Assembly of an injectable noncytotoxic peptide-based hydrogelator for sustained release of drugs

A new synthetic tripeptide-based hydrogel has been discovered at physiological pH and temperature. This hydrogel has been thoroughly characterized using different techniques including field emission scanning electron microscopic (FESEM) and high-resolution transmission electron microscopic (HR-TEM) imaging, small- and wide-angle X-ray diffraction analyses, FT-IR, circular dichroism, and rheometric analyses. Moreover, this gel exhibits thixotropy and injectability. This hydrogel has been used for entrapment and sustained release of an antibiotic vancomycin and vitamin B12 at physiological pH and temperature for about 2 days. Interestingly, MTT assay of these gelator molecules shows almost 100% cell viability of this peptide gelator, indicating its noncytotoxicity.

“There’s something very familiar about all this”: generic play and performance in the Back to the Future trilogy (Robert Zemeckis, 1985, 1989, 1990)

The Back to the Future Trilogy incorporates several different generic elements, including aspects of the fifties teen movie, science fiction, comedy and the western. These different modes playfully intertwine with each other creating a complex world of repetitions, echoes and modulations. This essay seeks to interrogate the construction of generic elements and the play between them through a close analysis of a repeated performance. Genre is signalled through various strategies employed within the construction of mise-en-scène, a significant portion of this, as I would like to argue, is transmitted through performance. The material detail of a performance – incorporating gesture, movement, voice, and even surrounding elements such as costume – as well as the way it its presented within a film is key to the establishment, invocation and coherence of genre. Furthermore, attention to the complexity of performance details, particularly in the manner in which they reverberate across texts, demonstrates the intricacy of genre and its inherent mutability. The Back to the Future trilogy represents a specific interest in the flexibility of genre. Within each film, and especially across all three, aspects of various genres are interlaced through both visual and narrative detail, thus constructing a dense layer of references both within and without the texts. To explore this patterning in more detail I will interrogate the contribution of performance to generic play through close analysis of Thomas F. Wilson’s performance of Biff/Griff/Burford Tannen and his central encounter with Marty McFly (Michael J. Fox) in each film. These moments take place in a fifties diner, a 1980s retro diner and a saloon respectively, each space contributing the similarities and differences in each repetition. Close attention to Wilson’s performance of each related character, which contains both modulations and repetitions used specifically to place each film’s central generic theme, demonstrates how embedded the play between genres and their flexibility is within the trilogy.

Effects of drugs that potentiate GABA on extinction of positively-reinforced operant behaviour

Extinction following positively reinforced operant conditioning reduces response frequency, at least in part through the aversive or frustrative effects of non-reinforcement. According to J.A. Gray's theory, non-reinforcement activates the behavioural inhibition system which in turn causes anxiety. As predicted, anxiolytic drugs including benzodiazepines affect the operant extinction process. Recent studies have shown that reducing GABA-mediated neurotransmission retards extinction of aversive conditioning. We have shown in a series of studies that anxiolytic compounds that potentiate GABA facilitate extinction of positively reinforced fixed-ratio operant behaviour in C57B1/6 male mice. This effect does not occur in the early stages of extinction, nor is it dependent on cumulative effects of the compound administered. Potentiation of GABA at later stages has the effect of increasing sensitivity to the extinction contingency and facilitates the inhibition of the behaviour that is no longer required. The GABAergic hypnotic, zolpidem, has the same selective effects on operant extinction in this procedure. The effects of zolpidem are not due to sedative action. There is evidence across our series of experiments that different GABA-A subtype receptors are involved in extinction facilitation and anxiolysis. Consequently, this procedure may not be an appropriate model for anxiolytic drug action, but it may be a useful technique for analysing the neural bases of extinction and designing therapeutic interventions in humans where failure to extinguish inappropriate behaviours can lead to pathological conditions such as post-traumatic stress disorder.

Subtype-selective GABAergic drugs facilitate extinction of mouse operant behaviour

Several recent studies have shown that reducing gamma-aminobutyric acid (GABA)-mediated neurotransmission retards extinction of aversive conditioning. However, relatively little is known about the effect of GABA on extinction of appetitively motivated tasks. We examined the effect of chlordiazepoxide (CDP), a classical benzodiazepine (BZ) and two novel subtype-selective BZs when administered to male C57Bl/6 mice during extinction following training on a discrete-trial fixed-ratio 5 (FR5) food reinforced lever-press procedure. Initially CDP had no effect, but after several extinction sessions CDP significantly facilitated extinction, i.e. slowed responding, compared with vehicle-treated mice. This effect was not due to drug accumulation because mice switched from vehicle treatment to CDP late in extinction showed facilitation immediately. Likewise, this effect could not be attributed to sedation because the dose of CDP used (15 mg/kg i.p.) did not suppress locomotor activity. The two novel subtype-selective BZ partial agonists, L-838417 and TP13, selectively facilitated extinction in similar fashion to CDP. The non-GABAergic anxiolytic buspirone was also tested and found to have similar effects when administered at a non-sedating dose. These studies demonstrate that GABA-mediated processes are important during extinction of an appetitively motivated task, but only after the animals have experienced several extinction sessions.

Reinterpreting ‘generic structure’: evolution, application and limitations of a concept

This paper traces the evolution of thegeneric structure concept in system dynamics and discusses the different practical uses to which they have been put. A review of previous work leads to the identification of three different views of what a ‘generic structure’ is and, hence, what transferability means. These different views are distinguishable in application as well as in theory. Examination of these interpretations shows that the assumptions behind them are quite distinct. From this analysis it is argued that it is no longer useful to treat ‘generic structure’ as a single concept since the unity it implies is only superficial. The conclusion is that the concept needs unbundling so that different assumptions about transferability of structure can be made explicit, and the role of generic structures as generalisable theories of dynamic behaviour in system dynamics theory and practice can be debated and clarified more effectively.

Can we have confidence in generic structures?

The system dynamics concept of `generic structure' is dividable into three sub-types. This paper analyses the validity of these three, using both practical and theoretical perspectives. Firstly, a new set of measures is developed for generating validity-`confidence'-amongst a group using generic structures in a practical modelling situation. It is concluded that different confidence criteria are implicitly employed; there is an argument for trading-off model precision and analytical quality for simplicity and ease of use and future research is needed to combine these `process' and `content' aspects of confidence. From a theoretical stance it is shown that with two of the sub-types a scientific notion of confidence is achievable whereas the third (`archetypes') involves merely metaphorical thinking. It is concluded that the theoretical status of archetypes requires further development, whilst ensuring that its benefits are retained.

Reinterpreting 'generic structure': evolution, application and limitations of a concept

This paper traces the evolution of the generic structure concept in system dynamics and discusses the different practical uses to which they have been put. A review of previous work leads to the identification of three different views of what a generic structure is and, hence, what transferability means. These different views are distinguishable in application as well as in theory. Examination of these interpretations shows that the assumptions behind them are quite distinct. From this analysis it is argued that it is no longer useful to treat generic structure as a single concept since the unity it implies is only superficial. The conclusion is that the concept needs unbundling so that different assumptions about transferability of structure can be made explicit, and the role of generic structures as generalisable theories of dynamic behaviour in system dynamics theory and practice can be debated and clarified more effectively.

A parallel formulation for the simulation of a generic branch predictor

A parallel formulation for the simulation of a branch prediction algorithm is presented. This parallel formulation identifies independent tasks in the algorithm which can be executed concurrently. The parallel implementation is based on the multithreading model and two parallel programming platforms: pthreads and Cilk++. Improvement in execution performance by up to 7 times is observed for a generic 2-bit predictor in a 12-core multiprocessor system.

Identifying the generic limits of the Cheilanthoid genus Doryopteris

Morphology-based delimitation of genera in the Cheilanthoid ferns has proved to be problematic and understanding of the phylogeny and relationships amongst Cheilanthoid ferns based on morphological characters has posed even further difficulties, owing perhaps in large part to adaptation by many taxa to xeric habitats, as well as convergent evolution. It is only now with the application of DNA sequence data that relationships of species and genera are becoming clear. Here, we present results of cpDNA sequence data from species that have been traditionally placed in the genus Doryopteris and, based on both these results, and morphological and distribution data, this study helps clarify the concept of the genus Doryopteris its position within the Cheilanthoid ferns and the status of Lytoneuron. As a result, three genera are redefined: Doryopteris, Lytoneuron and Ormopteris.

Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators

Nucleotide-based drug candidates such as antisense oligonucleotides, aptamers, immunoreceptor-activating nucleotides, or (anti)microRNAs hold great therapeutic promise for many human diseases. Phosphorothioate (PS) backbone modification of nucleotide-based drugs is common practice to protect these promising drug candidates from rapid degradation by plasma and intracellular nucleases. Effects of the changes in physicochemical properties associated with PS modification on platelets have not been elucidated so far. Here we report the unexpected binding of PS-modified oligonucleotides to platelets eliciting strong platelet activation, signaling, reactive oxygen species generation, adhesion, spreading, aggregation, and thrombus formation in vitro and in vivo. Mechanistically, the platelet-specific receptor glycoprotein VI (GPVI) mediates these platelet-activating effects. Notably, platelets from GPVI function-deficient patients do not exhibit binding of PS-modified oligonucleotides, and platelet activation is fully abolished. Our data demonstrate a novel, unexpected, PS backbone-dependent, platelet-activating effect of nucleotide-based drug candidates mediated by GPVI. This unforeseen effect should be considered in the ongoing development programs for the broad range of upcoming and promising DNA/RNA therapeutics.

Generic construction of monitors for floating point unit designs

This paper proposes a set of well defined steps to design functional verification monitors intended to verify Floating Point Units (FPU) described in HDL. The first step consists on defining the input and output domain coverage. Next, the corner cases are defined. Finally, an already verified reference model is used in order to test the correctness of the Device Under Verification (DUV). As a case study a monitor for an IEEE754-2008 compliant design is implemented. This monitor is built to be easily instantiated into verification frameworks such as OVM. Two different designs were verified reaching complete input coverage and successful compliant results.

Generic intertextuality in online social activism: the case of the It Gets Better project

The It Gets Better project has been held up as a model of successful social media activism. This article explores how narrators of It Gets Better videos make use of generic intertextuality, strategically combining the canonical narrative genres of the exemplum, the testimony, and the confession in a way that allows them to claim ‘textual authority’ and to make available multiple moral positions for themselves and their listeners. This strategy is further facilitated by the ambiguous participation frameworks associated with digital media, which make it possible for storytellers to tell different kinds of stories to different kinds of listeners at the same time, to simultaneously comfort the victims of anti-gay violence, confront its perpetrators, and elicit sympathy from ‘onlookers’. This analysis highlights the potential of new practices of online storytelling for social activism, and challenges notions that new media are contributing to the demise of common narrative traditions.