decline. Expression of an expanded polyglutamine repeat within the Huntingtin (Htt) protein impacts numerous cellular processes, including protein folding and clearance. A hallmark of the disease is the progressive formation of inclusions that represent the culmination of a complex aggregation process. Methylene blue (MB), has been shown to modulate aggregation of amyloidogenic disease proteins. We investigated whether MB could impact mutant Htt-mediated aggregation and neurotoxicity. MB inhibited recombinant protein aggregationin vitro, even when added to preformed oligomers and fibrils. MB also decreased oligomer number and size and decreased accumulation of insoluble mutant Htt in cells. In functional assays, MB increased survival of primary cortical neurons transduced with mutant Htt, reduced neurodegeneration and aggregation in aDrosophila melanogastermodel of HD, and reduced disease phenotypes inR6/2HD modeled mice. Furthermore, MB treatment also promoted an increase in levels of BDNF RNA and proteinin vivo. Thus, MB, which is well tolerated and used in humans, has therapeutic potential for HD.
Persistent Spatial Information in the Frontal Eye Field during Object-Based Short-Term Memory
Authors: Clark Kelsey L. , Noudoost Behrad , Moore Tirin
Published: August 2012

Spatial attention is known to gate entry into visual short-term memory, and some evidence suggests that spatial signals may also play a role in binding features or protecting object representations during memory maintenance. To examine the persistence of spatial signals during object short-term memory, the activity of neurons in the frontal eye field (FEF) of macaque monkeys was recorded during an object-based delayed match-to-sample task. In this task, monkeys were trained to remember an object image over a brief delay, regardless of the locations of the sample or target presentation. FEF neurons exhibited visual, delay, and target period activity, including selectivity for sample location and target location. Delay period activity represented the sample location throughout the delay, despite the irrelevance of spatial information for successful task completion. Furthermore, neurons continued to encode sample position in a variant of the task in which the matching stimulus never appeared in their response field, confirming that FEF maintains sample location independent of subsequent behavioral relevance. FEF neurons also exhibited target-position-dependent anticipatory activity immediately before target onset, suggesting that monkeys predicted target position within blocks. These results show that FEF neurons maintain spatial information during short-term memory, even when that information is irrelevant for task performance.
Stress Modulates the Engagement of Multiple Memory Systems in Classification Learning
Authors: Schwabe Lars , Wolf Oliver T.
Published: August 2012

Learning and memory are supported by anatomically and functionally distinct systems. Recent research suggests that stress may alter the contributions of multiple memory systems to learning, yet the underlying mechanism in the human brain remains completely unknown. Using event-related functional magnetic resonance imaging, we asked in the present experiment whether stress may modulate the engagement of hippocampus-based “declarative” and striatum-based “procedural” memory systems during classification learning in humans and what brain mechanisms are involved in this effect. We found that stress reduced declarative knowledge about the learning task and changed the used learning strategy from a single-cue-based declarative strategy to a multicue-based procedural strategy, whereas learning performance per se remained unaffected by stress. Neuroimaging revealed that hippocampal activity correlated positively with task performance in the control condition, whereas striatal activity correlated with performance in the stress condition. After stress, hippocampal activity was reduced and even negatively correlated with learning performance. These findings show for the first time that stress alters the engagement of multiple memory systems in the human brain. Stress impaired the hippocampus-dependent system and allowed the striatum to control behavior. The shift toward “procedural” learning after stress appears to rescue task performance, whereas attempts to engage the “declarative” system disrupt performance.
Rabconnectin3α Promotes Stable Activity of the H+Pump on Synaptic Vesicles in Hair Cells
Authors: Einhorn Zev , Trapani Josef G. , Liu Qianyong , Nicolson Teresa
Published: August 2012

Acidification of synaptic vesicles relies on the vacuolar-type ATPase (V-ATPase) and provides the electrochemical driving force for neurotransmitter exchange. The regulatory mechanisms that ensure assembly of the V-ATPase holoenzyme on synaptic vesicles are unknown. Rabconnectin3α (Rbc3α) is a potential candidate for regulation of V-ATPase activity because of its association with synaptic vesicles and its requirement for acidification of intracellular compartments. Here, we provide the first evidence for a role of Rbc3α in synaptic vesicle acidification and neurotransmission. In this study, we characterized mutant alleles ofrbc3α isolated from a large-scale screen for zebrafish with auditory/vestibular defects. We show that Rbc3α is localized to basal regions of hair cells in which synaptic vesicles are present. To determine whether Rbc3α regulates V-ATPase activity, we examined the acidification of synaptic vesicles and localization of the V-ATPase in hair cells. In contrast to wild-type hair cells, we observed that synaptic vesicles had elevated pH, and a cytosolic subunit of the V-ATPase was no longer enriched in synaptic regions of mutant hair cells. As a consequence of defective acidification of synaptic vesicles, afferent neurons inrbc3α mutants had reduced firing rates and reduced accuracy of phase-locked action potentials in response to mechanical stimulation of hair cells. Collectively, our data suggest that Rbc3α modulates synaptic transmission in hair cells by promoting V-ATPase activity in synaptic vesicles.
Upregulation of the E3 ligase NEDD4-1 by Oxidative Stress Degrades IGF-1 Receptor Protein in Neurodegeneration
Authors: Kwak Young-Don , Wang Bin , Li Jing Jing , Wang Ruishan , Deng Qiyue , Diao Shiyong , Chen Yaomin , Xu Raymond , Masliah Eliezer , Xu Huaxi , Sung Jung-Joon , Liao Francesca-Fang
Published: August 2012

The importance of ubiquitin E3 ligases in neurodegeneration is being increasingly recognized. The crucial role of NEDD4-1 in neural development is well appreciated; however, its role in neurodegeneration remains unexplored. Herein, we report increased NEDD4-1 expression in the degenerated tissues of several major neurodegenerative diseases. Moreover, its expression is upregulated in cultured neurons in response to various neurotoxins, including zinc and hydrogen superoxide, via transcriptional activation likely mediated by the reactive oxygen species (ROS)-responsive FOXM1B. Reduced protein levels of the insulin-like growth factor receptor (IGF-1Rβ) were observed as a consequence of upregulated NEDD4-1 via the ubiquitin-proteasome system. Overexpression of a familial mutant form of superoxide dismutase 1 (SOD1) (G93A) in neuroblastoma cells resulted in a similar reduction of IGF-1Rβ protein. This inverse correlation between NEDD4-1 and IGF-1Rβ was also observed in the cortex and spinal cords of mutant (G93A) SOD1 transgenic mice at a presymptomatic age, which was similarly induced byin vivo-administered zinc in wild-type C57BL/6 mice. Furthermore, histochemistry reveals markedly increased NEDD4-1 immunoreactivity in the degenerating/degenerated motor neurons in the lumbar anterior horn of the spinal cord, suggesting a direct causative role for NEDD4-1 in neurodegeneration. Indeed, downregulation of NEDD4-1 by shRNA or overexpression of a catalytically inactive form rescued neurons from zinc-induced cell death. Similarly, neurons with a NEDD4-1 haplotype are more resistant to apoptosis, largely due to expression of higher levels of IGF-1Rβ.Together, our work identifies a novel molecular mechanism for ROS-upregulated NEDD4-1 and the subsequently reduced IGF-1Rβ signaling in neurodegeneration.
An Essential Role for Histone Deacetylase 4 in Synaptic Plasticity and Memory Formation
Authors: Kim Mi-Sung , Akhtar M. Waseem , Adachi Megumi , Mahgoub Melissa , Bassel-Duby Rhonda , Kavalali Ege T. , Olson Eric N. , Monteggia Lisa M.
Published: August 2012

Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological HDAC inhibitors, primarily those targeted to class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed understanding of the role of class II HDACs in these processes remains elusive. Here, we show that selective loss ofHdac4in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss ofHdac5does not impact learning and memory demonstrating unique roles in brain for individual class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition ofHdac4activity may have unexpected detrimental effects to these processes.