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Most challenges during the development of solid dosage forms are related to the impact of any variations in raw material properties, batch size, or equipment scales on the product quality and the control of the manufacturing process. With the ever pertinent restrictions on time and resource availability versus heightened expectations to develop, optimize, and troubleshoot manufacturing processes, targeted and robust science-based process modeling platforms are essential. This review focuses on the modeling of unit operations and practices involved in batch manufacturing of solid dosage forms by direct compaction. An effort is made to highlight the key advances in the past five years, and to propose potentially beneficial future study directions.

A finite element study of the interparticle force–displacement laws on contacts of spheres at conditions corresponding to compacts pressed to high relative densities is presented here. Under these conditions, the response of a contact can be affected by the presence of neighboring contacts. Finite element simulations of axisymmetric models of equispaced and equally loaded contacts show that the force–displacement law is not unique and depends on the number of neighboring contacts. The force at a given interparticle deformation is minimum for Z = 2 but at higher coordination numbers becomes larger after a critical deformation due to the interaction of the stress fields of neighboring contacts. This difference is magnified when the local porosity closes. Furthermore, numerical simulations of periodic arrays of spheres were conducted to assess the effect of loading path and the formation of new contacts on the response of existing contacts. In both cases, it was found that, the contact response depends on the overall triaxiality of the deformation of the particle. A new deformation fabric tensor is proposed based on the deformation and direction of all contacts on a particle. The first and second invariants of this tensor are used to characterize the triaxiality of the deformation on a particle. These results form the basis for more appropriate force–displacement laws at contacts that can be implemented in discrete element simulations for high density problems.

Amorphous solid dispersions (ASDs) consisting of acetaminophen (APAP) and copovidone were systematically studied to identify effects of drug loading and moisture content on mechanical properties, thermal properties, and tableting behavior. ASDs containing APAP at different levels were prepared by film casting and characterized by differential scanning calorimetry and nanoindentation. The glass transition temperature (Tg) continuously decreased with increasing amount of APAP, but the hardness of ASDs was increased at a low APAP content and reduced at high APAP content. This in turn significantly influenced tablet quality. Water reduced both the hardness and Tg of ASDs, and the APAP loading level corresponding to the transition to the softening mechanism was lower at a higher relative humidity. Overall, the mechanical properties, rather than the thermal properties, better represent the plasticization/antiplasticization effect of small molecule to ASDs.

Small ankyrin 1 (sAnk1; Ank1.5) is a ~20 kDa protein of striated muscle that concentrates in the network compartment of the sarcoplasmic reticulum (nSR). We used siRNA targeted to sAnk1 to assess its role in organizing the sarcoplasmic reticulum (SR) of skeletal myofibers in vitro. siRNA reduced sAnk1 mRNA and protein levels and disrupted the organization of the remaining sAnk1. Sarcomeric proteins were unchanged, but two other proteins of the nSR, SERCA and sarcolipin, decreased significantly in amount and segregated into distinct structures containing sarcolipin and sAnk1, and SERCA, respectively. Exogenous sAnk1 restored SERCA to its normal distribution. Ryanodine receptors and calsequestrin in the junctional SR, and L-type Ca2+ channels in the transverse tubules were not reduced, although their striated organization was mildly altered. Consistent with the loss of SERCA, uptake and release of Ca2+ were significantly inhibited. Our results show that sAnk1 stabilizes the nSR and that its absence causes the nSR to fragment into distinct membrane compartments.

Intermediate filaments, composed of desmin and of keratins, play important roles in linking contractile elements to each other and to the sarcolemma in striated muscle. Our previous results show that the tibialis anterior (TA) muscles of mice lacking keratin 19 (K19) lose costameres, accumulate mitochondria under the sarcolemma, and generate lower specific tension than controls. Here we compare the physiology and morphology of TA muscles of mice lacking K19 with muscles lacking desmin or both proteins [double knockout (DKO)]. K19−/− mice and DKO mice showed a threefold increase in the levels of creatine kinase (CK) in the serum. The absence of desmin caused a larger change in specific tension (−40%) than the absence of K19 (−19%) and played the predominant role in contractile function (−40%) and decreased tolerance to exercise in the DKO muscle. By contrast, the absence of both proteins was required to obtain a significantly greater loss of contractile torque after injury (−48%) compared with wild type (−39%), as well as near-complete disruption of costameres. The DKO muscle also showed a significantly greater misalignment of myofibrils than either mutant alone. In contrast, large subsarcolemmal gaps and extensive accumulation of mitochondria were only seen in K19-null TA muscles, and the absence of both K19 and desmin yielded milder phenotypes. Our results suggest that keratin filaments containing K19- and desmin-based intermediate filaments can play independent, complementary, or antagonistic roles in the physiology and morphology of fast-twitch skeletal muscle.

Process control of aqueous tablet coating depends on a number of thermodynamic and psychrometric variables. Since many of these variables are interdependent, the choice of parameters by which to control the process or designate a design space is not necessarily obvious. Several mass or heat conservation models for aqueous tablet coating can be found in the literature, varying in approach and proposed method for controlling the coating process. A commonly used first-principles model built upon the coupled heat and mass transfer in evaporative mass transfer derives an "Environmental Equivalency" (EE) factor as an indicator of the relative rate of water evaporation from the tablet bed surface and as a relevant scaling factor for aqueous coating. The EE factor is expressed by an equation involving ten individual parameters; however, if the derivation of EE is extended further under the context of an adiabatic process, a much-simplified yet equivalent expression for EE emerges consisting of only three parameters, each directly measurable or obtainable from a psychrometric chart and which bear direct significance to the gross thermodynamic conditions of the coating. The psychrometric model herein is presented as a more physically evocative description of the coating process, enhancing process understanding and potentially playing a key role in a Quality by Design approach to defining an aqueous coating design space.

Owing to its cable-free deployment, wireless sensor networks (WSNs) have drawn great attention as a new technique for industrial data acquisition. However, the harsh environment of the gas turbine engine provides a number of challenges to deployment of wireless sensors. A definitive study of the impact of harsh environments on WSNs is currently lacking, which represents an obstacle to WSN's deployment in safety-critical industrial instrumentation and automation. In this study, the authors report the test results of applying WSNs to data acquisition in gas turbine engine testing and the development of a realistic software simulator with the purpose of de-risking the wireless data transmission technology in a project called WIDAGATE (wireless data acquisition in gas turbine engine testing). This study provides an overview of the simulation platform developed and investigates how small-scale tests of a WSN deployed on a real engine were used to validate and improve the simulator platform. This work proposes realistic modelling of the physical layer (radio channel) when subject to interference in harsh industry environment during aero-engine testing. Based on the validated, realistic physical layer model, different medium access control protocols are simulated to demonstrate how this improved simulator can be used to select an appropriate protocol.

We present a novel, low-power and untethered pneumatic haptic device, namely the ACTIVE-Hand, for realistic and real-time 3D gaming experience. Currently, body-motion based 3D gaming systems primarily use visual feedback to provide partly immersive gaming experiences. Tactile feedback systems in Virtual Reality provide immersion with high tactile resolution, but they are expensive and difficult to setup and calibrate. The conceptually economical modular design of the ACTIVE-Hand allows easily configurable tactile feedback as per application requirements. Contrary to commercial systems like Wii™ which provide global vibrations as a proxy for synthetic tactile feed-back, the ACTIVE Hand is comparably lightweight, yet scalable to meet localized tactile resolution requirements. The ACTIVE-Hand provides controllable pulses for dynamic virtual interactions such as pressing virtual buttons and hitting moving virtual balls. We successfully demonstrate the paradigm of dynamic tactile interactions in virtual environments through a 3D Pong game by integrating the ACTIVE-Hand with Kinect™ camera.Copyright © 2012 by ASME

In the United States and many developed countries, obesity is a rising health problem. Obesity is the result of an imbalance in lipid homeostasis and is evidenced by the excessive accumulation of cytoplasmic lipid droplets (CLDs) in cardiac muscles. The CLD is a dynamic organelle that functions in maintaining cellular lipid storage and metabolism [1]. It interacts with various cell organelles such as the endoplasmic reticulum, endosomes and mitochondria for lipid transport, storage and beta oxidation to generate energy. To date, only a few lipid droplet-associated proteins have been identified; among these, perilipin proteins are the most abundant. In cardiac myocytes, perilipin 5 has been shown to play a role in the recruitment of mitochondria to CLDs and is a negative regulator of lipolysis [2]. Our ultimate goal is to understand how CLDs in cardiac muscle cooperate, spatially and metabolically with mitochondria and the role of perilipin 5 in the dynamic interactions between these two organelles. Due to the small size of CLDs, electron microscopy (EM) techniques are required to characterize their physical and molecular interactions with mitochondria. However, lipids are prone to be extracted during traditional EM and light microscopy sample processing steps. Using fluorescence microscopy, it has been shown previously that methanol and acetone fixation can induce lipid droplets fusion and alter the size and morphology of CLDs [3]. In the electron microscope, lipid droplets can be seen both as electron dense or electron opaque vacuoles in cells or tissues prepared by different fixation and staining methods. Here we summarize our findings on the effect of various fixation and staining methods on the morphology of CLDs in cardiac muscles.

Laboratory study was conducted on the molecular and atomic emissions which are considered detectable in the IR radiative background of the upper atmosphere. The IR spectra of glow discharge emission formed in air and other atmospheric constituent gases of 0.1-Torr pressure and a 30-m long column were surveyed using the technique of Fourier spectroscopy. Several features hitherto unobserved were detected in our survey study.

This short biographical paper supplements, with personal recollections, the record of the life of R. W. Wood, doyen of American physics, as given in DR. WOOD by William Seabrook, and the summary of his work, that appeared in the Journal of the Optical Society of America in 1933 on the occasion of his being awarded the Ives Medal of the Optical Society of America.

Three procedures are described: a modified Pfund triple-pass absorption cell; an improved image slicer; and new achromatic, doublet lenses. Design parameters for prism dispersion for various prism angles—both simple and composite prisms—are displayed by graphs. The relationships of dispersion and transmission are useful in designing prism spectrometers, predispersion systems for grating spectrometers, and LN-2 cooled predispersion systems for use with helium-cooled detectors. In combination with a suitable chopper they provide instrumentation suited to a study of the validity of the Lorentz line shape.

The interpretation procedures here for observations of ir absorption spectra recorded under conditions of low pressure and long path, assuming Lorentzian line shape, are treated with the help of a universal absorption contour. The central dip and slopes of the sides of the observed line contour are the measured quantities. An expression is given to correct for intruding wing absorption. The use of the line itself as a chopper to test validity of the Lorentzian line shape assumption is described.

Several lamellar gratings of 18-in. aperture, with 300 diffraction elements per inch, have been made for determining stellar spectra with wide angle telescopes. Central orders are missing at lambda4800, and weak at adjacent wavelengths. The two, equal first orders are about l(m) weaker than spectra by a prism or echelette grating. Dispersion is linear. The procedure of manufacture is adaptable to larger size. The wavelength at which the central order is missing can be controlled by varying the lamellae thickness. The lamellae are evaporated strips of quartz of 0.5-micro thickness, covering half the face of the support-a spectacle crown, plane parallel plate of ?-in. thickness. The lamellae were deposited by thermal evaporation.

The theory of a thin bolometer strip is developed. It explains observation of enhanced response to spot illumination near the trip terminals, and predicts enhanced thermal fluctuation at the same point for uniform chopped illumination.

A 58-kD protein, identified in extracts of postsynaptic membrane from Torpedo electric organ, is enriched at sites where acetylcholine receptors (AChR) are concentrated in vertebrate muscle (Froehner, S. C., A. A. Murnane, M. Tobler, H. B. Peng, and R. Sealock. 1987. J. Cell Biol. 104:1633-1646). We have studied the 58-kD protein in AChR clusters isolated from cultured rat myotubes. Using immunofluorescence microscopy we show that the 58-kD protein is highly enriched at AChR clusters, but is also present in regions of the myotube membrane lacking AChR. Within clusters, the 58-kD protein codistributes with AChR, and is absent from adjacent membrane domains involved in myotube-substrate contact. Semiquantitative fluorescence measurements suggest that molecules of the 58-kD protein and AChR are present in approximately equal numbers. Differential extraction of peripheral membrane proteins from isolated AChR clusters suggests that the 58-kD protein is more tightly bound to cluster membrane than is actin or spectrin, but less tightly bound than the receptor-associated 43-kD protein. When AChR clusters are disrupted either in intact cells or after isolation, the 58-kD protein still codistributes with AChR. Clusters visualized by electron microscopy after immunogold labeling and quick-freeze, deep-etch replication show that, within AChR clusters, the 58-kD protein is sharply confined to AChR-rich domains, where it is present in a network of filaments lying on the cytoplasmic surface of the membrane. Additional actin filaments overlie, and are attached to, this network. Our results suggest that within AChR domains of clusters, the 58-kD protein lies between AChR and the receptor-associated 43-kD protein, and the membrane-skeletal proteins, beta-spectrin, and actin.

Obscurin is an approximately 800-kDa protein composed of structural and signaling domains that organizes contractile structures in striated muscle. We have studied the Rho-GEF domain of obscurin to understand its roles in morphogenesis and signaling. We used adenoviral overexpression of this domain, together with ultrastructural and immunofluorescence methods, to examine its effect on maturing myofibrils. We report that overexpression of the Rho-GEF domain specifically inhibits the incorporation of titin into developing Z-disks and disrupts the structure of the Z-disk and Z/I junction, and alters features of the A/I junction. The organization of other sarcomeric markers, including alpha-actinin, was not affected. We identified Ran binding protein 9 (RanBP9) as a novel ligand of the Rho-GEF domain and showed that binding is specific, with an apparent binding affinity of 1.9 microM. Overexpression of the binding region of RanBP9 also disrupted the incorporation of titin into developing Z-disks. Immunofluorescence localization during myofibrillogenesis indicated that the Rho-GEF domain assembles into sarcomeres before RanBP9, which first occurs in myonuclei and later in development translocates to the myoplasm, where it colocalizes with obscurin. Both the Rho-GEF domain and its binding region on RanBP9 bind directly to the N-terminal Ig domains of titin, which flank the Z-disk. Our results suggest that the Rho-GEF domain interacts with RanBP9 and that both can interact with the N-terminal region of titin to influence the formation of the Z-disk and A/I junction.

Intermediate filaments, composed of desmin and of keratins, play important roles in linking contractile elements to each other and to the sarcolemma in striated muscle. We examined the contractile properties and morphology of fast-twitch skeletal muscle from mice lacking keratin 19. Tibialis anterior muscles of keratin-19-null mice showed a small but significant decrease in mean fiber diameter and in the specific force of tetanic contraction, as well as increased plasma creatine kinase levels. Costameres at the sarcolemma of keratin-19-null muscle, visualized with antibodies against spectrin or dystrophin, were disrupted and the sarcolemma was separated from adjacent myofibrils by a large gap in which mitochondria accumulated. The costameric dystrophin-dystroglycan complex, which co-purified with γ-actin, keratin 8 and keratin 19 from striated muscles of wild-type mice, co-purified with γ-actin but not keratin 8 in the mutant. Our results suggest that keratin 19 in fast-twitch skeletal muscle helps organize costameres and links them to the contractile apparatus, and that the absence of keratin 19 disrupts these structures, resulting in loss of contractile force, altered distribution of mitochondria and mild myopathy. This is the first demonstration of a mammalian phenotype associated with a genetic perturbation of keratin 19.

Obscurin (approximately 800 kDa) in striated muscle closely surrounds sarcomeres at the level of the M-band and Z-disk where, we hypothesize, it participates in the assembly of the contractile apparatus and membrane systems required for Ca2+ homeostasis. In this study, we used small inhibitory RNA (siRNA) technology to reduce the levels of obscurin in primary cultures of skeletal myotubes to study its role in myofibrillogenesis and the organization of the sarcoplasmic reticulum (SR). siRNA-treated myotubes showed a specific and dramatic reduction in the approximately 800 kDa form of obscurin by reverse transcription-polymerase chain reaction, immunoblotting, and immunofluorescence. M-bands and A-bands, but not Z-disks or I-bands, were disrupted when the synthesis of obscurin was inhibited. Small ankyrin 1, an integral protein of the network SR that binds to obscurin, also failed to align around developing sarcomeres in treated myotubes. Myosin and myomesin levels were significantly reduced in treated myotubes but alpha-actinin was not, suggesting that down-regulation of obscurin destabilizes proteins of the M-band and A-band but not of the Z-disk. Our findings suggest that obscurin is required for the assembly of the M-band and A-band and for the regular alignment of the network SR around the contractile apparatus.

We studied the distribution of the giant sarcomeric protein obscurin during de novo myofibrillogenesis in C(2)C(12) myotubes to learn when it is integrated into developing sarcomeres. Obscurin becomes organized first at the developing M band and later at the mature Z disk. Primordial M bands consisting of obscurin, myomesin, and M band epitopes of titin assemble before adult fast-twitch sarcomeric myosin is organized periodically and nearly concurrently with primitive Z disks, which are composed of alpha-actinin and Z disk epitopes of titin. Z disks and M bands can assemble independently at spatially distant sites. As sarcomerogenesis proceeds, these structures interdigitate to produce a more mature organization. Fast-twitch muscle myosin accumulates in the myoplasm and assembles into A bands only after Z disks and M bands assume their typical interdigitated striations. The periodicities of M bands remain constant at approximately 1.8 microm throughout sarcomerogenesis, whereas distances between Z disks increase from approximately 1.1 microm in early sarcomeres to approximately 1.8 microm in more mature structures. Our findings indicate for the first time that primitive M bands self-assemble independently of Z disks, that obscurin is a component of these primitive M bands in skeletal muscle cells, and that A bands assemble only after M bands and Z disks integrate into maturing sarcomeres.

Obscurin is a giant sarcomeric protein composed of adhesion modules and signaling domains. It surrounds myofibrils at the level of the Z disk and the M line. To study the role of obscurin during myofibrillogenesis, we used adenovirus-mediated gene delivery to overexpress part of its COOH terminus in primary cultures of postnatal day 1 (P1) skeletal myotubes. Examination of the subcellular distribution of a number of sarcomeric proteins revealed that the organization of myosin into A bands was dramatically reduced. Myosin assembled into A bands normally in mock- or control-infected P1 myotubes. Overexpression of the COOH terminus of obscurin did not affect the organization of other sarcomeric markers, including actin, alpha-actinin, titin, and myomesin. Assembly of myomesin into nascent M lines in treated myotubes suggests that these structures can form independently of A bands. Immunoblot analysis indicated that there was a small ( approximately 20%) but consistent decrease in the amount of myosin expressed in cells infected with the COOH terminus of obscurin. Coimmunoprecipitation experiments in which we used adult skeletal muscle homogenates demonstrated that obscurin exists in a complex with myosin. Thus our findings suggest that the COOH-terminal region of obscurin interacts with sarcomeric myosin and may play a critical role in its ability to assemble into A bands in striated muscle.

Obscurin is a multidomain protein composed of adhesion and signaling domains that plays key roles in the organization of contractile and membrane structures in striated muscles. We used adenoviral-mediated gene transfer to overexpress its extreme NH2-terminus in developing myofibers, followed by immunofluorescence and ultrastructural methods to study its effects in sarcomerogenesis. We found that overexpression of obscurin's second immunoglobulin domain (Ig2) inhibits the assembly of A- and M-bands, but not Z-disks and I-bands. This effect is mediated by the direct interaction of obscurin's Ig2 with a novel isoform of the thick filament associated protein, Myosin Binding Protein-C Slow (MyBP-C slow), that corresponds to transcript variant-1. Variant-1 contains all the structural motifs known to be present in MyBP-C slow (variant-3), but has a unique COOH-terminus consisting of twenty-six amino acids and a new termination codon. RT-PCR showed that variant-1 is abundantly expressed in skeletal muscles during development and at maturity. Quantitative RT-PCR further demonstrated that transcripts containing the novel COOH-terminus are expressed in higher amounts than those lacking it. Three different antibodies to the unique COOH-terminus of variant-1 labeled M-bands and flanking regions in both developing and adult myofibers, suggesting that unlike other forms of MyBP-C that reside in C-zones, variant-1 preferentially concentrates in the middle of the A band. Adenoviral overexpression of obscurin's Ig2 domain and reduction of obscurin via siRNA inhibited the integration of variant 1 of MyBP-C slow into forming M-bands in skeletal myotubes. Collectively, our experiments identify a new ligand of obscurin at the M-band, MyBP-C slow variant-1, and suggest that its interaction with obscurin contributes to the assembly and maintenance of M- and A-bands.

This guide to the issues at stake when toll roads are privatized answers many questions that privatization teams and regulators should be asking-providing useful information to project specialists, many of whom are now learning how much they did not know when they started. Road transport has long been the dominant form of transport for freight and passenger movement throughout the world. Because most road projects require investments with long amortization periods and because many projects do not generate enough demand to become self-financing through some type of user fee or toll, the road sector remains in the hands of the public sector to a much greater extent than other transport activities. But governments throughout the world, including those of many poor African and South Asian countries, are commercializing their operations to cut costs, improve user orientation, and increase sector-specific revenue. There seems to be demand for toll roads in specific settings, but the problems met by many of this first generation of road concessions - from Mexico to Thailand - have given toll projects a bad reputation. Many mistakes were made, and tolling is obviously not the best solution for every road. Most of the alternatives aim at improving efficiency (lowering costs). But there are many ways of getting the private sector involved in toll roads, thus reducing public sector financing requirements for the sector. Understanding the context in which toll roads are viable is essential both for their initial success and for effective long-run regulation. Estache, Romero, and Strong provide a broad overview of issues at stake from the viewpoint of both privatization teams and regulators responsible for supervising contractual commitments of private operators and the government, to each other and to users. This paper - a product of Governance, Regulation, and Finance, World Bank Institute - is part of a larger effort in the institute to increase understanding of infrastructure regulation.

Many transport projects undertaken during the boom period of the 1990s came to a crashing halt in 1997, and conditions in emerging markets worsened in 1998 and 1999. Many projects failed, victim of everything from overoptimistic forecasts to excessive debt to an inability to refinance bridge loans. As available financing dried up, many projects went bankrupt, had to be renegotiated, or were taken over by the government. What have we learned from all this? Recent developments in emerging financial markets have dramatically changed the appetite for (and terms of) transport infrastructure projects. As a result of defaults in Asia and Russia and devaluations in Asia, Brazil, and Russia, political and currency and exchange risk premia have increased dramatically. Given large needs for sovereign debt financing, infrastructure project finance will be seeking guarantees at the same time as governments are issuing primary securities. Large portfolio outflows in emerging market funds mean that the sources of both equity and debt capital that became available in the mid-1990s are drying up for all but the most creditworthy projects. Moreover, real economic effects from financial events have consequences in the transport sector, since transport is a derived demand. Any decline in real economic activity is felt quickly in traffic levels and revenues. Currency devaluations that help spur exports may generate higher volumes for seaports and air cargo activity. These effects vary by sector, especially over the medium to longer term. Declines in real economic activity make matters especially difficult for toll roads, as drivers shift to free alternatives and reduce the number of trips taken. What does all this mean for project finance in transport? Risks have increased. Debt finance costs more. The available tenor of debt instruments has shortened and more equity is required for projects. The sources and availability of equity finance have changed. Project finance efforts have shifted from new projects to the privatization, rehabilitation, and expansion of existing facilities. And a "superclass" of sponsors, bankers, and investors has emerged. Failures and mistakes in project finance deals in the 1990s were sharp and persistent. But much has been learned about sound project economics, conservative financial structures, comprehensive sensitivity analysis, the effects of macroeconomic factors, and the need for proper incentives and sound institutional and regulatory arrangements. This paper-a product of Governance, Regulation, and Finance, World Bank Institute-is part of a larger effort in the institute to increase understanding of infrastructure regulation.

Former consultant radiologist Stratford upon Avon, Leominster, and Warwick (b 1924; q Edinburgh 1946; FRCR), d 25 October 2002. He worked in surgical posts in Chertsey, Harrow, Exeter, and West Africa. He held the surgical fellowship at both Edinburgh and London but then decided to train as a radiologist at University College London. He then took up a consultant post at Stratford, Leominster, and Warwick until his retirement in 1989. A skilled cabinet maker, he enjoyed making beautiful pieces of furniture in his workshop. He leaves a wife; and three children.