Artículos de revistas sobre el tema "Drum sound synthesis"

A novel 3D auto-drum machine system for the generation and recording of percussion sounds is developed and presented. The capabilities of the machine, along with a calibration, sound production, and collection protocol are demonstrated. The sounds are generated by a drumstick at pre-defined positions and by known impact forces from the programmable 3D auto-drum machine. The generated percussion sounds are accompanied by the spatial excitation coordinates and the correspondent impact forces, allowing for large databases to be built, which are required by machine learning models. The recordings of the radiated sound by a microphone are analyzed using a pre-trained deep learning model, evaluating the consistency of the physical sample generation method. The results demonstrate the ability to perform regression and classification tasks when fine tuning the deep learning model with the gathered data. The produced databases can properly train machine learning models, aiding in the investigation of alternative and cost-effective materials and geometries with relevant sound characteristics and in the development of accurate vibroacoustic numerical models for studying percussion instruments sound synthesis.

For the last 20 years, silica-based mesoporous materials have provided a sound platform for the development of biomedical technology applied to tissue engineering and drug delivery. Their unique structural and textural characteristics, chiefly, the ordered distribution of homogeneous and tunable pores with high surface areas and large pore volume, and their excellent biocompatibility provide an excellent starting point for bone tissue regeneration on the mesoporous surface, and also to load species of interest inside the pores. Adequate control of the synthesis conditions and functionalization of the mesoporous surface are critical factors in the design of new systems that are suitable for use in specific medical applications. Simultaneously, the use of appropriate characterization techniques in the several stages of design and manufacture of mesoporous particles allows us to ascertain the textural, structural and compositional modifications induced during the synthesis, functionalization and post-in vitro assays processes. In this scenario, the present paper shows, through several examples, the role of transmission electron microscopy and associated spectroscopic techniques in the search for useful information in the early design stages of mesoporous systems, with application in the fields of tissue regeneration and drug delivery systems.

OBJECTIVE: To review some of the abuses and proper uses of the Food and Drug Administration's (FDA's) spontaneous adverse-reaction reporting system, as a way of educating the reader to its strengths and limitations. DATA SOURCE: Published literature and reports based on information obtained from the FDA's database of spontaneous adverse drug-event reports. DATA SYNTHESIS: The Freedom of Information Act has increased public access to the FDA's database of spontaneous adverse drug reaction reports. As these reports are voluntarily received and reported to the FDA, their use for comparisons of drug safety is severely limited. Despite these limitations and the FDA's caveats for use of these data, consumer advocacy groups, researchers, and various pharmaceutical marketing groups have used this source to project the incidence of adverse drug reactions. CONCLUSIONS: The FDA's spontaneous adverse-event reporting system is designed to generate signals of unexpected adverse drug events. Use of the data gathered by this system to make drug safety comparisons is beyond their credible scope because many factors influence the reporting of adverse events. Researchers and peer reviewers should place these data in the proper perspective and support sound research into questions of drug safety.

The objective of the present study was to produce extended release nateglinide nanosponges for oral delivery. Preparation of nanosponges leads to solubility enhancement. Nateglinide is a BCS Class II drug, having low solubility. So, to increase the solubility of nateglinide it is formulated into nanosponges. Nanosponges using ethyl cellulose as a polymer and dichloromethane as a cross-linker were prepared successfully by ultra-sound assisted synthesis method. The effects of different drug: placebo ratios on the physical characteristics of the nanosponges as well as the drug content and in vitro drug release of the nanosponges were investigated. Particle size analysis and surface morphology of nanosponges were performed. The scanning and transmission electron microscopy of nanosponges showed that they were spongy in nature. The particle size was found to be in the range 46.37 - 97.23 nm out of which particle size of the optimized formulation was 51.79 nm and the drug content was found to 79.43 %. The optimized nanosponge formulations were selected for preparing nanosponge tablets for extended drug delivery by oral route. These tablets were prepared using xanthan gum and PVP K-30 and were evaluated by pre-compression and post-compression parameters. The nateglinide nanosponges tablet formulation were studied for different parameters using Design Expert Software. All formulations were evaluated for in vitro drug release analyzed according to various release kinetic models and it was found that it follows zero order release kinetics.

Ezetimibe prevents intestinal cholesterol synthesis, which in turn reduces the quantity of cholesterol and thereby helps to reduce heart problems and strokes. In the production of ezetimibe, several organic chemical solvents such as methanol, acetone, isopropyl alcohol, dichloromethane, n-hexane, ethyl acetate, tetrahydrofuran, toluene and dimethyl formamide were used. The measurement of residual solvents is necessary for release checks of all drug substances, based on sound manufacturing processes. The analysis of above mentioned nine solvents in ezetimibe drug was investigated using gas chromatographic method employing detection with flame ionization mode. All analyses were performed using ZB-624 column (30 m length × 0.53 mm identification, 3.0 μm thickness film). The column oven temperature flux was managed to maintain for 11 min at 40 ºC and then continued to upsurge to a temperature close of 240 ºC at a rate of 20 ºC/min and retained for 4 min. The flame ionization detector and injector port were managed at 260 and 200 ºC, respectively. Results after the validation of the gas chromatographic method showed the satisfactory linearity, sensitivity, robustness, accuracy, selectivity and precision for the tested organic solvents. This gas chromatographic approach can therefore be exploited in the assessment of studied nine residual chemical solvents for periodic analysis by gas chromatography for samples of ezetimibe drug.

The computer modelling of structural complexes generated from two or more interacting molecules are referred to as molecular docking. It is an indispensable tool in computer-aided drug design and structural molecular biology. Using this technology, large libraries of compounds may be digitally screened, and the results can be graded along with structural assumptions about how the ligands impact the target's reduction. Recent advances in the synthesis of anti-infectious medicines prompted by structural insights have enabled the application of computer-assisted drug design in the quest for innovative mechanism- or structure-based drugs. Molecular docking is an important phase in the drug development process because it determines the best positions for molecules to occupy when they are coupled together and predicts how effectively two molecules will bind once they have been docked. The input structure's design is also critical, and the results are assessed using sampling methods and scoring systems. The recently developed docking software Local Move Monte Carlo [LMMC] provides a strong choice for customizable receptor docking strategies. Docking is a technique for determining how ligands and proteins interact. It is structurally sound and compatible with computer-assisted medication design. Successful docking discovers high-dimensional spaces and ranks function utilisation, resulting in a candidate docking rating that is acceptable. It may also be used to screen vast libraries of molecules and offer structural hypotheses for the process.

IntroductionEssential tremor (ET), a tremor disorder, is one of the most common movement disorders. Only oral drugs (propranolol, primidone, topiramate, etc）are still the first-line treatment recommended by the Food and Drug Administration. Propranolol is thought to potentially reduce upper limb action tremor. However, it has a poor effect on axial tremor symptoms, such as essential head tremor and voice tremor. Studies have shown that tremor severity develops over time, possibly producing other clinical tremors and neurological soft signs (such as memory loss, gait abnormalities, balance disorders, etc), which further increases the difficulty of treating tremors. However, some recent studies provide emerging evidence for oral propranolol on subgroups of ET, which is based on the anatomical distribution of ET (lower extremities, head, sound, tongue, etc). This systematic review aims to synthesise these new data to improve the efficacy of propranolol in ET subgroups.Methods and analysisWe will search for randomised controlled trials from the PubMed, MEDLINE, EMBASE, Cochrane Library, UptoDate and PEDro databases from inception to June 2019. All data will be extracted independently by two reviewers and compared at the end of the review. The two reviewers will screen the study quality, and the Cochrane Collaboration’s tool in Review Manager (RevMan) V.5.3.3 will be used to evaluate risk of bias. Our primary outcome will be the functional disability component related to tremors, as measured by the Fahn-Tolosa-Marin Tremor Rating Scale subscales B and C. Secondary outcomes will include severity of tremors and quality of life. Narrative and meta-analytical syntheses are planned.Ethics and disseminationPublished aggregated data will be used in this review analysis and therefore no ethical approval is required. The results will be published in peer-reviewed journals, and proliferation activities will include diverse social stakeholders, non-academic groups and patients.PROSPERO registration numberCRD42018112580

Many investigations are currently being performed to develop the effective synthesis methodology of magnetic nanoparticles with appropriately functionalized surfaces. Here, the novelty of the presented work involves the preparation of nano-sized PEGylated Fe3O4@Ag particles, i.e., the main purpose was the synthesis of magnetic nanoparticles with a functionalized surface. Firstly, Fe3O4 particles were prepared via the Massart process. Next, Ag+ reduction was conducted in the presence of Fe3O4 particles to form a nanosilver coating. The reaction was performed with arabic gum as a stabilizing agent. Sound energy-using sonication was applied to disintegrate the particles’ agglomerates. Next, the PEGylation process aimed at the formation of a coating on the particles’ surface using PEG (poly(ethylene glycol)) has been performed. It was proved that the arabic gum limited the agglomeration of nanoparticles, which was probably caused by the steric effect caused by the branched compounds from the stabilizer that adsorbed on the surface of nanoparticles. This effect was also enhanced by the electrostatic repulsions. The process of sonication caused the disintegration of aggregates. Formation of iron (II, III) oxide with a cubic structure was proved by diffraction peaks. Formation of a nanosilver coating on the Fe3O4 nanoparticles was confirmed by diffraction peaks with 2θ values 38.15° and 44.35°. PEG coating on the particles’ surface was proven via FT-IR (Fourier Transform Infrared Spectroscopy) analysis. Obtained PEG–nanosilver-coated Fe3O4 nanoparticles may find applications as carriers for targeted drug delivery using an external magnetic field.

Background:Barbituric acid derivatives are a versatile group of compounds which are identified as potential pharmacophores for the treatment of anxiety, epilepsy and other psychiatric disorders. They are also used as anesthetics and have sound effects on the motor and sensory functions. Barbiturates are malonylurea derivatives with a variety of substituents at C-5 position showing resemblance with nitrogen and sulfur containing compounds like thiouracil which exhibited potent anticancer and antiviral activities. Recently, barbituric acid derivatives have also received great interest for applications in nanoscience.Objective:Synthesis of 5-arylidene-N,N-diethylthiobarbiturates, biological evaluation as potential α-glucosidase inhibitors and molecular modeling.Methods:In the present study, N,N-Diethylthiobarbituric acid derivatives were synthesized by refluxing of N,N-diethylthiobarbituric acid and different aromatic aldehydes in distilled water. In a typical reaction; a mixture of N,N-diethylthiobarbituric acid 0.20 g (1 mmol) and 5-bromo-2- hydroxybenzaldehyde 0.199 g (1 mmol) mixed in 10 mL distilled water and reflux for 30 minutes. After completion of the reaction, the corresponding product 1 was filtered and dried and yield calculated. It was crystallized from ethanol. The structures of synthesized compounds 1-25 were carried out by using 1H, 13C NMR, EI spectroscopy and CHN analysis used for the determination of their structures. The α-glucosidase inhibition assay was performed as given by Chapdelaine et al., with slight modifications and optimization.Results:Our newly synthesized compounds showed a varying degree of α-glucosidase inhibition and at least four of them were found as potent inhibitors. Compounds 6, 5, 17, 11 exhibited IC50 values (Mean±SEM) of 0.0006 ± 0.0002, 18.91 ± 0.005, 19.18 ± 0.002, 36.91 ± 0.003 µM, respectively, as compared to standard acarbose (IC50, 38.25 ± 0.12 µM).Conclusion:Our present study has shown that compounds 6, 5, 17, 11 exhibited IC50 values of 0.0006 ± 0.0002, 18.91 ± 0.005, 19.18 ± 0.002, 36.91 ± 0.003 µM, respectively. The studies were supported by in silico data analysis.

Protein tyrosine kinases (PTKs) are the most potential therapeutic targets for cancer. Herein, we present a sound rationale for synthesis of a series of novel 2-(methylthio), 2-(substituted alkylamino), 2-(heterocyclic substituted), 2-amino, 2,4-dioxo and 2-deoxo-5-deazaalloxazine derivatives by applying structure-based drug design (SBDD) using AutoDock 4.2. Their antitumor activities against human CCRF-HSB-2, KB, MCF-7 and HeLa have been investigated in vitro. Many 5-deazaalloxazine analogs revealed high selective activities against MCF-7 tumor cell lines (IC50: 0.17–2.17 µM) over HeLa tumor cell lines (IC50 > 100 µM). Protein kinase profiling revealed that compound 3h induced multi- targets kinase inhibition including −43% against (FAK), −40% against (CDKI) and −36% against (SCR). Moreover, the Annexin-V/PI apoptotic assay elucidate that compound 3h showed 33% and potentially 140% increase in early and late apoptosis to MCF-7 cells respectively, compared to the control. The structure-activity relationship (SAR) and molecular docking study using PTK as a target enzyme for the synthesized 7-deazaalloaxazine derivatives were investigated as potential antitumor agents. The AutoDock binding affinities of the 5-deazaalloxazine analogs into c-kit PTK (PDB code: 1t46) revealed reasonable correlations between their AutoDock binding free energy and IC50.

Abstract: A variety of computational tools that are used to assist drug design are reviewed. Particular emphasis is given to the limitations and merits of different methodologies. Recently, a number of general methods have been proposed for clustering compounds in classes of drug­ like and non-drug-like molecules. The usefulness of this classification for drug design is discussed. The estimation of (relative) binding affinities is from a theoretical point of view the most challenging part of ligand design. We review three methods for the estimation of binding energies. Firstly, quantitative structure-activity relationships (QSAR) are presented. These have gained significantly from recent developments of experimental techniques for combinatorial synthesis and high-throughput screening as well as the use of powerful computational procedures like genetic algorithms and neural networks for the derivation of models. Secondly, empirical energy functions are shown to lead to more general models than standard QSAR, since they are fitted to a variety of complexes. They have been used recently with considerable success. Thirdly, we briefly outline free energy calculations based on molecular dynamics simulations, the method with the most sound theoretical foundation. Recent developments are reestablishing the interest in this approach. In the last part of this review structure-based ligand design programs are described. These are closely related to docking, with the difference that in design, unlike in most docking procedures, ligands are built on a fragment-by-fragment basis. Finally, a short description of our approach to computational combinatorial ligand design is given.

The Vietnamese government has set the task of creating a prosperous people and a strong, democratic society, a just and civilized country. This task cannot be achieved without a sound domestic policy that includes the fight against anti-social phenomena such as domestic drunkenness, chronic alcoholism, and drug addiction as an essential component, which create the ground for criminogenic behavior. The Objective of the study is to study the basic acts of Vietnamese legislation on the regulation of the prevention of deviant behavior among alcoholics and drug addicts and the resocialization of persons who committed crimes and are in prison, as well as those released from them. The general methodological basis is represented by the dialectical method, which allowed studying the research object in development to establish the corresponding cause-and-effect relationships. The authors used general scientific methods, including analysis and synthesis, induction, and deduction methods, to obtain reliable and scientifically significant results. Attention is drawn to the specific methods of resocialization combined with methadone treatment for drug addicts in the Socialist Republic of Vietnam, the conditions and regime of such treatment, and specific individuals’ responsibilities. In the twenty-first century, there are gradual changes in the worldview of the political leadership and the legal practice of Vietnam concerning people with addictions that can be treated and corrected. This has led to the adoption of evidence-based resocialization methods, particularly the use of methadone substitution therapy for drug addicts. Russian scientists are actively engaged in the problem of resocialization in the context of Russian criminal law issues. This article is the first to raise the issue of the Vietnamese approach, information about which is taken from sources in the Vietnamese language.

Particle assembly is a promising technique to create functional materials and devices from nanoscale building blocks. However, the control of particle arrangement and orientation is challenging and requires careful design of the assembly methods and conditions. In this study, the static and dynamic methods of particle assembly are reviewed, focusing on their applications in biomaterial sciences. Static methods rely on the equilibrium interactions between particles and substrates, such as electrostatic, magnetic, or capillary forces. Dynamic methods can be associated with the application of external stimuli, such as electric fields, magnetic fields, light, or sound, to manipulate the particles in a non-equilibrium state. This study discusses the advantages and limitations of such methods as well as nanoarchitectonic principles that guide the formation of desired structures and functions. It also highlights some examples of biomaterials and devices that have been fabricated by particle assembly, such as biosensors, drug delivery systems, tissue engineering scaffolds, and artificial organs. It concludes by outlining the future challenges and opportunities of particle assembly for biomaterial sciences. This review stands as a crucial guide for scholars and professionals in the field, fostering further investigation and innovation. It also highlights the necessity for continuous research to refine these methodologies and devise more efficient techniques for nanomaterial synthesis. The potential ramifications on healthcare and technology are substantial, with implications for drug delivery systems, diagnostic tools, disease treatments, energy storage, environmental science, and electronics.

mRNA drugs are synthesized using cell-free systems without complex and stringent manufacturing processes, which makes their preparation simple, efficient, and economical. Over the past few years, mRNAs encoding antibodies have been one of the research frontiers of antibody drug development. In cancer immunotherapy, mRNAs encoding immune checkpoint antibodies may be advantageous regarding antibody persistence and durability of the anti-tumor immune response of patients. In our previous study, a candidate antibody—AET2010—targeting the novel immune checkpoint TIGIT was reported. Its anti-tumor activity was also investigated using adoptive transfer of NK-92MI cells in a xenograft mouse model, but the limitations of the model did not facilitate precise evaluation. In the present study, we further investigated the therapeutic potential of AET2010 for cancer in TIGIT-humanized BALB/c mice. Next, we explored the design, synthesis, and optimization of mRNAs encoding AET2010 and ultimately obtained a candidate mRNA (mRNA-BU) with favorable in vitro and in vivo expression levels of active AET2010. Particularly, lipid-nanoparticle-encapsulated mRNA-BU delivered to mice produced AET2010 with significantly higher peak concentration and expression duration than an equivalent dose of original AET2010. This study provides a sound basis for developing novel drugs targeting TIGIT.

Green synthesis of nanoparticles known as the synthesis of nanoparticles using biosynthetic methods involving naturally reducing agents such as polysaccharides, biological microorganism such as bacteria and fungus or plants extract. The synthesis of nanoparticles by the use of biological methods have reached a colossal signification above physical and chemical procedures, this is due to the use of innocuous, biocompatible, and ecologically-sound substrates and remarkably uncomplicated synthetic processes at encompassing conditions. In this research, the synthesis, characterization and the determination of the antibacterial activity of Zinc oxide Nanoparticles (ZnO NPs) was ascertained using stem bark extract of Ficus thonningii (Blume) as a stabilizing agent. However, the anti-diabetic activity and some biochemical changes caused by the synthesized ZnO NPs on alloxan-induced diabetic Wistar Rats were also determined. ZnO NPs were synthesized using biological method at different concentrations of ZnO solution (1mM, 2mM, 3mM and 4mM), these NPs were characterized using UV-visible spectroscopy, FTIR and SEM. Wistar rats weight 185 ± 5g were grouped into nine (9) groups (A, B, C, D, E, F, G, and I). Group A served as normal control which was given only feed and water, group B, C, D and E, were induce and treated with 1mM, 2mM, 3mM and 4mM ZnONPs respectively, then F and G were induced and treated with aqueous extract and ethanolic extract while H was induced and treated with Glibenclamide (standard drug for diabetes) by gavage method and finally I was induced and untreated which served as diabetic control. The results showed that ZnO NPs were synthesized with the indication of the change in colour from yellow to dark brown colour. The UV-visible spectroscopy was taken at range between 200nm to 700nm which displayed different peaks at the range of 209nm to 383nm. However, the FTIR showed the existence of various functional groups such as C=C stretch, C≡C stretch and Alcohol OH stretch representing the bioactive compounds such as phenol, amine and many others. The Nanoparticles were analyzed with SEM to examine the morphology of the Nanoparticles. The diabetic induced rats revealed significant decrease in fasting blood glucose after treatment compared with the diabetic untreated rats, the doses were effective when compared with Glibenclamide treated rats. The levels of serum Alkaline phosphatase, Alanine Amino transferase, Albumin, Globulin, Bilirubin, Total Protein, Urea, Creatinine and Electrolytes concentrations displayed no significant increase relative to diabetic control (p < 0.05; n ≥ 5).

The scientific article is devoted the investigation of the most actual questions concerning distance educational form into the light of the specialized training disciplines a namely „Ensemble” and „Special class”. The author has approved that the problem of distance educational form in relation to underlined musical subjects is maximally indicated their practical nature, what have had presentation in the professional communicative sensation of general (simultaneous) performing act, in the process for development and correlation of musician's performing apparatus, in detail-hearing comprehension of particularity for artistic musically-expressive means a namely timbre and attack of sound, traits and articulation, strong and dynamic of instrument (vocal) sounding. The importance of introduction to the contemporary educational process the mixed thematic-integrated learning, specifically the synthesis of distance and full-time educational forms. This interaction must be in the presence of academic musical compositions solo at the training repertoires, specialized musical pieces that were written by vocational composer for playing only one performer-soloist (instrumentalist, vocalist). It is necessary to emphasize that maximally active, result way for keep qualitative high level of creatively artistic practice, musical lessons into the special class (wind wood and brass, drums, vocal, string-bowed, string-plucked specializations) is creative appeal of contemporary pedagogue-musicians to the academic compositions, that were written by authors in to performing form solo, namely the address to masterpieces for performing only one artist-soloist. These academic stagesingle musical pieces are artistically self-sufficient, at the same time, this kind compositions are performed by musician without fortepiano. The pieces of music solo absorb by the power of composer's talent, artistic thoughts the excellently most potential of artistically expressive possibilities, intonation sounding means one or another instrument (voice) - chord sounding (monophonic instruments), microinterval (microchromatics), sound oscillation, playing with four mallets, hidden polyphony and others. This type of compositions (music solo) will be giving the distance professional development of artistically expressive means for student's practice, the formation of independence concerning artistically imaginative thinking of pupils, as well as the upbringing of academic ensemble performing skills among contemporary students.

240 Background: MEK1/2 is an integral component of the Ras/Raf/MEK/ERK signaling pathway, implicated in uncontrolled cell proliferation and cell survival, a key hallmark of cancer. AZD6244, a novel inhibitor of MEK1/2, is currently completing Phase II clinical trials in biliary cancer, with modest antitumor activity observed as monotherapy. Gemcitabine is a cytotoxic drug commonly used in biliary cancer therapy but many patients showed early resistance. In this preclinical study, we investigated the sequence-dependent antitumor effects of AZD6244 combined with gemcitabine in biliary cancer models. Methods: Two biliary cancer cell lines (EGI-1 and TFK-1) were used. In vitro the effects of single drug or three combination protocols(concurrently; AZD6244 followed by GEM or Gem followed by AZD6244) on cell proliferation, DNA synthesis, and cell cycle distribution were evaluated by MTS, clonogenic assay, EdU uptake and flow cytometry. Drug interactions were analyzed by Chou-Talaly method. In vivo, 4 tumor models subcutaneously xenografted in SCID mice from the two cell lines and 2 human patients were set up to compare the therapeutic effects of different sequence-scheduled combinations. Results: AZD6244 caused G1-S cell cycle arrest in biliary cancer cells in vitro and in vivo, and this effect is correlated with the MEK/ERK signaling pathway blocking. Synchronized progression of the population through S phase were observed in 15h after removal of AZD6244 in cell culture or 48h after final dose of acute AZD6244 treatment in vivo. Antagonistic or additive effects was observed in vitro when combination were given as concurrently(CI=2.03~2.46) or Gem followed by AZD6244(CI=1.34~1.78). In contrast, a synergistic antiproliferative activity was obtained when AZD6244 was given first followed by a drug-free interval before Gem treatment (CI=0.53~0.69). In vivo, the best therapeutic effects were obtained with the sequence of AZD6244 followed by Gem, compared with concurrent or reverse sequence. Conclusions: This study provides a sound rationale for a Phase II trial of a potentially synergistic sequence of MEK inhibitor AZD6244 followed by gemcitabine in patients with advanced biliary cancer.

Diabetes mellitus (DM) is a group of metabolic diseases, and there is an urgent need to develop new therapeutic DM oral drugs with fewer side effects and sound therapeutic efficacy. In this study, a β cell expansion factor A (BefA) production strain of Escherichia coli (BL21-pet 28C-BefA) was constructed, and the antidiabetes effect of BefA was evaluated using type 1 DM (T1DM) and type 2 DM (T2DM) mice models. The T1DM mice results indicated that BefA significantly reduced blood glucose levels; exerted a protective effect on islet β cell morphology; downregulated the expressions of TLR-4, p-NFκB/NFκB, and Bax/Bcl-2, and the secretion levels of IL-1β and TNF-α; increased the expression of PDX-1 protein and insulin secretion in a concentration-dependent manner; and restored the disturbed microbial diversity to normal levels. Similarly with the T1DM mice, BefA obviously increased islet β cells and reduced the inflammatory reaction and apoptosis in T2DM mice, as well as improved liver lipid metabolism by downregulating the expressions of CEBP-α, ACC, and Fasn; inhibited the synthesis of triglycerides; and induced Cpt-1, Hmgcs2, and Pparα in a concentration-dependent manner. In conclusion, BefA alleviates diabetes via increasing the number of islet β cells, reducing the inflammatory reaction and apoptosis, improving liver lipid metabolism, and restoring microbial diversity to normal levels, which provides a new strategy for a DM oral drug.

Members of the nuclear steroid hormone superfamily mediate essential physiological functions. Steroid hormone receptors (SHR) act directly on DNA, regulate the synthesis of their target genes and are usually activated by ligand binding. Both endogenous and exogenous compounds and their metabolites may act as activators of SHR and disruptors of endocrine, cellular and lipid homeostasis. The endogenous ligands are generally steroids such as 17β-oestradiol, androgens, progesterone and pregnenolone. The exogenous compounds are usually delivered through the diet and include non-steroidal ligands. Examples of such ligands include isoflavanoids or phyto-oestrogens, and food contaminants such as exogenous oestrogens from hormone-treated cattle, pesticides, polychlorinated biphenyls and plasticisers. Certain drugs are also ligands; so nuclear receptors are also important drug targets for intervention in disease processes. The present review summarises recent reports on ligand-activated SHR that describe the selective regulation of a tightly-controlled cross-talking network involving exchange of ligands, and the control of major classes of cytochrome P450 (CYP) isoforms which metabolise many bioactive exogenous compounds. Many CYP have broad substrate activity and appear to be integrated into a coordinated metabolic pathway, such that whilst some receptors are ligand specific, other sensors may have a broader specificity and low ligand affinity to monitor aggregate levels of inducers. They can then trigger production of metabolising enzymes to defend against possible toxic nutrients and xenobiotic compounds. The influence of dietary intakes of nutrients and non-nutrients on the human oestrogen receptors (α and β), the aryl hydrocarbon receptor, the pregnane X receptor, the constitutive androstane receptor, and the peroxisome proliferator-activated receptors (α and γ), can be examined by utilising computer-generated molecular models of the ligand–receptor interaction, based on information generated from crystallographic data and sequence homology. In relation to experimental and observed data, molecular modelling can provide a scientifically sound perspective on the potential risk and benefits to human health from dietary exposure to hormone-mimicking chemicals, providing a useful tool in drug development and in a situation of considerable public concern.

OBJECTIVE: To discuss the role of low-molecular-weight heparins (LMWHs) in the prevention of venous thromboembolism (VTE) in medical and orthopedic surgery patients. VTE prophylaxis trials in these practice settings establishing the current use of LMWHs marketed in the US are included. An overview is also provided of VTE incidence, risk factors, and prophylaxis consensus guidelines. DATA SOURCES AND STUDY SELECTION: Clinical trials, review articles, and meta-analyses for Food and Drug Administration–approved LMWHs were identified from a MEDLINE search (1980–March 2002). Search terms included dalteparin, enoxaparin, internal medicine, low-molecular-weight heparin, orthopedic surgery, risk factors, tinzaparin, and venous thromboembolism. DATA SYNTHESIS: Consensus guidelines are useful as an initial guide to appropriate VTE prophylaxis; however, a review of the primary literature is needed to identify optimal agents, regimens, or interventions. LMWHs have demonstrated sound efficacy in VTE prevention; however, the quantity and quality of literature are not always comparable for the available agents. CONCLUSIONS: Enoxaparin has demonstrated efficacy and safety in VTE prevention in medical patients, whereas information is limited or lacking for dalteparin and tinzaparin. Total hip replacement (THR) trials have been conducted with all US-marketed LMWHs and have demonstrated the efficacy and safety of each agent. Trials specifically establishing the efficacy of an LMWH in total knee replacement surgery (TKR) have been published for enoxaparin. One combination THR and TKR trial has been published for tinzaparin. These trial outcomes have positioned the LMWHs as key alternatives to adjusted-dose warfarin for VTE prophylaxis in orthopedic surgery. Inherent differences between LMWHs prevent the extrapolation of clinical outcomes from 1 trial to another.

Background. One of the main positions of the vocalist’s practice is to understand the recitation as a kind of interpretation of the musical text, which is fixed in the notes. In the process of performing a piece of music, be it the song, the romance, the recitative, the aria in an opera or a musical drama, one specific variant is selected each time from its many potential meanings. This is the performer’s interpretation of the declamatory intonation, because the composer usually does not indicate the tone, timbre and strength of the voice, minimally orienting a singer in the desired intonation, in the duration and location of pauses for breath and in another wide arsenal of methods of declamatory expression. The aim of this research is to study the interpretive properties of recitation in the sphere of vocal music. Discovering the nature of the interpretive properties of declamatory intonation, based on the simultaneous and consistent sound of speech and music, will help to overcome the performance difficulties in the vocalist’s work on mastering the artistic technique of this area of expression. The main results. The specificity of the combination of words and music in the structure of melodic declamation, its origins in various national cultures, both European and Chinese, the peculiarities of being in different genre conditions (musical drama, opera recitative) are considered, certain difficulties and tasks for the singer-reciter are outlined. In European art, the tradition of melodic recitation has its roots in ancient mysteries. The beginning of European secular melodic recitation was marked at the end of the 16th century, but it was developing in the works of musicians known as the “Florentine Camerata” (Vincenzo Galilei, Giulio Cacchini, Jacopo Peri, Ottavio Rinuccini, etc.), becoming one of the origins of opera. A distinctive feature of melody recitation at that time was the desire for solo recitative singing. Later, as an expressive mean, recitation was existing within the opera genre, and from the middle of the 18 century in Europe, this technique was contributing to the formation of an independent concert genre – chamber and vocal works with ballad texts, which found their place in the works of romantic composers (F. Schubert, R. Schumann, etc.). Note, that in the process of historical development, the genre of melodic declamation, on the one hand, modifies in the form of a recitative in European opera, on the other – remains independent within the musical-stage drama, still popular in various national cultures. The Chinese Suzhou musical drama, which is indicative of our study, originated more than 200 years ago, beginning with folk melodies, including xiaochang (“little songs’), tales, dance movements, gestures (khuaguden dances – “with flowers, drums and lanterns’) etc., and gradually spread at the area near the city Suzhou in the lower Yellow River. It later spread to Anhui Province, the Northern parts of Jiangsu Province, and the Southern parts of Shandong Province. The creative achievements of this art, local at the beginning, later assimilated in the national Beijing Opera. But from its origins, this kind of musical and stage action is inextricably linked with the life of the Chinese people, is based on unpretentious plots, so it remains popular to this day, capable of significant emotional impact on the recipient – the audience and listener. Note, that the genre varieties of musical drama developed from the 16–17 centuries both, in China and in the different cultures of the European, American, and Asian continents, where they exist and today. This stability of the genre is not least due to the fact that in the structure of musical drama is an artistic synthesis of several types of art: the word interacts with music, live stage action. The melodic reciter in this context faces certain difficulties. So, one of the basic means of musical expression for the singer is diction, clear pronunciation of a word, which, in close connection with the melody, is subject to the task of transmitting the artistic content of the work – from composer to listener. It is impossible to convey the musical idea of the composition, to create a certain emotional mood, to embody one’s interpretation of the poetic image of the performed music without a clear proclamation of language inversions, which contain the significance of the immanent artistic content. This requirement does not apply to technical musical constructions used for singing, for “warming up” the singer’s vocal apparatus, nor does it apply to vocals performed without words. Every artist, including a vocalist who uses a verbal word, must understand its importance in creating a unique artistic image, consciously use diction as an articulatory technique of revealing the musical text content in the poetic context of chamber, opera, or musical-dramatic genres. Conclusions. So, verbal-musical factors of declamatory intonation have the immanent possibility of various interpretations in the process of vocal performance. Recitation is based on the expressiveness of the word, perceived by the listener or theatrical spectator on several levels: 1) auditory – we hear the intonation richness of shades of musical speech; 2) mental – we understand the logical meaning of texts; 3) psycho-emotional – with the help of imagination, fantasy, we sympathize with the moods, emotions of the heroes of the work of art. At the same time, the basis of interpretation in the art of singing is the voice as a physical phenomenon: it is not only a material carrier of speech sounds, but also the main tool for expressing musical meanings: the variety of voice sound modulations is inexhaustible. Therefore, the role of breathing in the process of clear proclamation of the word, diction in the process of vocal intonation is difficult to overestimate. It is necessary to emphasize the presence of constant transitions in the part of the performer-reciter from linguistic constructions to recitative and pure vocal. Mastering the techniques of correlation of singing and recitation is relevant for any vocalist, which caused an in-details study of this problem.

In 1956, John Cage predicted that “in the future, records will be made from records” (Duffel, 202). Certainly, musical creativity has always involved a certain amount of appropriation and adaptation of previous works. For example, Vivaldi appropriated and adapted the “Cum sancto spiritu” fugue of Ruggieri’s Gloria (Burnett, 4; Forbes, 261). If stuck for a guitar solo on stage, Keith Richards admits that he’ll adapt Buddy Holly for his own purposes (Street, 135). Similarly, Nirvana adapted the opening riff from Killing Jokes’ “Eighties” for their song “Come as You Are”. Musical “quotation” is actively encouraged in jazz, and contemporary hip-hop would not exist if the genre’s pioneers and progenitors had not plundered and adapted existing recorded music. Sampling technologies, however, have taken musical adaptation a step further and realised Cage’s prediction. Hardware and software samplers have developed to the stage where any piece of audio can be appropriated and adapted to suit the creative impulses of the sampling musician (or samplist). The practice of sampling challenges established notions of creativity, with whole albums created with no original musical input as most would understand it—literally “records made from records.” Sample-based music is premised on adapting audio plundered from the cultural environment. This paper explores the ways in which technology is used to adapt previous recordings into new ones, and how musicians themselves have adapted to the potentials of digital technology for exploring alternative approaches to musical creativity. Sampling is frequently defined as “the process of converting an analog signal to a digital format.” While this definition remains true, it does not acknowledge the prevalence of digital media. The “analogue to digital” method of sampling requires a microphone or instrument to be recorded directly into a sampler. Digital media, however, simplifies the process. For example, a samplist can download a video from YouTube and rip the audio track for editing, slicing, and manipulation, all using software within the noiseless digital environment of the computer. Perhaps it is more prudent to describe sampling simply as the process of capturing sound. Regardless of the process, once a sound is loaded into a sampler (hardware or software) it can be replayed using a MIDI keyboard, trigger pad or sequencer. Use of the sampled sound, however, need not be a faithful rendition or clone of the original. At the most basic level of manipulation, the duration and pitch of sounds can be altered. The digital processes that are implemented into the Roland VariOS Phrase Sampler allow samplists to eliminate the pitch or melodic quality of a sampled phrase. The phrase can then be melodically redefined as the samplist sees fit: adapted to a new tempo, key signature, and context or genre. Similarly, software such as Propellerhead’s ReCycle slices drum beats into individual hits for use with a loop sampler such as Reason’s Dr Rex module. Once loaded into Dr Rex, the individual original drum sounds can be used to program a new beat divorced from the syncopation of the original drum beat. Further, the individual slices can be subjected to pitch, envelope (a component that shapes the volume of the sound over time) and filter (a component that emphasises and suppresses certain frequencies) control, thus an existing drum beat can easily be adapted to play a new rhythm at any tempo. For example, this rhythm was created from slicing up and rearranging Clyde Stubblefield’s classic break from James Brown’s “Funky Drummer”. Sonic adaptation of digital information is not necessarily confined to the auditory realm. An audio editor such as Sony’s Sound Forge is able to open any file format as raw audio. For example, a Word document or a Flash file could be opened with the data interpreted as audio. Admittedly, the majority of results obtained are harsh white noise, but there is scope for serendipitous anomalies such as a glitchy beat that can be extracted and further manipulated by audio software. Audiopaint is an additive synthesis application created by Nicolas Fournel for converting digital images into audio. Each pixel position and colour is translated into information designating frequency (pitch), amplitude (volume) and pan position in the stereo image. The user can determine which one of the three RGB channels corresponds to either of the stereo channels. Further, the oscillator for the wave form can be either the default sine wave or an existing audio file such as a drum loop can be used. The oscillator shapes the end result, responding to the dynamics of the sine wave or the audio file. Although Audiopaint labours under the same caveat as with the use of raw audio, the software can produce some interesting results. Both approaches to sound generation present results that challenge distinctions between “musical sound” and “noise”. Sampling is also a cultural practice, a relatively recent form of adaptation extending out of a time honoured creative aesthetic that borrows, quotes and appropriates from existing works to create new ones. Different fields of production, as well as different commentators, variously use terms such as “co-creative media”, “cumulative authorship”, and “derivative works” with regard to creations that to one extent or another utilise existing works in the production of new ones (Coombe; Morris; Woodmansee). The extent of the sampling may range from subtle influence to dominating significance within the new work, but the constant principle remains: an existing work is appropriated and adapted to fit the needs of the secondary creator. Proponents of what may be broadly referred to as the “free culture” movement argue that creativity and innovation inherently relies on the appropriation and adaptation of existing works (for example, see Lessig, Future of Ideas; Lessig, Free Culture; McLeod, Freedom of Expression; Vaidhyanathan). For example, Gwen Stefani’s 2004 release “Rich Girl” is based on Louchie Lou and Michie One’s 1994 single of the same title. Lou and One’s “Rich Girl”, in turn, is a reggae dance hall adaptation of “If I Were a Rich Man” from Fiddler on the Roof. Stefani’s “na na na” vocal riff shares the same melody as the “Ya ha deedle deedle, bubba bubba deedle deedle dum” riff from Fiddler on the Roof. Samantha Mumba adapted David Bowie’s “Ashes to Ashes” for her second single “Body II Body”. Similarly, Richard X adapted Tubeway Army’s “Are ‘Friends’ Electric?’ and Adina Howard’s “Freak Like Me” for a career saving single for Sugababes. Digital technologies enable and even promote the adaptation of existing works (Morris). The ease of appropriating and manipulating digital audio files has given rise to a form of music known variously as mash-up, bootleg, or bastard pop. Mash-ups are the most recent stage in a history of musical appropriation and they epitomise the sampling aesthetic. Typically produced in bedroom computer-based studios, mash-up artists use software such as Acid or Cool Edit Pro to cut up digital music files and reassemble the fragments to create new songs, arbitrarily adding self-composed parts if desired. Comprised almost exclusively from sections of captured music, mash-ups have been referred to as “fictional pop music” because they conjure up scenarios where, for example, Destiny’s Child jams in a Seattle garage with Nirvana or the Spice Girls perform with Nine Inch Nails (Petridis). Once the initial humour of the novelty has passed, the results can be deeply alluring. Mash-ups extract the distinctive characteristics of songs and place them in new, innovative contexts. As Dale Lawrence writes: “the vocals are often taken from largely reviled or ignored sources—cornball acts like Aguilera or Destiny’s Child—and recast in wildly unlikely contexts … where against all odds, they actually work”. Similarly, Crawford argues that “part of the art is to combine the greatest possible aesthetic dissonance with the maximum musical harmony. The pleasure for listeners is in discovering unlikely artistic complementarities and revisiting their musical memories in mutated forms” (36). Sometimes the adaptation works in the favour of the sampled artist: George Clinton claims that because of sampling he is more popular now than in 1976—“the sampling made us big again” (Green). The creative aspect of mash-ups is unlike that usually associated with musical composition and has more in common with DJing. In an effort to further clarify this aspect, we may regard DJ mixes as “mash-ups on the fly.” When Grandmaster Flash recorded his quilt-pop masterpiece, “Adventures of Grandmaster Flash on the Wheels of Steel,” it was recorded while he performed live, demonstrating his precision and skill with turntables. Modern audio editing software facilitates the capture and storage of sound, allowing mash-up artists to manipulate sounds bytes outside of “real-time” and the live performance parameters within which Flash worked. Thus, the creative element is not the traditional arrangement of chords and parts, but rather “audio contexts”. If, as Riley pessimistically suggests, “there are no new chords to be played, there are no new song structures to be developed, there are no new stories to be told, and there are no new themes to explore,” then perhaps it is understandable that artists have searched for new forms of musical creativity. The notes and chords of mash-ups are segments of existing works sequenced together to produce inter-layered contexts rather than purely tonal patterns. The merit of mash-up culture lies in its function of deconstructing the boundaries of genre and providing new musical possibilities. The process of mashing-up genres functions to critique contemporary music culture by “pointing a finger at how stifled and obvious the current musical landscape has become. … Suddenly rap doesn’t have to be set to predictable funk beats, pop/R&B ballads don’t have to come wrapped in cheese, garage melodies don’t have to recycle the Ramones” (Lawrence). According to Theodor Adorno, the Frankfurt School critic, popular music (of his time) was irretrievably simplistic and constructed from easily interchangeable, modular components (McLeod, “Confessions”, 86). A standardised and repetitive approach to musical composition fosters a mode of consumption dubbed by Adorno “quotation listening” and characterised by passive acceptance of, and obsession with, a song’s riffs (44-5). As noted by Em McAvan, Adorno’s analysis elevates the producer over the consumer, portraying a culture industry controlling a passive audience through standardised products (McAvan). The characteristics that Adorno observed in the popular music of his time are classic traits of contemporary popular music. Mash-up artists, however, are not representative of Adorno’s producers for a passive audience, instead opting to wrest creative control from composers and the recording industry and adapt existing songs in pursuit of their own creative impulses. Although mash-up productions may consciously or unconsciously criticise the current state of popular music, they necessarily exist in creative symbiosis with the commercial genres: “if pop songs weren’t simple and formulaic, it would be much harder for mashup bedroom auteurs to do their job” (McLeod, “Confessions”, 86). Arguably, when creating mash-ups, some individuals are expressing their dissatisfaction with the stagnation of the pop industry and are instead working to create music that they as consumers wish to hear. Sample-based music—as an exercise in adaptation—encourages a Foucauldian questioning of the composer’s authority over their musical texts. Recorded music is typically a passive medium in which the consumer receives the music in its original, unaltered form. DJ Dangermouse (Brian Burton) breached this pact to create his Grey Album, which is a mash-up of an a cappella version of Jay-Z’s Black Album and the Beatles’ eponymous album (also known as the White Album). Dangermouse says that “every kick, snare, and chord is taken from the Beatles White Album and is in their original recording somewhere.” In deconstructing the Beatles’ songs, Dangermouse turned the recordings into a palette for creating his own new work, adapting audio fragments to suit his creative impulses. As Joanna Demers writes, “refashioning these sounds and reorganising them into new sonic phrases and sentences, he creates acoustic mosaics that in most instances are still traceable to the Beatles source, yet are unmistakeably distinct from it” (139-40). Dangermouse’s approach is symptomatic of what Schütze refers to as remix culture: an open challenge to a culture predicated on exclusive ownership, authorship, and controlled distribution … . Against ownership it upholds an ethic of creative borrowing and sharing. Against the original it holds out an open process of recombination and creative transformation. It equally calls into question the categories, rifts and borders between high and low cultures, pop and elitist art practices, as well as blurring lines between artistic disciplines. Using just a laptop, an audio editor and a calculator, Gregg Gillis, a.k.a. Girl Talk, created the Night Ripper album using samples from 167 artists (Dombale). Although all the songs on Night Ripper are blatantly sampled-based, Gillis sees his creations as “original things” (Dombale). The adaptation of sampled fragments culled from the Top 40 is part of Gillis’ creative process: “It’s not about who created this source originally, it’s about recontextualising—creating new music. … I’ve always tried to make my own songs” (Dombale). Gillis states that his music has no political message, but is a reflection of his enthusiasm for pop music: “It’s a celebration of everything Top 40, that’s the point” (Dombale). Gillis’ “celebratory” exercises in creativity echo those of various fan-fiction authors who celebrate the characters and worlds that constitute popular culture. Adaptation through sampling is not always centred solely on music. Sydney-based Tom Compagnoni, a.k.a. Wax Audio, adapted a variety of sound bytes from politicians and media personalities including George W. Bush, Alexander Downer, Alan Jones, Ray Hadley, and John Howard in the creation of his Mediacracy E.P.. In one particular instance, Compagnoni used a myriad of samples culled from various media appearances by George W. Bush to recreate the vocals for John Lennon’s Imagine. Created in early 2005, the track, which features speeded-up instrumental samples from a karaoke version of Lennon’s original, is an immediate irony fuelled comment on the invasion of Iraq. The rationale underpinning the song is further emphasised when “Imagine This” reprises into “Let’s Give Peace a Chance” interspersed with short vocal fragments of “Come Together”. Compagnoni justifies his adaptations by presenting appropriated media sound bytes that deliberately set out to demonstrate the way information is manipulated to present any particular point of view. Playing the media like an instrument, Wax Audio juxtaposes found sounds in a way that forces the listener to confront the bias, contradiction and sensationalism inherent in their daily intake of media information. … Oh yeah—and it’s bloody funny hearing George W Bush sing “Imagine”. Notwithstanding the humorous quality of the songs, Mediacracy represents a creative outlet for Compagnoni’s political opinions that is emphasised by the adaptation of Lennon’s song. Through his adaptation, Compagnoni revitalises Lennon’s sentiments about the Vietnam War and superimposes them onto the US policy on Iraq. An interesting aspect of sampled-based music is the re-occurrence of particular samples across various productions, which demonstrates that the same fragment can be adapted for a plethora of musical contexts. For example, Clyde Stubblefield’s “Funky Drummer” break is reputed to be the most sampled break in the world. The break from 1960s soul/funk band the Winstons’ “Amen Brother” (the B-side to their 1969 release “Color Him Father”), however, is another candidate for the title of “most sampled break”. The “Amen break” was revived with the advent of the sampler. Having featured heavily in early hip-hop records such as “Words of Wisdom” by Third Base and “Straight Out of Compton” by NWA, the break “appears quite adaptable to a range of music genres and tastes” (Harrison, 9m 46s). Beginning in the early 1990s, adaptations of this break became a constant of jungle music as sampling technology developed to facilitate more complex operations (Harrison, 5m 52s). The break features on Shy FX’s “Original Nutta”, L Double & Younghead’s “New Style”, Squarepusher’s “Big Acid”, and a cover version of Led Zepplin’s “Whole Lotta Love” by Jane’s Addiction front man Perry Farrell. This is to name but a few tracks that have adapted the break. Wikipedia offers a list of songs employing an adaptation of the “Amen break”. This list, however, falls short of the “hundreds of tracks” argued for by Nate Harrison, who notes that “an entire subculture based on this one drum loop … six seconds from 1969” has developed (8m 45s). The “Amen break” is so ubiquitous that, much like the twelve bar blues structure, it has become a foundational element of an entire genre and has been adapted to satisfy a plethora of creative impulses. The sheer prevalence of the “Amen break” simultaneously illustrates the creative nature of music adaptation as well as the potentials for adaptation stemming from digital technology such as the sampler. The cut-up and rearrangement aspect of creative sampling technology at once suggests the original but also something new and different. Sampling in general, and the phenomenon of the “Amen break” in particular, ensures the longevity of the original sources; sampled-based music exhibits characteristics acquired from the source materials, yet the illegitimate offspring are not their parents. Sampling as a technology for creatively adapting existing forms of audio has encouraged alternative approaches to musical composition. Further, it has given rise to a new breed of musician that has adapted to technologies of adaptation. Mash-up artists and samplists demonstrate that recorded music is not simply a fixed or read-only product but one that can be freed from the composer’s original arrangement to be adapted and reconfigured. Many mash-up artists such as Gregg Gillis are not trained musicians, but their ears are honed from enthusiastic consumption of music. Individuals such as DJ Dangermouse, Gregg Gillis and Tom Compagnoni appropriate, reshape and re-present the surrounding soundscape to suit diverse creative urges, thereby adapting the passive medium of recorded sound into an active production tool. References Adorno, Theodor. “On the Fetish Character in Music and the Regression of Listening.” The Culture Industry: Selected Essays on Mass Culture. Ed. J. Bernstein. London, New York: Routledge, 1991. Burnett, Henry. “Ruggieri and Vivaldi: Two Venetian Gloria Settings.” American Choral Review 30 (1988): 3. Compagnoni, Tom. “Wax Audio: Mediacracy.” Wax Audio. 2005. 2 Apr. 2007 http://www.waxaudio.com.au/downloads/mediacracy>. Coombe, Rosemary. The Cultural Life of Intellectual Properties. Durham, London: Duke University Press, 1998. Demers, Joanna. Steal This Music: How Intellectual Property Law Affects Musical Creativity. Athens, London: University of Georgia Press, 2006. Dombale, Ryan. “Interview: Girl Talk.” Pitchfork. 2006. 9 Jan. 2007 http://www.pitchforkmedia.com/article/feature/37785/Interview_Interview_Girl_Talk>. Duffel, Daniel. Making Music with Samples. San Francisco: Backbeat Books, 2005. Forbes, Anne-Marie. “A Venetian Festal Gloria: Antonio Lotti’s Gloria in D Major.” Music Research: New Directions for a New Century. Eds. M. Ewans, R. Halton, and J. Phillips. London: Cambridge Scholars Press, 2004. Green, Robert. “George Clinton: Ambassador from the Mothership.” Synthesis. Undated. 15 Sep. 2005 http://www.synthesis.net/music/story.php?type=story&id=70>. Harrison, Nate. “Can I Get an Amen?” Nate Harrison. 2004. 8 Jan. 2007 http://www.nkhstudio.com>. Lawrence, Dale. “On Mashups.” Nuvo. 2002. 8 Jan. 2007 http://www.nuvo.net/articles/article_292/>. Lessig, Lawrence. The Future of Ideas. New York: Random House, 2001. ———. Free Culture: How Big Media Uses Technology and the Law to Lock Down Culture and Control Creativity. New York: The Penguin Press, 2004. McAvan, Em. “Boulevard of Broken Songs: Mash-Ups as Textual Re-Appropriation of Popular Music Culture.” M/C Journal 9.6 (2006) 3 Apr. 2007 http://journal.media-culture.org.au/0612/02-mcavan.php>. McLeod, Kembrew. “Confessions of an Intellectual (Property): Danger Mouse, Mickey Mouse, Sonny Bono, and My Long and Winding Path as a Copyright Activist-Academic.” Popular Music & Society 28.79. ———. Freedom of Expression: Overzealous Copyright Bozos and Other Enemies of Creativity. United States: Doubleday Books. Morris, Sue. “Co-Creative Media: Online Multiplayer Computer Game Culture.” Scan 1.1 (2004). 8 Jan. 2007 http://scan.net.au/scan/journal/display_article.php?recordID=16>. Petridis, Alexis. “Pop Will Eat Itself.” The Guardian UK. March 2003. 8 Jan. 2007 http://www.guardian.co.uk/arts/critic/feature/0,1169,922797,00.html>. Riley. “Pop Will Eat Itself—Or Will It?”. The Truth Unknown (archived at Archive.org). 2003. 9 Jan. 2007 http://web.archive.org/web/20030624154252 /www.thetruthunknown.com/viewnews.asp?articleid=79>. Schütze, Bernard. “Samples from the Heap: Notes on Recycling the Detritus of a Remixed Culture”. Horizon Zero 2003. 8 Jan. 2007 http://www.horizonzero.ca/textsite/remix.php?tlang=0&is=8&file=5>. Vaidhyanathan, Siva. Copyrights and Copywrongs: The Rise of Intellectual Property and How It Threatens Creativity. New York, London: New York University Press, 2003. Woodmansee, Martha. “On the Author Effect: Recovering Collectivity.” The Construction of Authorship: Textual Appropriation in Law and Literature. Eds. M. Woodmansee, P. Jaszi and P. Durham; London: Duke University Press, 1994. 15. Citation reference for this article MLA Style Collins, Steve. "Amen to That: Sampling and Adapting the Past." M/C Journal 10.2 (2007). echo date('d M. Y'); ?> <http://journal.media-culture.org.au/0705/09-collins.php>. APA Style Collins, S. (May 2007) "Amen to That: Sampling and Adapting the Past," M/C Journal, 10(2). Retrieved echo date('d M. Y'); ?> from <http://journal.media-culture.org.au/0705/09-collins.php>.

Chronopharmaceutical drug delivery systems release drug at a rhythm that ideally matches the biological requirement of a given disease therapy or prevention. The sound knowledge of the biological processes and their functions utilized in biomedical and pharmaceutical sciences is necessary for effective design and evaluation of pharmaceutical dosage forms. Circadian phase master the circadian clock of the body, the supra chiasmatic nucleus is known to regulate the endogenous circadian rhythms present inside the human body and the peak evidences of some diseases are reported as per circadian rhythm. The secretion of melatonin, a hormone, released by the pineal gland during darkness, help to reset the internal clock, which regulates the timing of different body functions. In certain diseases like asthma, airway resistance increases progressively in early morning, also release of adrenaline and noradrenaline in the morning causes rise in the blood pressure. In hypercholesterolemia, cholesterol synthesis is higher during the night time than day light; in diabetes mellitus blood sugar level is higher in the day time; myocardial insufficiency occurs early in the morning, and many others. The present review addresses the approaches to chronopharmaceuticals, identifies existing technologies, and study of recent chronopharmaceutical drug delivery systems for management of various chronic diseases like diabetes, hypertension and various types of cancers according to the circadian rhythms of diseases in order to optimize therapeutic outcomes and reduce side effects. Recently chronopharmaceutical drug delivery systems are attaining huge importance in the field of pharmaceutical technology for product development because they are proved to reduce dosing frequency, toxicity and also they deliver the drug in particular disease as and when required considering the peak time of the disease, offering better patient compliance.

Auditory perception can be significantly disrupted by noise. To discriminate sounds from noise, auditory scene analysis (ASA) extracts the functionally relevant sounds from acoustic input. The zebra finch communicates in noisy environments. Neurons in their secondary auditory pallial cortex (caudomedial nidopallium; NCM) can encode song from background chorus, or scenes, and this capacity may aid behavioral ASA. Furthermore, song processing is modulated by the rapid synthesis of neuroestrogens when hearing conspecific song. To examine whether neuroestrogens support neural and behavioral ASA in both sexes, we retrodialyzed fadrozole (aromatase inhibitor, FAD) and recordedin vivoawake extracellular NCM responses to songs and scenes. We found that FAD affected neural encoding of songs by decreasing responsiveness and timing reliability in inhibitory (narrow-spiking), but not in excitatory (broad-spiking) neurons. Congruently, FAD decreased neural encoding of songs in scenes for both cell types, particularly in females. Behaviorally, we trained birds using operant conditioning and tested their ability to detect songs in scenes after administering FAD orally or injected bilaterally into NCM. Oral FAD increased response bias and decreased correct rejections in females, but not in males. FAD in NCM did not affect performance. Thus, FAD in the NCM impaired neuronal ASA but that did not lead to behavioral disruption suggesting the existence of resilience or compensatory responses. Moreover, impaired performance after systemic FAD suggests involvement of other aromatase-rich networks outside the auditory pathway in ASA. This work highlights how transient estrogen synthesis disruption can modulate higher-order processing in an animal model of vocal communication.Significance StatementThe ability to extract relevant sounds from a complex acoustic input, or acoustic scene, can decline with age and is often impaired in auditory and neurological disorders. Moreover, hearing decline and speech-in-noise processing have been associated with hormonal changes during perimenopause or menopause in women. However, hormone-dependent hearing impairments are understudied in female animal models. Here, we explore the role of neuroestrogen synthesis in auditory scene analysis (ASA) in a songbird. We found that blocking the synthesis of neuroestrogens with the drug fadrozole (FAD) impaired ASA in auditory neurons. FAD administered orally caused females to decrease correct rejections and respond indiscriminately during behavioral ASA using operant conditioning. These results elucidate potential neural and hormonal mechanisms underlying speech-in-noise impairments in women.

The computer modelling of structural complexes generated from two or more interacting molecules are referred to as molecular docking. It is an indispensable tool in computer-aided drug design and structural molecular biology. Using this technology, large libraries of compounds may be digitally screened, and the results can be graded along with structural assumptions about how the ligands impact the target's reduction. Recent advances in the synthesis of anti-infectious medicines prompted by structural insights have enabled the application of computer-assisted drug design in the quest for innovative mechanism-or structure-based drugs. Molecular docking is an important phase in the drug development process because it determines the best positions for molecules to occupy when they are coupled together and predicts how effectively two molecules will bind once they have been docked. The input structure's design is also critical, and the results are assessed using sampling methods and scoring systems. The recently developed docking software Local Move Monte Carlo provides a strong choice for customizable receptor docking strategies. Docking is a technique for determining how ligands and proteins interact. It is structurally sound and compatible with computer-assisted medication design. Successful docking discovers high-dimensional spaces and ranks function utilisation, resulting in a candidate docking rating that is acceptable. It may also be used to screen vast libraries of molecules and offer structural hypotheses for the process.

Aims: A computational approach has been adopted to find therapeutically potent herbal compounds with anti-TB properties Background: The second largest cause of death globally is Mycobacterium tuberculosis. Considering that the BCG vaccine is only marginally effective. This study has focused on enoyl- (acyl carrier protein)- reductase (InhA), one of the important enzymes in M. tuberculosis's type II fatty acid (mycolic acid synthesis) biosynthesis pathway. Bioinformatics-based tools have been used to explore therapeutically sound phytocompounds against InhA. Objective: To conduct an insightful study using bioinformatics-based tools to explore phytocompounds originating from different medicinal plants which would act as potent inhibitors of enoyl - (acyl carrier protein)- reductase (InhA) to obstruct the growth of M. tuberculosis. method: Molecular docking (using EasyDockVina) has been used for screening the 150 phytocompounds of medicinal plants against Enoyl - (acyl carrier protein)- reductase (InhA). AMDET analysis was performed using DruLito and protox II to test drug likeness properties of phytocompounds. Method: Molecular docking (using EasyDockVina) has been used for screening the 150 phytocompounds against Enoyl - (acyl carrier protein)- reductase (InhA). AMDET analysis was performed using DruLito and protox II to test the drug-likeness properties of phytocompounds. Result: From the results of molecular docking and two-dimensional interaction, it is concluded that Licoflavone B, Tembaterine, Colubrine and Shinpterocarpin are the potent inhibitors of InhA. Conclusion: According to this study, Licoflavone B, Tembaterine, Columbin, and Shinpterocarpin have positively passed AMDET screening and have high docking scores. These phytocompounds can be considered safe drug candidates against InhA of Mycobacterium tuberculosis. other: NIL

Abstract Background Metabolism is an important component of the kinetic characteristics of herbal constituents, and it often determines the internal dose and concentration of these effective constituents at the target site. The metabolic profile of plant extracts and pure compounds need to be determined for any possible herb-drug metabolic interactions that might occur. Methods Various concentrations of the essential oil of Lippia scaberrima, the ethanolic extract of Lippia scaberrima alone and their combinations with fermented and unfermented Aspalathus linearis extract were used to determine the inhibitory potential on placental, microsomal and recombinant human hepatic Cytochrome P450 enzymes. Furthermore, the study investigated the synthesis and characterization of gold nanoparticles from the ethanolic extract of Lippia scaberrima as a lead sample. Confirmation and characterization of the synthesized gold nanoparticles were conducted through various methods. Additionally, the cytotoxic properties of the ethanolic extract of Lippia scaberrima were compared with the gold nanoparticles synthesized from Lippia scaberrima using gum arabic as a capping agent. Results All the samples showed varying levels of CYP inhibition. The most potent inhibition took place for CYP2C19 and CYP1B1 with 50% inhibitory concentration (IC50) values of less than 0.05 µg/L for the essential oil tested and IC50-values between 0.05 µg/L-1 µg/L for all the other combinations and extracts tested, respectively. For both CYP1A2 and CYP2D6 the IC50-values for the essential oil, the extracts and combinations were found in the range of 1 – 10 µg/L. The majority of the IC50 values found were higher than 10 µg/L and, therefore, were found to have no inhibition against the CYP enzymes tested. Conclusion Therefore, the essential oil of Lippia scaberrima, the ethanolic extract of Lippia scaberrima alone and their combinations with Aspalathus linearis do not possess any clinically significant CYP interaction potential and may be further investigated for their adjuvant potential for use in the tuberculosis treatment regimen. Furthermore, it was shown that the cytotoxic potential of the Lippia scaberrima gold nanoparticles was reduced by twofold when compared to the ethanolic extract of Lippia scaberrima.

'He did what the cipher could not, he rescued himself.' -- Alfred Bester, The Stars My Destination (23) On many levels, the new Nine Inch Nails album The Fragile is a gritty meditation about different types of End: the eternal relationship cycle of 'fragility, tension, ordeal, fragmentation' (adapted, with apologies to Wilhelm Reich); fin-de-siècle anxiety; post-millennium foreboding; a spectre of the alien discontinuity that heralds an on-rushing future vastly different from the one envisaged by Enlightenment Project architects. In retrospect, it's easy for this perspective to be dismissed as jargon-filled cyber-crit hyperbole. Cyber-crit has always been at its best too when it invents pre-histories and finds hidden connections between different phenomena (like the work of Greil Marcus and early Mark Dery), and not when it is closer to Chinese Water Torture, name-checking the canon's icons (the 'Deleuze/Guattari' tag-team), texts and key terms. "The organization of sound is interpreted historically, politically, socially ... . It subdues music's ambition, reins it in, restores it to its proper place, reconciles it to its naturally belated fate", comments imagineer Kodwo Eshun (4) on how cyber-crit destroys albums and the innocence of the listening experience. This is how official histories are constructed a priori and freeze-dried according to personal tastes and prior memes: sometimes the most interesting experiments are Darwinian dead-ends that fail to make the canon, or don't register on the radar. Anyone approaching The Fragile must also contend with the music industry's harsh realities. For every 10 000 Goth fans who moshed to the primal 'kill-fuck-dance' rhythms of the hit single "Closer" (heeding its siren-call to fulfil basic physiological needs and build niche-space), maybe 20 noted that the same riff returned with a darker edge in the title track to The Downward Spiral, undermining the glorification of Indulgent hedonism. "The problem with such alternative audiences," notes Disinformation Creative Director Richard Metzger, "is that they are trying to be different -- just like everyone else." According to author Don Webb, "some mature Chaos and Black Magicians reject their earlier Nine Inch Nails-inspired Goth beginnings and are extremely critical towards new adopters because they are uncomfortable with the subculture's growing popularity, which threatens to taint their meticulously constructed 'mysterious' worlds. But by doing so, they are also rejecting their symbolic imprinting and some powerful Keys to unlocking their personal history." It is also difficult to separate Nine Inch Nails from the commercialisation and colossal money-making machine that inevitably ensued on the MTV tour circuit: do we blame Michael Trent Reznor because most of his audience are unlikely to be familiar with 'first-wave' industrial bands including Cabaret Voltaire and the experiments of Genesis P. Orridge in Throbbing Gristle? Do we accuse Reznor of being a plagiarist just because he wears some of his influences -- Dr. Dre, Daft Punk, Atari Teenage Riot, Pink Floyd's The Wall (1979), Tom Waits's Bone Machine (1992), David Bowie's Low (1977) -- on his sleeve? And do we accept no-brain rock critic album reviews who quote lines like 'All the pieces didn't fit/Though I really didn't give a shit' ("Where Is Everybody?") or 'And when I suck you off/Not a drop will go to waste' ("Starfuckers Inc") as representative of his true personality? Reznor evidently has his own thoughts on this subject, but we should let the music speak for itself. The album's epic production and technical complexity turned into a post-modern studio Vision Quest, assisted by producer Alan Moulder, eleventh-hour saviour Bob Ezrin (brought in by Reznor to 'block-out' conceptual and sonic continuity), and a group of assault-technicians. The fruit of these collaborations is an album where Reznor is playing with our organism's time-binding sense, modulating strange emotions through deeply embedded tonal angularities. During his five-year absence, Trent Reznor fought diverse forms of repetitious trauma, from endogenous depression caused by endless touring to the death of his beloved grandmother (who raised him throughout childhood). An end signals a new beginning, a spiral is an open-ended and ever-shifting structure, and so Reznor sought to re-discover the Elder Gods within, a shamanic approach to renewal and secular salvation utilised most effectively by music PR luminary and scientist Howard Bloom. Concerned with healing the human animal through Ordeals that hard-wire the physiological baselines of Love, Hate and Fear, Reznor also focusses on what happens when 'meaning-making' collapses and hope for the future cannot easily be found. He accurately captures the confusion that such dissolution of meaning and decline of social institutions brings to the world -- Francis Fukuyama calls this bifurcation 'The Great Disruption'. For a generation who experienced their late childhood and early adolescence in Reagan's America, Reznor and his influences (Marilyn Manson and Filter) capture the Dark Side of recent history, unleashed at Altamont and mutating into the Apocalyptic style of American politics (evident in the 'Star Wars'/SDI fascination). The personal 'psychotic core' that was crystallised by the collapse of the nuclear family unit and supportive social institutions has returned to haunt us with dystopian fantasies that are played out across Internet streaming media and visceral MTV film-clips. That such cathartic releases are useful -- and even necessary (to those whose lives have been formed by socio-economic 'life conditions') is a point that escapes critics like Roger Scruton, some Christian Evangelists and the New Right. The 'escapist' quality of early 1980s 'Rapture' and 'Cosmocide' (Hal Lindsey) prophecies has yielded strange fruit for the Children of Ezekiel, whom Reznor and Marilyn Manson are unofficial spokes-persons for. From a macro perspective, Reznor's post-human evolutionary nexus lies, like J.G. Ballard's tales, in a mythical near-future built upon past memory-shards. It is the kind of worldview that fuses organic and morphogenetic structures with industrial machines run amok, thus The Fragile is an artefact that captures the subjective contents of the different mind produced by different times. Sonic events are in-synch but out of phase. Samples subtly trigger and then scramble kinaesthetic-visceral and kinaesthetic-tactile memories, suggestive of dissociated affective states or body memories that are incapable of being retrieved (van der Kolk 294). Perhaps this is why after a Century of Identity Confusion some fans find it impossible to listen to a 102-minute album in one sitting. No wonder then that the double album is divided into 'left' and 'right' discs (a reference to split-brain research?). The real-time track-by-track interpretation below is necessarily subjective, and is intended to serve as a provisional listener's guide to the aural ur-text of 1999. The Fragile is full of encrypted tones and garbled frequencies that capture a world where the future is always bleeding into a non-recoverable past. Turbulent wave-forms fight for the listener's attention with prolonged static lulls. This does not make for comfortable or even 'nice' listening. The music's mind is a snapshot, a critical indicator, of the deep structures brewing within the Weltanschauung that could erupt at any moment. "Somewhat Damaged" opens the album's 'Left' disc with an oscillating acoustic strum that anchor's the listener's attention. Offset by pulsing beats and mallet percussion, Reznor builds up sound layers that contrast with lyrical epitaphs like 'Everything that swore it wouldn't change is different now'. Icarus iconography is invoked, but perhaps a more fitting mythopoeic symbol of the journey that lies ahead would be Nietzsche's pursuit of his Ariadne through the labyrinth of life, during which the hero is steadily consumed by his numbing psychosis. Reznor fittingly comments: 'Didn't quite/Fell Apart/Where were you?' If we consider that Reznor has been repeating the same cycle with different variations throughout all of his music to date, retro-fitting each new album into a seamless tapestry, then this track signals that he has begun to finally climb out of self-imposed exile in the Underworld. "The Day the World Went Away" has a tremendously eerie opening, with plucked mandolin effects entering at 0:40. The main slashing guitar riff was interpreted by some critics as Reznor's attempt to parody himself. For some reason, the eerie backdrop and fragmented acoustic guitar strums recalls to my mind civil defence nuclear war films. Reznor, like William S. Burroughs, has some powerful obsessions. The track builds up in intensity, with a 'Chorus of the Damned' singing 'na na nah' over apocalyptic end-times imagery. At 4:22 the track ends with an echo that loops and repeats. "The Frail" signals a shift to mournful introspectiveness with piano: a soundtrack to faded 8 mm films and dying memories. The piano builds up slowly with background echo, holds and segues into ... "The Wretched", beginning with a savage downbeat that recalls earlier material from Pretty Hate Machine. 'The Far Aways/Forget It' intones Reznor -- it's becoming clear that despite some claims to the contrary, there is redemption in this album, but it is one borne out of a relentless move forward, a strive-drive. 'You're finally free/You could be' suggest Reznor studied Existentialism during his psychotherapy visits. This song contains perhaps the ultimate post-relationship line: 'It didn't turn out the way you wanted it to, did it?' It's over, just not the way you wanted; you can always leave the partner you're with, but the ones you have already left will always stain your memories. The lines 'Back at the beginning/Sinking/Spinning' recall the claustrophobic trapped world and 'eternal Now' dislocation of Post-Traumatic Stress Disorder victims. At 3:44 a plucked cello riff, filtered, segues into a sludge buzz-saw guitar solo. At 5:18 the cello riff loops and repeats. "We're in This Together Now" uses static as percussion, highlighting the influence of electricity flows instead of traditional rock instrument configurations. At 0:34 vocals enter, at 1:15 Reznor wails 'I'm impossible', showing he is the heir to Roger Waters's self-reflective rock-star angst. 'Until the very end of me, until the very end of you' reverts the traditional marriage vow, whilst 'You're the Queen and I'm the King' quotes David Bowie's "Heroes". Unlike earlier tracks like "Reptile", this track is far more positive about relationships, which have previously resembled toxic-dyads. Reznor signals a delta surge (breaking through barriers at any cost), despite a time-line morphing between present-past-future. At 5:30 synths and piano signal a shift, at 5:49 the outgoing piano riff begins. The film-clip is filled with redemptive water imagery. The soundtrack gradually gets more murky and at 7:05 a subterranean note signals closure. "The Fragile" is even more hopeful and life-affirming (some may even interpret it as devotional), but this love -- representative of the End-Times, alludes to the 'Glamour of Evil' (Nico) in the line 'Fragile/She doesn't see her beauty'. The fusion of synths and atonal guitars beginning at 2:13 summons forth film-clip imagery -- mazes, pageants, bald eagles, found sounds, cloaked figures, ruined statues, enveloping darkness. "Just like You Imagined" opens with Soundscapes worthy of Robert Fripp, doubled by piano and guitar at 0:39. Drums and muffled voices enter at 0:54 -- are we seeing a pattern to Reznor's writing here? Sonic debris guitar enters at 1:08, bringing forth intensities from white noise. This track is full of subtle joys like the 1:23-1:36 solo by David Bowie pianist Mike Garson and guitarist Adrian Belew's outgoing guitar solo at 2:43, shifting back to the underlying soundscapes at 3:07. The sounds are always on the dissipative edge of chaos. "Just like You Imagined" opens with Soundscapes worthy of Robert Fripp, doubled by piano and guitar at 0:39. Drums and muffled voices enter at 0:54 -- are we seeing a pattern to Reznor's writing here? Sonic debris guitar enters at 1:08, bringing forth intensities from white noise. This track is full of subtle joys like the 1:23-1:36 solo by David Bowie pianist Mike Garson and guitarist Adrian Belew's outgoing guitar solo at 2:43, shifting back to the underlying soundscapes at 3:07. The sounds are always on the dissipative edge of chaos. "Pilgrimage" utilises a persistent ostinato and beat, with a driving guitar overlay at 0:18. This is perhaps the most familiar track, using Reznor motifs like the doubling of the riff with acoustic guitars between 1:12-1:20, march cries, and pitch-shift effects on a 3:18 drumbeat/cymbal. Or at least I could claim it was familiar, if it were not that legendary hip-hop producer and 'edge-of-panic' tactilist Dr. Dre helped assemble the final track mix. "No, You Don't" has been interpreted as an attack on Marilyn Manson and Hole's Courntey Love, particularly the 0:47 line 'Got to keep it all on the outside/Because everything is dead on the inside' and the 2:33 final verse 'Just so you know, I did not believe you could sink so low'. The song's structure is familiar: a basic beat at 0:16, guitars building from 0:31 to sneering vocals, a 2:03 counter-riff that merges at 2:19 with vocals and ascending to the final verse and 3:26 final distortion... "La Mer" is the first major surprise, a beautiful and sweeping fusion of piano, keyboard and cello, reminiscent of Symbolist composer Debussy. At 1:07 Denise Milfort whispers, setting the stage for sometime Ministry drummer Bill Reiflin's jazz drumming at 1:22, and a funky 1:32 guitar/bass line. The pulsing synth guitar at 2:04 serves as anchoring percussion for a cinematic electronica mindscape, filtered through new layers of sonic chiaroscuro at 2:51. 3:06 phase shifting, 3:22 layer doubling, 3:37 outgoing solo, 3:50-3:54 more swirling vocal fragments, seguing into a fading cello quartet as shadows creep. David Carson's moody film-clip captures the end more ominously, depicting the beauty of drowning. This track contains the line 'Nothing can stop me now', which appears to be Reznor's personal mantra. This track rivals 'Hurt' and 'A Warm Place' from The Downward Spiral and 'Something I Can Never Have' from Pretty Hate Machine as perhaps the most emotionally revealing and delicate material that Reznor has written. "The Great Below" ends the first disc with more multi-layered textures fusing nostalgia and reverie: a twelve-second cello riff is counter-pointed by a plucked overlay, which builds to a 0:43 washed pulse effect, transformed by six second pulses between 1:04-1:19 and a further effects layer at 1:24. E-bow effects underscore lyrics like 'Currents have their say' (2:33) and 'Washes me away' (2:44), which a 3:33 sitar riff answers. These complexities are further transmuted by seemingly random events -- a 4:06 doubling of the sitar riff which 'glitches' and a 4:32 backbeat echo that drifts for four bars. While Reznor's lyrics suggest that he is unable to control subjective time-states (like The Joker in the Batman: Dark Knight series of Kali-yuga comic-books), the track constructions show that the Key to his hold over the listener is very carefully constructed songs whose spaces resemble Pythagorean mathematical formulas. Misdirecting the audience is the secret of many magicians. "The Way Out Is Through" opens the 'Right' disc with an industrial riff that builds at 0:19 to click-track and rhythm, the equivalent of a weaving spiral. Whispering 'All I've undergone/I will keep on' at 1:24, Reznor is backed at 1:38 by synths and drums coalescing into guitars, which take shape at 1:46 and turn into a torrential electrical current. The models are clearly natural morphogenetic structures. The track twists through inner storms and torments from 2:42 to 2:48, mirrored by vocal shards at 2:59 and soundscapes at 3:45, before piano fades in and out at 4:12. The title references peri-natal theories of development (particularly those of Stanislav Grof), which is the source of much of the album's imagery. "Into the Void" is not the Black Sabbath song of the same name, but a catchy track that uses the same unfolding formula (opening static, cello at 0:18, guitars at 0:31, drums and backbeat at 1:02, trademark industrial vocals and synth at 1:02, verse at 1:23), and would not appear out of place in a Survival Research Laboratories exhibition. At 3:42 Reznor plays with the edge of synth soundscapes, merging vocals at 4:02 and ending the track nicely at 4:44 alone. "Where Is Everybody?" emulates earlier structures, but relies from 2:01 on whirring effects and organic rhythms, including a flurry of eight beat pulses between 2:40-2:46 and a 3:33 spiralling guitar solo. The 4:26 guitar solo is pure Adrian Belew, and is suddenly ended by spluttering static and white noise at 5:13. "The Mark Has Been Made" signals another downshift into introspectiveness with 0:32 ghostly synth shimmers, echoed by cello at 1:04 which is the doubled at 1:55 by guitar. At 2:08 industrial riffs suddenly build up, weaving between 3:28 distorted guitars and the return of the repressed original layer at 4:16. The surprise is a mystery 32 second soundscape at the end with Reznor crooning 'I'm getting closer, all the time' like a zombie devil Elvis. "Please" highlights spacious noise at 0:48, and signals a central album motif at 1:04 with the line 'Time starts slowing down/Sink until I drown'. The psychic mood of the album shifts with the discovery of Imagination as a liberating force against oppression. The synth sound again is remarkably organic for an industrial album. "Starfuckers Inc" is the now infamous sneering attack on rock-stardom, perhaps at Marilyn Manson (at 3:08 Reznor quotes Carly Simon's 'You're So Vain'). Jungle beats and pulsing synths open the track, which features the sound-sculpting talent of Pop Will Eat Itself member Clint Mansell. Beginning at 0:26, Reznor's vocals appear to have been sampled, looped and cut up (apologies to Brion Gysin and William S. Burroughs). The lines 'I have arrived and this time you should believe the hype/I listened to everyone now I know everyone was right' is a very savage and funny exposure of Manson's constant references to Friedrich Nietzsche's Herd-mentality: the Herd needs a bogey-man to whip it into submission, and Manson comes dangerous close to fulfilling this potential, thus becoming trapped by a 'Stacked Deck' paradox. The 4:08 lyric line 'Now I belong I'm one of the Chosen Ones/Now I belong I'm one of the Beautiful Ones' highlights the problem of being Elect and becoming intertwined with institutionalised group-think. The album version ditches the closing sample of Gene Simmons screaming "Thankyou and goodnight!" to an enraptured audience on the single from KISS Alive (1975), which was appropriately over-the-top (the alternate quiet version is worth hearing also). "The danger Marilyn Manson faces", notes Don Webb (current High Priest of the Temple of Set), "is that he may end up in twenty years time on the 'Tonight Show' safely singing our favourite songs like a Goth Frank Sinatra, and will have gradually lost his antinomian power. It's much harder to maintain the enigmatic aura of an Evil villain than it is to play the clown with society". Reznor's superior musicianship and sense of irony should keep him from falling into the same trap. "Complication" juggernauts in at 0:57 with screaming vocals and a barrage of white noise at 1:56. It's clear by now that Reznor has read his psychological operations (PSYOP) manuals pertaining to blasting the hell out of his audiences' psyche by any means necessary. Computer blip noise and black light flotation tank memories. Dislocating pauses and time-bends. The aural equivalent of Klein bottles. "Complication" juggernauts in at 0:57 with screaming vocals and a barrage of white noise at 1:56. It's clear by now that Reznor has read his psychological operations (PSYOP) manuals pertaining to blasting the hell out of his audiences' psyche by any means necessary. Computer blip noise and black light flotation tank memories. Dislocating pauses and time-bends. The aural equivalent of Klein bottles. "The Big Come Down" begins with a four-second synth/static intro that is smashed apart by a hard beat at 0:05 and kaleidoscope guitars at 0:16. Critics refer to the song's lyrics in an attempt to project a narcissistic Reznor personality, but don't comment on stylistic tweaks like the AM radio influenced backing vocals at 1:02 and 1:19, or the use of guitars as a percussion layer at 1:51. A further intriguing element is the return of the fly samples at 2:38, an effect heard on previous releases and a possible post-human sub-text. The alien mythos will eventually reign over the banal and empty human. At 3:07 the synths return with static, a further overlay adds more synths at 3:45 as the track spirals to its peak, before dissipating at 3:1 in a mesh of percussion and guitars. "Underneath It All" opens with a riff that signals we have reached the album's climatic turning point, with the recurring theme of fragmenting body-memories returning at 0:23 with the line 'All I can do/I can still feel you', and being echoed by pulsing static at 0:42 as electric percussion. A 'Messiah Complex' appears at 1:34 with the line 'Crucify/After all I've died/After all I've tried/You are still inside', or at least it appears to be that on the surface. This is the kind of line that typical rock critics will quote, but a careful re-reading suggests that Reznor is pointing to the painful nature of remanifesting. Our past shapes us more than we would like to admit particularly our first relationships. "Ripe (With Decay)" is the album's final statement, a complex weaving of passages over a repetitive mesh of guitars, pulsing echoes, back-beats, soundscapes, and a powerful Mike Garson piano solo (2:26). Earlier motifs including fly samples (3:00), mournful funeral violas (3:36) and slowing time effects (4:28) recur throughout the track. Having finally reached the psychotic core, Reznor is not content to let us rest, mixing funk bass riffs (4:46), vocal snatches (5:23) and oscillating guitars (5:39) that drag the listener forever onwards towards the edge of the abyss (5:58). The final sequence begins at 6:22, loses fidelity at 6:28, and ends abruptly at 6:35. At millennium's end there is a common-held perception that the world is in an irreversible state of decay, and that Culture is just a wafer-thin veneer over anarchy. Music like The Fragile suggests that we are still trying to assimilate into popular culture the 'war-on-Self' worldviews unleashed by the nineteenth-century 'Masters of Suspicion' (Charles Darwin, Sigmund Freud, Friedrich Nietzsche). This 'assimilation gap' is evident in industrial music, which in the late 1970s was struggling to capture the mood of the Industrial Revolution and Charles Dickens, so the genre is ripe for further exploration of the scarred psyche. What the self-appointed moral guardians of the Herd fail to appreciate is that as the imprint baseline rises (reflective of socio-political realities), the kind of imagery prevalent throughout The Fragile and in films like Strange Days (1995), The Matrix (1999) and eXistenZ (1999) is going to get even darker. The solution is not censorship or repression in the name of pleasing an all-saving surrogate god-figure. No, these things have to be faced and embraced somehow. Such a process can only occur if there is space within for the Sadeian aesthetic that Nine Inch Nails embodies, and not a denial of Dark Eros. "We need a second Renaissance", notes Don Webb, "a rejuvenation of Culture on a significant scale". In other words, a global culture-shift of quantum (aeon or epoch-changing) proportions. The tools required will probably not come just from the over-wordy criticism of Cyber-culture and Cultural Studies or the logical-negative feeding frenzy of most Music Journalism. They will come from a dynamic synthesis of disciplines striving toward a unity of knowledge -- what socio-biologist Edward O. Wilson has described as 'Consilience'. Liberating tools and ideas will be conveyed to a wider public audience unfamiliar with such principles through predominantly science fiction visual imagery and industrial/electronica music. The Fragile serves as an invaluable model for how such artefacts could transmit their dreams and propagate their messages. For the hyper-alert listener, it will be the first step on a new journey. But sadly for the majority, it will be just another hysterical industrial album promoted as selection of the month. References Bester, Alfred. The Stars My Destination. London: Millennium Books, 1999. Eshun, Kodwo. More Brilliant than the Sun: Adventures in Sonic Fiction. London: Quartet Books, 1998. Van der Kolk, Bessel A. "Trauma and Memory." Traumatic Stress: The Effects of Overwhelming Experience on Mind, Body, and Society. Eds. Bessel A. van der Kolk et al. New York: Guilford Press, 1996. Nine Inch Nails. Downward Spiral. Nothing/Interscope, 1994. ---. The Fragile. Nothing, 1999. ---. Pretty Hate Machine. TVT, 1989. Citation reference for this article MLA style: Alex Burns. "'This Machine Is Obsolete': A Listeners' Guide to Nine Inch Nails' The Fragile." M/C: A Journal of Media and Culture 2.8 (1999). [your date of access] <http://www.uq.edu.au/mc/9912/nine.php>. Chicago style: Alex Burns, "'This Machine Is Obsolete': A Listeners' Guide to Nine Inch Nails' The Fragile," M/C: A Journal of Media and Culture 2, no. 8 (1999), <http://www.uq.edu.au/mc/9912/nine.php> ([your date of access]). APA style: Alex Burns. (1999) 'This machine is obsolete': a listeners' guide to Nine Inch Nails' The fragile. M/C: A Journal of Media and Culture 2(8). <http://www.uq.edu.au/mc/9912/nine.php> ([your date of access]).

The contemporary video game market is as recognisable for its brands as it is for the characters that populate their game worlds, from franchise-leading characters like Garrus Vakarian (Mass Effect original trilogy), Princess Zelda (The Legend of Zelda franchise) and Cortana (HALO franchise) to more recent game icons like Miles Morales (Marvel's Spiderman game franchise) and Judy Alvarez (Cyberpunk 2077). Interactions with these casts of characters enhance the richness of games and their playable worlds, giving a sense of weight and meaning to player actions, emphasising thematic interests, and in some cases acting as buffers to (or indeed hindering) different aspects of gameplay itself. As Jordan Erica Webber writes in her essay The Road to Journey, “videogames are often examined through the lens of what you do and what you feel” (14). For many games, the design of interactions between the player and other beings in the world—whether they be intrinsic to the world (non-playable characters or NPCs) or other live players—is a bridging aspect between what you do and how you feel and is thus central to the communication of more cohesive and focussed work. This essay will discuss two examples of game design techniques present in Transistor by Supergiant Games and Journey by thatgamecompany. It will consider how the design of “playful” interactions between the player and other characters in the game world (both non-player characters and other player characters) can be used as a tool to align a player’s experience of “intent” with the thematic objectives of the designer. These games have been selected as both utilise design techniques that allow for this “playful” interaction (observed in this essay as interactions that do not contribute to “progression” in the traditional sense). By looking closely at specific aspects of game design, it aims to develop an accessible examination by “focusing on the dimensions of involvement the specific game or genre of games affords” (Calleja, 222). The discussion defines “intent”, in the context of game design, through a synthesis of definitions from two works by game designers. The first being Greg Costikyan’s definition of game structure from his 2002 presentation I Have No Words and I Must Design, a paper subsequently referenced by numerous prominent game scholars including Ian Bogost and Jesper Juul. The second is Steven Swink’s definition of intent in relation to video games, from his 2009 book Game Feel: A Game Designer’s Guide to Virtual Sensation—an extensive reference text of game design concepts, with a particular focus on the concept of “game feel” (the meta-sensation of involvement with a game). This exploratory essay suggests that examining these small but impactful design techniques, through the lens of their contribution to overall intent, is a useful tool for undertaking more holistic studies of how games are affective. I align with the argument that understanding “playfulness” in game design is useful in understanding user engagement with other digital communication platforms. In particular, platforms where the presentation of user identity is relational or performative to others—a case explored in Playful Identities: The Ludification of Digital Media Cultures (Frissen et al.). Intent in Game Design Intent, in game design, is generated by a complex, interacting economy, ecosystem, or “game structure” (Costikyan 21) of thematic ideas and gameplay functions that do not dictate outcomes, but rather guide behaviour and progression forward through the need to achieve a goal (Costikyan 21). Intent brings player goals in line with the intrinsic goals of the player character, and the thematic or experiential goals the game designer wants to convey through the act of play. Intent makes it easier to invest in the game’s narrative and spatial context—its role is to “motivate action in game worlds” (Swink 67). Steven Swink writes that it is the role of game design to create compelling intent from “a seemingly arbitrary collection of abstracted variables” (Swink 67). He continues that whether it is good or bad is a broader question, but that “most games do have in-born intentionality, and it is the game designer who creates it” (67). This echoes Costikyan’s point: game designers “must consciously set out to decide what kind of experiences [they] want to impart to players and create systems that enable those experiences” (20). Swink uses Mario 64 as one simple example of intent creation through design—if collecting 100 coins did not restore Mario’s health, players would simply not collect them. Not having health restricts the ability for players to fulfil the overarching intent of progression by defeating the game’s main villain (what he calls the “explicit” intent), and collecting coins also provides a degree of interactivity that makes the exploration itself feel more fulfilling (the “implicit” intent). This motivation for action may be functional, or it may be more experiential—how a designer shapes variables into particular forms to encourage the particular kinds of experience that they want a player to have during the act of play (such as in Journey, explored in the latter part of this essay). This essay is interested in the design of this compelling thematic intent—and the role “playful” interactions have as a variable that contributes to aligning player behaviours and experience to the thematic or experiential goals of game design. “Playful” Communication and Storytelling in Transistor Transistor is the second release from independent studio Supergiant Games and has received over 100 industry accolades (Kasavin) since its publication in 2014. Transistor incorporates the suspense of turn-based gameplay into an action role-playing game—neatly mirroring a style of gameplay to the suspense of its cyber noir narrative. The game is also distinctly “artful”. The city of Cloudbank, where the game takes place, is a cyberpunk landscape richly inspired by art nouveau and art deco style. There is some indication that Cloudbank may not be a real city at all—but rather a virtual city, with an abundance of computer-related motifs and player combat abilities named as if they were programming functions. At release, Transistor was broadly recognised in the industry press for its strength in “combining its visuals and music to powerfully convey narrative information and tone” (Petit). If intent in games in part stems from a unification of goals between the player and design, the interactivity between player input and the actions of the player character furthers this sense of “togetherness”. This articulation and unity of hand movement and visual response in games are what Kirkpatrick identified in his 2011 work Aesthetic Theory and the Video Game as the point in which videogames “broke from the visual entertainment culture of the last two centuries” (Kirkpatrick 88). The player character mediates access to the space by which all other game information is given context and allows the player a degree of self-expression that is unique to games. Swink describes it as an amplified impression of virtual proprioception, that is “an impression of space created by illusory means but is experienced as real by the senses … the effects of motion, sound, visuals, and responsive effects combine” (Swink 28). If we extend Swink’s point about creating an “impression of space” to also include an “impression of purpose”, we can utilise this observation to further understand how the design of the playful interactions in Transistor work to develop and align the player’s experience of intent with the overarching narrative goal (or, “explicit” intent) of the game—to tell a compelling “science-fiction love story in a cyberpunk setting, without the gritty backdrop” (Wallace) through the medium of gameplay. At the centre of any “love story” is the dynamic of a relationship, and in Transistor playful interaction is a means for conveying the significance and complexity of those dynamics in relation to the central characters. Transistor’s exposition asks players to figure out what happened to Red and her partner, The Boxer (a name he is identified by in the game files), while progressing through various battles with an entity called The Process to uncover more information. Transistor commences with player-character, Red, standing next to the body of The Boxer, whose consciousness and voice have been uploaded into the same device that impaled him: the story’s eponymous Transistor. The event that resulted in this strange circumstance has also caused Red to lose her ability to speak, though she is still able to hum. The first action that the player must complete to progress the game is to pull the Transistor from The Boxer’s body. From this point The Boxer, speaking through the Transistor, becomes the sole narrator of the game. The Boxer’s first lines of dialogue are responsive to player action, and position Red’s character in the world: ‘Together again. Heh, sort of …’ [Upon walking towards an exit a unit of The Process will appear] ‘Yikes … found us already. They want you back I bet. Well so do I.’ [Upon defeating The Process] ‘Unmarked alley, east of the bay. I think I know where we are.’ (Supergiant Games) This brief exchange and feedback to player movement, in medias res, limits the player’s possible points of attention and establishes The Boxer’s voice and “character” as the reference point for interacting with the game world. Actions, the surrounding world, and gameplay objectives are given meaning and context by being part of a system of intent derived from the significance of his character to the player character (Red) as both a companion and information-giver. The player may not necessarily feel what an individual in Red’s position would feel, but their expository position is aligned with Red’s narrative, and their scope of interaction with the world is intrinsically tied to the “explicit” intent of finding out what happened to The Boxer. Transistor continues to establish a loop between Red’s exploration of the world and the dialogue and narration of The Boxer. In the context of gameplay, player movement functions as the other half of a conversation and brings the player’s control of Red closer to how Red herself (who cannot communicate vocally) might converse with The Boxer gesturally. The Boxer’s conversational narration is scripted to occur as Red moves through specific parts of the world and achieves certain objectives. Significantly, The Boxer will also speak to Red in response to specific behaviours that only occur should the player choose to do them and that don’t necessarily contribute to “progressing” the game in the mechanical sense. There are multiple points where this is possible, but I will draw on two examples to demonstrate. Firstly, The Boxer will have specific reactions to a player who stands idle for too long, or who performs a repetitive action. Jumping repeatedly from platform to platform will trigger several variations of playful and exasperated dialogue from The Boxer (who has, at this point, no choice but to be carried around by Red): [Upon repeatedly jumping between the same platform] ‘Round and round.’ ‘Okay that’s enough.’ ‘I hate you.’ (Supergiant Games) The second is when Red “hums” (an activity initiated by the player by holding down R1 on a PlayStation console). At certain points of play, when making Red hum, The Boxer will chime in and sing the lyrics to the song she is humming. This musical harmonisation helps to articulate a particular kind of intimacy and flow between Red and The Boxer —accentuated by Red’s animation when humming: she is bathed in golden light and holds the Transistor close, swaying side to side, as if embracing or dancing with a lover. This is a playful, exploratory interaction. It technically doesn’t serve any “purpose” in terms of finishing the game—but is an action a player might perform while exploring controls and possibilities of interactivity, in turn exploring what it is to “be” Red in relation to the game world, the story being conveyed, and The Boxer. It delivers a more emotional and affective thematic idea about a relationship that nonetheless relies just as much on mechanical input and output as engaging in movement, exploration, and combat in the game world. It’s a mechanic that provides texture to the experience of inhabiting Red’s identity during play, showcasing a more individual complexity to her story, driven by interactivity. In techniques like this, Transistor directly unifies its method for information-giving, interactivity, progression, and theme into a single design language. To once again nod to Swink and Costikyan, it is a complex, interacting economy or ecosystem of thematic ideas and gameplay structures that guide behaviour and progression forward through the need to achieve a single goal (Costikyan 21), guiding the player towards the game’s “explicit” intent of investment in its “science fiction love story”. Companionship and Collaboration in Journey Journey is regularly praised in many circles of game review and discussion for its powerful, pared-back story conveyed through its exceptional game design. It has won a wide array of awards, including multiple British Academy Games Awards and Game Developer’s Choice Awards, and has been featured in highly regarded international galleries such as the Victoria and Albert Museum in London. Its director, Jenova Chen, articulated that the goal of the game (and thus, in the context of this essay, the intent) was “to create a game where people who interact with each other in an online community can connect at an emotional level, regardless of their gender, age, ethnicity, and social status” (Webber 14). In Journey, the player controls a small robed figure moving through a vast desert—the only choices for movement are to slide gracefully through the sand or to jump into the air by pressing the X button (on a PlayStation console), and gracefully float down to the ground. You cannot attack anything or defend yourself from the elements or hostile beings. Each player will “periodically find another individual in the landscape” (Isbister 121) of similar design to the player and can only communicate with them by experimenting with simple movements, and via short chirping noises. As the landscape itself is vast and unknown, it is what one player referred to as a sense of “reliance on one another” that makes the game so captivating (Isbister 12). Much like The Boxer in Transistor, the other figure in Journey stands out as a reference point and imbues a sense of collaboration and connection that makes the goal to reach the pinprick of light in the distance more meaningful. It is only after the player has finished the game that the screen reveals the other individual is a real person, another player, by displaying their gamer tag. One player, playing the game in 2017 (several years after its original release in 2012), wrote: I went through most of the game by myself, and when I first met my companion, it was right as I walked into the gate transitioning to the snow area. And I was SO happy that there was someone else in this desolate place. I felt like it added so much warmth to the game, so much added value. The companion and I stuck together 100% of the way. When one of us would fall the slightest bit behind, the other would wait for them. I remember saying out loud how I thought that my companion was the best programmed AI that I had ever seen. In the way that he waited for me to catch up, it almost seemed like he thanked me for waiting for him … We were always side-by-side which I was doing to the "AI" for "cinematic-effect". From when I first met him up to the very very end, we were side-by-side. (Peace_maybenot) Other players indicate a similar bond even when their companion is perhaps less competent: I thought my traveller was a crap AI. He kept getting launched by the flying things and was crap at staying behind cover … But I stuck with him because I was like, this is my buddy in the game. Same thing, we were communicating the whole time and I stuck with him. I finish and I see a gamer tag and my mind was blown. That was awesome. (kerode4791) Although there is a definite object of difference in that Transistor is narrated and single-player while Journey is not, there are some defined correlations between the way Supergiant Games and thatgamecompany encourage players to feel a sense of investment and intent aligned with another individual within the game to further thematic intent. Interactive mechanics are designed to allow players a means of playful and gestural communication as an extension of their kinetic interaction with the game; travellers in Journey can chirp and call out to other players—not always for an intrinsic goal but often to express joy, or just to experience and sense of connectivity or emotional warmth. In Transistor, the ability to hum and hear The Boxer’s harmony, and the animation of Red holding the Transistor close as she does so, implying a sense of protectiveness and affection, says more in the context of “play” than a literal declaration of love between the two characters. Graeme Kirkpatrick uses dance as a suitable metaphor for this kind of experience in games, in that both are characterised by a certainty that communication has occurred despite the “eschewal of overt linguistic elements and discursive meanings” (120). There is also a sense of finite temporality in these moments. Unlike scripted actions, or words on a page, they occur within a moment of being that largely belongs to the player and their actions alone. Kirkpatrick describes it as “an inherent ephemerality about this vanishing and that this very transience is somehow essential” (120). This imbuing of a sense of time is important because it implies that even if one were to play the game again, repeating the interaction is impossible. The communication of narrative within these games is not a static form, but an experience that hangs unique at that moment and space of play. Thatgamecompany discussed in their 2017 interviews with Webber, published as part of her essay for the Victoria & Albert’s Video Games: Design/Play/Disrupt exhibition, how by creating and restricting the kind of playful interaction available to players within the world, they could encourage the kind of emotional, collaborative, and thoughtful intent they desired to portray (Webber 14). They articulate how in the development process they prioritised giving the player a variety of responses for even the smallest of actions and how that positive feedback, in turn, encourages play and prevented players from being “bored” (Webber 22). Meanwhile, the team reduced responsiveness for interactions they didn’t want to encourage. Chen describes the approach as “maximising feedback for things you want and minimising it for things you don’t want” (Webber 27). In her essay, Webber writes that Chen describes “a person who enters a virtual world, leaving behind the value system they’ve learned from real life, as like a baby banging their spoon to get attention” (27): initially players could push each other, and when one baby [player] pushed the other baby [player] off the cliff that person died. So, when we tested the gameplay, even our own developers preferred killing each other because of the amount of feedback they would get, whether it’s visual feedback, audio feedback, or social feedback from the players in the room. For quite a while I was disappointed at our own developers’ ethics, but I was able to talk to a child psychologist and she was able to clarify why these people are doing what they are doing. She said, ‘If you want to train a baby not to knock the spoon, you should minimise the feedback. Either just leave them alone, and after a while they’re bored and stop knocking, or give them a spoon that does not make a sound. (27) The developers then made it impossible for players to kill, steal resources from, or even speak to each other. Players were encouraged to stay close to each other using high-feedback action and responsiveness for doing so (Webber 27). By using feedback design techniques to encourage players to behave a certain way to other beings in the world—both by providing and restricting playful interactivity—thatgamecompany encourage a resonance between players and the overarching design intent of the project. Chen’s observations about the behaviour of his team while playing different iterations of the game also support the argument (acknowledged in different perspectives by various scholarship, including Costikyan and Bogost) that in the act of gameplay, real-life personal ethics are to a degree re-prioritised by the interactivity and context of that interactivity in the game world. Intent and the “Actualities of (Game) Existence” Continuing and evolving explorations of “intent” (and other parallel terms) in games through interaction design is of interest for scholars of game studies; it also is an important endeavour when considering influential relationships between games and other digital mediums where user identity is performative or relational to others. This influence was examined from several perspectives in the aforementioned collection Playful Identities: The Ludification of Digital Media Cultures, which also examined “the process of ludification that seems to penetrate every cultural domain” of modern life, including leisure time, work, education, politics, and even warfare (Frissen et al. 9). Such studies affirm the “complex relationship between play, media, and identity in contemporary culture” and are motivated “not only by the dominant role that digital media plays in our present culture but also by the intuition that ‘“play is central … to media experience” (Frissen et al. 10). Undertaking close examinations of specific “playful” design techniques in video games, and how they may factor into the development of intent, can help to develop nuanced lines of questioning about how we engage with “playfulness” in other digital communication platforms in an accessible, comparative way. We continue to exist in a world where “ludification is penetrating the cultural domain”. In the first few months of the global COVID-19 pandemic, Nintendo released Animal Crossing: New Horizons. With an almost global population in lockdown, Animal Crossing became host to professional meetings (Espiritu), weddings (Garst), and significantly, a media channel for brands to promote content and products (Deighton). TikTok, panoramically, is a platform where “playful” user trends— dances, responding to videos, the “Tell Me … Without Telling Me” challenge—occur in the context of an extremely complex algorithm, that while automated, is created by people—and is thus unavoidably embedded with bias (Dias et al.; Noble). This is not to say that game design techniques and broader “playful” design techniques in other digital communication platforms are interchangeable by any measure, or that intent in a game design sense and intent or bias in a commercial sense should be examined through the same lens. Rather that there is a useful, interdisciplinary resource of knowledge that can further illuminate questions we might ask about this state of “ludification” in both the academic and public spheres. We might ask, for example, what would the implications be of introducing an intent design methodology similar to Journey, but using it for commercial gain? Or social activism? Has it already happened? There is a quotation from Nathan Jurgensen’s 2016 essay Fear of Screens (published in The New Inquiry) that often comes to my mind when thinking about interaction design in video games in this way. In his response to Sherry Turkle’s book, Reclaiming Conversation, Jurgensen writes: each time we say “IRL,” “face-to-face,” or “in person” to mean connection without screens, we frame what is “real” or who is a person in terms of their geographic proximity rather than other aspects of closeness — variables like attention, empathy, affect, erotics, all of which can be experienced at a distance. We should not conceptually preclude or discount all the ways intimacy, passion, love, joy, pleasure, closeness, pain, suffering, evil and all the visceral actualities of existence pass through the screen. “Face to face” should mean more than breathing the same air. (Jurgensen) While Jurgensen is not talking about communication in games specifically, there are comparisons to be drawn between his “variables” and “visceral actualities of existence” as the drivers of social meaning-making, and the methodology of games communicating intent and purpose through Swink’s “seemingly arbitrary collection of abstracted variables” (67). When players interact with other characters in a game world (whether they be NPCs or other players), they are inhabiting a shared virtual space, and how designers articulate and present the variables of “closeness”, as Jurgensen defines it, can shape player alignment with the overarching design intent. These design techniques take the place of Jurgensen’s “visceral actualities of existence”. While they may not intrinsically share an overarching purpose, their experiential qualities have the ability to align ethics, priorities, and values between individuals. Interactivity means game design has the potential to facilitate a particular kind of engagement for the player (as demonstrated in Journey) or give opportunities for players to explore a sense of what an emotion might feel like by aligning it with progression or playful activity (as discussed in relation to Transistor). Players may not “feel” exactly what their player-characters do, or care for other characters in the world in the same way a game might encourage them to, but through thoughtful intent design, something of recognition or unity of belief might pass through the screen. References Bogost, Ian. Persuasive Games: The Expressive Power of Video Games. MIT P, 2007. Calleja, Gordon. “Ludic Identities and the Magic Circle.” Playful Identities: The Ludification of Digital Media Cultures. Eds. Valerie Frissen et al. Amsterdam UP, 2015. 211–224. Costikyan, Greg. “I Have No Words & I Must Design: Toward a Critical Vocabulary for Games.” Computer Games and Digital Cultures Conference Proceedings 2002. Ed. Frans Mäyrä. Tampere UP. 9-33. Dias, Avani, et al. “The TikTok Spiral.” ABC News, 26 July 2021. <https://www.abc.net.au/news/2021-07-26/tiktok-algorithm-dangerous-eating-disorder-content-censorship/100277134>. Deighton, Katie. “Animal Crossing Is Emerging as a Media Channel for Brands in Lockdown.” The Drum, 21 Apr. 2020. <https://www.thedrum.com/news/2020/04/21/animal-crossing-emerging-media-channel-brands-lockdown>. Espiritu, Abby. “Japanese Company Attempts to Work Remotely in Animal Crossing: New Horizons.” The Gamer, 29 Mar. 2020. <https://www.thegamer.com/animal-crossing-new-horizons-work-remotely/>. Frissen, Valerie, et al., eds. Playful Identities: The Ludification of Digital Media Cultures. Amsterdam UP, 2015. Garst, Aron. “The Pandemic Canceled Their Wedding. So They Held It in Animal Crossing.” The Washington Post, 2 Apr. 2020. <https://www.washingtonpost.com/video-games/2020/04/02/animal-crossing-wedding-coronavirus/>. Isbister, Katherine. How Games Move Us: Emotion by Design. MIT P, 2016. Journey. thatgamecompany. 2012. Jurgensen, Nathan. “Fear of Screens.” The New Inquiry, 25 Jan. 2016. <https://thenewinquiry.com/fear-of-screens/>. Kasavin, Greg. “Transistor Earns More than 100+ Industry Accolades, Sells More than 600k Copies.” Supergiant Games, 8 Jan. 2015. <https://www.supergiantgames.com/blog/transistor-earns60-industry-accolades-sells-more-than-600k-copies/>. kerode4791. "Wanted to Share My First Experience with the Game, It Was That Awesome.”Reddit, 22 Mar. 2017. <https://www.reddit.com/r/JourneyPS3/comments/60u0am/wanted_to_share_my_f rst_experience_with_the_game/>. Kirkpatrick, Graeme. Aesthetic Theory and the Video Game. Manchester UP, 2011. Noble, Safiya Umoja. Algorithms of Oppression: How Search Engines Reinforce Racism. New York UP, 2018. peace_maybenot. "Wanted to Share My First Experience with the Game, It Was that Awesome” Reddit, 22 Mar. 2017. <https://www.reddit.com/r/JourneyPS3/comments/60u0am/wanted_to_share_my_f rst_experience_with_the_game/>. Petit, Carolyn. “Ghosts in the Machine." Gamespot, 20 May 2014. <https://www.gamespot.com/reviews/transistor-review/1900-6415763/>. Swink, Steve. Game Feel: A Game Designer’s Guide to Virtual Sensation. Amsterdam: Morgan Kaufmann Publishers/Elsevier, 2009. Transistor. Supergiant Games. 2014. Wallace, Kimberley. “The Story behind Supergiant Games’ Transistor.” Gameinformer, 20 May 2021. <https://www.gameinformer.com/2021/05/20/the-story-behind-supergiant-games-transistor>. Webber, Jordan Erica. “The Road to Journey.” Videogames: Design/Play/Disrupt. Eds. Marie Foulston and Kristian Volsing. V&A Publishing, 2018. 14–31.

Practically any good story follows certain narrative conventions in order to hold its readers' attention and leave them with a feeling of satisfaction -- this goes for fictional tales as well as for many news reports (we do tend to call them 'news stories', after all), for idle gossip as well as for academic papers. In the Western tradition of storytelling, it's customary to start with the exposition, build up to major events, and end with some form of narrative closure. Indeed, audience members will feel disturbed if there is no sense of closure at the end -- their desire for closure is a powerful one. From this brief description of narrative patterns it is also clear that such narratives depend crucially on linear progression through the story in order to work -- there may be flashbacks and flashforwards, but very few stories, it seems, could get away with beginning with their point of closure, and work back to the exposition. Closure, as the word suggests, closes the story, and once reached, the audience is left with the feeling of now knowing the whole story, of having all the pieces necessary to understand its events. To understand how important the desire to reach this point is to the audience, just observe the discussions of holes in the plot which people have when they're leaving a cinema: they're trying to reach a better sense of closure than was afforded them by the movie itself. In linearly progressing media, this seems, if you'll pardon the pun, straightforward. Readers know when they've finished an article or a book, viewers know when a movie or a broadcast is over, and they'll be able to assess then if they've reached sufficient closure -- if their desires have been fulfilled. On the World Wide Web, this is much more difficult: "once we have it in our hands, the whole of a book is accessible to us readers. However, in front of an electronic read-only hypertext document we are at the mercy of the author since we will only be able to activate the links which the author has provided" (McKnight et al. 119). In many cases, it's not even clear whether we've reached the end of the text already: just where does a Website end? Does the question even make sense? Consider the following example, reported by Larry Friedlander: I watched visitors explore an interactive program in a museum, one that contained a vast amount of material -- pictures, film, historic explanations, models, simulations. I was impressed by the range of subject matter and by the ambitiousness and polish of the presentation. ... But to my surprise, as I watched visitors going down one pathway after another, I noticed a certain dispirited glaze spread over their faces. They seemed to lose interest quite quickly and, in fact, soon stopped their explorations. (163) Part of the problem here may just have been the location of the programme, of course -- when you're out in public, you might just not have the time to browse as extensively as you could from your computer at home. But there are other explanations, too: the sheer amount of options for exploration may have been overwhelming -- there may not have been any apparent purpose to aim for, any closure to arrive at. This is a problem inherent in hypertext, particularly in networked systems like the Web: it "changes our conception of an ending. Different readers can choose not only to end the text at different points but also to add to and extend it. In hypertext there is no final version, and therefore no last word: a new idea or reinterpretation is always possible. ... By privileging intertextuality, hypertext provides a large number of points to which other texts can attach themselves" (Snyder 57). In other words, there will always be more out there than any reader could possibly explore, since new documents are constantly being added. There is no ending if a text is constantly extended. (In print media this problem appears only to a far more limited extent: there, intertextuality is mostly implicit, and even though new articles may constantly be added -- 'linked', if you will -- to a discourse, due to the medium's physical nature they're still very much separate entities, while Web links make intertextuality explicit and directly connect texts.) Does this mark the end of closure, then? Adding to the problem is the fact that it's not even possible to know how much of the hypertextual information available is still left unexplored, since there is no universal register of all the information available on the Web -- "the extent of hypertext is unknowable because it lacks clear boundaries and is often multi-authored" (Snyder 19). While reading a book you can check how many more pages you've got to go, but on the Web this is not an option. Our traditions of information transmission create this desire for closure, but the inherent nature of the medium prevents us from ever satisfying it. Barrett waxes lyrical in describing this dilemma: contexts presented online are often too limited for what we really want: an environment that delivers objects of desire -- to know more, see more, learn more, express more. We fear being caught in Medusa's gaze, of being transfixed before the end is reached; yet we want the head of Medusa safely on our shield to freeze the bitstream, the fleeting imagery, the unstoppable textualisations. We want, not the dead object, but the living body in its connections to its world, connections that sustain it, give it meaning. (xiv-v) We want nothing less, that is, than closure without closing: we desire the knowledge we need, and the feeling that that knowledge is sufficient to really know about a topic, but we don't want to devalue that knowledge in the same process by removing it from its context and reducing it to trivial truisms. We want the networked knowledge base that the Web is able to offer, but we don't want to feel overwhelmed by the unfathomable dimensions of that network. This is increasingly difficult the more knowledge is included in that network -- "with the growth of knowledge comes decreasing certainty. The confidence that went with objectivity must give way to the insecurity that comes from knowing that all is relative" (Smith 206). The fact that 'all is relative' is one which predates the Net, of course, and it isn't the Internet or the World Wide Web that has destroyed objectivity -- objectivity has always been an illusion, no matter how strongly journalists or scientists have at times laid claims ot it. Internet-based media have simply stripped away more of the pretences, and laid bare the subjective nature of all information; in the process, they have also uncovered the fact that the desire for closure must ultimately remain unfulfilled in any sufficiently non-trivial case. Nonetheless, the early history of the Web has seen attempts to connect all the information available (LEO, one of the first major German Internet resource centres, for example, took its initials from its mission to 'Link Everything Online') -- but as the amount of information on the Net exploded, more and more editorial choices of what to include and what to leave out had to be made, so that now even search engines like Yahoo! and Altavista quite clearly and openly offer only a selection of what they consider useful sites on the Web. Web browsers still hoping to find everything on a certain topic would be well-advised to check with all major search engines, as well as important resource centres in the specific field. The average Web user would probably be happy with picking the search engine, Web directory or Web ring they find easiest to use, and sticking with it. The multitude of available options here actually shows one strength of the Internet and similar networks -- "the computer permits many [organisational] structures to coexist in the same electronic text: tree structures, circles, and lines can cross and recross without obstructing one another. The encyclopedic impulse to organise can run riot in this new technology of writing" (Bolter 95). Still, this multitude of options is also likely to confuse some users: in particular, "novices do not know in which order they need to read the material or how much they should read. They don't know what they don't know. Therefore learners might be sidetracked into some obscure corner of the information space instead or covering the important basic information" (Nielsen 190). They're like first-time visitors to a library -- but this library has constantly shifting aisles, more or less well-known pathways into specialty collections, fiercely competing groups of librarians, and it extends almost infinitely. Of course, the design of the available search and information tools plays an important role here, too -- far more than it is possible to explore at this point. Gay makes the general observation that "visual interfaces and navigational tools that allow quick browsing of information layout and database components are more effective at locating information ... than traditional index or text-based search tools. However, it should be noted that users are less secure in their findings. Users feel that they have not conducted complete searches when they use visual tools and interfaces" (185). Such technical difficulties (especially for novices) will slow take-up of and low satisfaction with the medium (and many negative views of the Web can probably be traced to this dissatisfaction with the result of searches -- in other words, to a lack of satisfaction of the desire for closure); while many novices eventually overcome their initial confusion and become more Web-savvy, others might disregard the medium as unsuitable for their needs. At the other extreme of the scale, the inherent lack for closure, in combination with the societally deeply ingrained desire for it, may also be a strong contributing factor for another negative phenomenon associated with the Internet: that of Net users becoming Net junkies, who spend every available moment online. Where the desire to know, to get to the bottom (or more to the point: to the end) of a topic, becomes overwhelming, and where the fundamental unattainability of this goal remains unrealised, the step to an obsession with finding information seems a small one; indeed, the neverending search for that piece of knowledge surpassing all previously found ones seems to have obvious similarities to drug addiction with its search for the high to better all previous highs. And most likely, the addiction is only heightened by the knowledge that on the Web, new pieces of information are constantly being added -- an endless, and largely free, supply of drugs... There is no easy solution to this problem -- in the end, it is up to the user to avoid becoming an addict, and to keep in mind that there is no such thing as total knowledge. Web designers and content providers can help, though: "there are ways of orienting the reader in an electronic document, but in any true hypertext the ending must remain tentative. An electronic text never needs to end" (Bolter 87). As Tennant & Heilmeier elaborate, "the coming ease-of-use problem is one of developing transparent complexity -- of revealing the limits and the extent of vast coverage to users, and showing how the many known techniques for putting it all together can be used most effectively -- of complexity that reveals itself as powerful simplicity" (122). We have been seeing, therefore, the emergence of a new class of Websites: resource centres which help their visitors to understand a certain topic and view it from all possible angles, which point them in the direction of further information on- and off-site, and which give them an indication of how much they need to know to understand the topic to a certain degree. In this, they must ideally be very transparent, as Tennant & Heilmeier point out -- having accepted that there is no such thing as objectivity, it is necessary for these sites to point out that their offered insight into the field is only one of many possible approaches, and that their presented choice of information is based on subjective editorial decisions. They may present preferred readings, but they must indicate that these readings are open for debate. They may help satisfy some of their readers' desire for closure, but they must at the same time point out that they do so by presenting a temporary ending beyond which a more general story continues. If, as suggested above, closure crucially depends on a linear mode of presentation, such sites in their arguments help trace one linear route through the network of knowledge available online; they impose a linear from-us-to-you model of transmission on the normally unordered many-to-many structure of the Net. In the face of much doomsaying about the broadcast media, then, here is one possible future for these linear transmission media, and it's no surprise that such Internet 'push' broad- or narrowcasting is a growth area of the Net -- simply put, it serves the apparent need of users to be told stories, to have their desire for closure satisfied through clear narrative progressions from exposition through development to end. (This isn't 'push' as such, really: it's more a kind of 'push on demand'.) But at the same time, this won't mean the end of the unstructured, networked information that the Web offers: even such linear media ultimately build on that networked pool of knowledge. The Internet has simply made this pool public -- passively as well as actively accessible to everybody. Now, however, Web designers (and this includes each and every one of us, ultimately) must work "with the users foremost in mind, making sure that at every point there is a clear, simple and focussed experience that hooks them into the welter of information presented" (Friedlander 164); they must play to the desire for closure. (As with any preferred reading, however, there is also a danger that that closure is premature, and that the users' process or meaning-making is contained and stifled rather than aided.) To return briefly to Friedlander's experience with the interactive museum exhibit: he draws the conclusion that visitors were simply overwhelmed by the sheer mass of information and were reluctant to continue accumulating facts without a guiding purpose, without some sense of how or why they could use all this material. The technology that delivers immense bundles of data does not simultaneously deliver a reason for accumulating so much information, nor a way for the user to order and make sense of it. That is the designer's task. The pressing challenge of multimedia design is to transform information into usable and useful knowledge. (163) Perhaps this transformation is exactly what is at the heart of fulfilling the desire for closure: we feel satisfied when we feel we know something, have learnt something from a presentation of information (no matter if it's a news report or a fictional story). Nonetheless, this satisfaction must of necessity remain intermediate -- there is always much more still to be discovered. "From the hypertext viewpoint knowledge is infinite: we can never know the whole extent of it but only have a perspective on it. ... Life is in real-time and we are forced to be selective, we decide that this much constitutes one node and only these links are worth representing" (Beardon & Worden 69). This is not inherently different from processes in other media, where bandwidth limitations may even force much stricter gatekeeping regiments, but as in many cases the Internet brings these processes out into the open, exposes their workings and stresses the fundamental subjectivity of information. Users of hypertext (as indeed users of any medium) must be aware of this: "readers themselves participate in the organisation of the encyclopedia. They are not limited to the references created by the editors, since at any point they can initiate a search for a word or phrase that takes them to another article. They might also make their own explicit references (hypertextual links) for their own purposes ... . It is always a short step from electronic reading to electronic writing, from determining the order of texts to altering their structure" (Bolter 95). Significantly, too, it is this potential for wide public participation which has made the Internet into the medium of the day, and led to the World Wide Web's exponential growth; as Bolter describes, "today we cannot hope for permanence and for general agreement on the order of things -- in encyclopedias any more than in politics and the arts. What we have instead is a view of knowledge as collections of (verbal and visual) ideas that can arrange themselves into a kaleidoscope of hierarchical and associative patterns -- each pattern meeting the needs of one class of readers on one occasion" (97). To those searching for some meaningful 'universal truth', this will sound defeatist, but ultimately it is closer to realism -- one person's universal truth is another one's escapist phantasy, after all. This doesn't keep most of us from hoping and searching for that deeper insight, however -- and from the preceding discussion, it seems likely that in this we are driven by the desire for closure that has been imprinted in us so deeply by the multitudes of narrative structures we encounter each day. It's no surprise, then, that, as Barrett writes, "the virtual environment is a place of longing. Cyberspace is an odyssey without telos, and therefore without meaning. ... Yet cyberspace is also the theatre of operations for the reconstruction of the lost body of knowledge, or, perhaps more correctly, not the reconstruction, but the always primary construction of a body of knowing. Thought and language in a virtual environment seek a higher synthesis, a re-imagining of an idea in the context of its truth" (xvi). And so we search on, following that by definition end-less quest to satisfy our desire for closure, and sticking largely to the narrative structures handed down to us through the generations. This article is no exception, of course -- but while you may gain some sense of closure from it, it is inevitable that there is a deeper feeling of a lack of closure, too, as the article takes its place in a wider hypertextual context, where so much more is still left unexplored: other articles in this issue, other issues of M/C, and further journals and Websites adding to the debate. Remember this, then: you decide when and where to stop. References Barrett, Edward, and Marie Redmont, eds. Contextual Media: Multimedia and Interpretation. Cambridge, Mass.: MIT P, 1995. Barrett, Edward. "Hiding the Head of Medusa: Objects and Desire in a Virtual Environment." Barrett & Redmont xi- vi. Beardon, Colin, and Suzette Worden. "The Virtual Curator: Multimedia Technologies and the Roles of Museums." Barrett & Redmont 63-86. Bolter, Jay David. Writing Space: The Computer, Hypertext, and the History of Writing. Hillsdale, N.J.: Lawrence Erlbaum Associates, 1991. Friedlander, Larry. "Spaces of Experience on Designing Multimedia Applications." Barrett & Redmont 163-74. Gay, Geri. "Issues in Accessing and Constructing Multimedia Documents." Barrett & Redmont 175-88. McKnight, Cliff, John Richardson, and Andrew Dillon. "The Authoring of Hypertext Documents." Hypertext: Theory into Practice. Ed. Ray McAleese. Oxford: Intellect, 1993. Nielsen, Jakob. Hypertext and Hypermedia. Boston: Academic Press, 1990. Smith, Anthony. Goodbye Gutenberg: The Newspaper Revolution of the 1980's [sic]. New York: Oxford UP, 1980. Snyder, Ilana. Hypertext: The ELectronic Labyrinth. Carlton South: Melbourne UP, 1996. Tennant, Harry, and George H. Heilmeier. "Knowledge and Equality: Harnessing the Truth of Information Abundance." Technology 2001: The Future of Computing and Communications. Ed. Derek Leebaert. Cambridge, Mass.: MIT P, 1991. Citation reference for this article MLA style: Axel Bruns. "What's the Story: The Unfulfilled Desire for Closure on the Web." M/C: A Journal of Media and Culture 2.5 (1999). [your date of access] <http://www.uq.edu.au/mc/9907/closure.php>. Chicago style: Axel Bruns, "What's the Story: The Unfulfilled Desire for Closure on the Web," M/C: A Journal of Media and Culture 2, no. 5 (1999), <http://www.uq.edu.au/mc/9907/closure.php> ([your date of access]). APA style: Axel Bruns. (1999) What's the story: the unfulfilled desire for closure on the Web. M/C: A Journal of Media and Culture 2(5). <http://www.uq.edu.au/mc/9907/closure.php> ([your date of access]).