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Cytotoxic chemotherapy remains the mainstay of treatment for advanced pancreatic adenocarcinoma (PDAC). Emerging studies support metronomic chemotherapy (MCT) as effective, challenging established paradigms of dosing and schedules. The blood-based ChemoSensitivity Assay has been shown to predict response and survival in advanced PDAC patients treated with standard chemotherapy. The current study combines these concepts for a highly personalized treatment approach. This was a retrospective analysis; a pilot (n = 50) and validation cohort (n = 45) were studied. The ChemoSensitivity Assay was performed at baseline and during therapy; results were correlated to drugs administered and patient outcomes. MCT was administered based on the assay results at the treating physician′s discretion. Patients in the pilot cohort experienced favorable survival compared with historical controls (median overall survival (mOS) 16.8 mo). Patients whose treatment closely matched the ChemoSensitivity Assay predictions experienced longer median time on lines of therapy (5.3 vs. 3.3 mo, p = 0.02) and showed a trend for longer mOS (20.9 vs. 12.5 mo, p = 0.055) compared with those not closely matched. These findings were confirmed in the validation cohort. Overall, patients treated with MCT closely matching Assay results experienced a remarkable mOS of 27.7 mo. ChemoSensitivity profiling-guided MCT is a promising approach for personalized therapy in advanced PDAC.

Pancreatic adenocarcinoma (PDAC) remains a refractory disease; however, modern cytotoxic chemotherapeutics can induce tumor regression and extend life. A blood-based, pharmacogenomic, chemosensitivity assay using gene expression profiling of circulating tumor and invasive cells (CTICs) to predict treatment response was previously developed. The combination regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel (G/nab-P) are established frontline approaches for treating advanced PDAC; however, there are no validated biomarkers for treatment selection. A similar unmet need exists for choosing second-line therapy.The chemosensitivity assay was evaluated in metastatic PDAC patients presenting for frontline treatment. A prospective study enrolled patients (n = 70) before receiving either FOLFIRINOX or G/nab-P at a 1:1 ratio. Six milliliters of peripheral blood was collected at baseline and at time of disease progression. CTICs were isolated, gene-expression profiling was performed, and the assay was used to predict effective and ineffective chemotherapeutic agents. Treating physicians were blinded to the assay prediction results.Patients receiving an effective regimen as predicted by the chemosensitivity assay experienced significantly longer median progression-free survival (mPFS; 7.8 months vs. 4.2 months; hazard ratio [HR], 0.35; p = .0002) and median overall survival (mOS; 21.0 months vs. 9.7 months; HR, 0.40; p = .005), compared with an ineffective regimen. Assay prediction for effective second-line therapy was explored. The entire study cohort experienced favorable outcomes compared with historical controls, 7.1-month mPFS and 12.3-month mOS.Chemosensitivity assay profiling is a promising tool for guiding therapy in advanced PDAC. Further prospective validation is under way (clinicaltrials.gov NCT03033927).

Recently, the fungal sphingolipid glucosylceramide (GlcCer) synthesis has emerged as a highly promising new target for drug discovery of next-generation antifungal agents, and we found two aromatic acylhydrazones as effective inhibitors of GlcCer synthesis based on HTP screening. In the present work, we have designed libraries of new aromatic acylhydrazones, evaluated their antifungal activities (MIC(80) and time-kill profile) against C. neoformans and performed an extensive SAR study, which led to the identification of five promising lead compounds, exhibiting excellent fungicidal activities with very large selectivity index. Moreover, two compounds demonstrated broad spectrum antifungal activity against six other clinically relevant fungal strains. These five lead compounds were examined for their synergism/cooperativity with five clinical drugs against seven fungal strains and very encouraging results were obtained, e.g., the combination of all five lead compounds with voriconazole exhibited either synergistic or additive effect to all seven fungal strains.

Fungal infections are a universal problem and are routinely associated with high morbidity and mortality rates in immunocompromised patients. Existing therapies comprise five different classes of antifungal agents, four of which target the synthesis of ergosterol and cell wall glucans. However, the currently available antifungals have many limitations, including poor oral bioavailability, narrow therapeutic indices, and emerging drug resistance resulting from their use, thus making it essential to investigate the development of novel drugs which can overcome these limitations and add to the antifungal armamentarium. Advances have been made in antifungal drug discovery research and development over the past few years as evidenced by the presence of several new compounds currently in various stages of development. In the following minireview, we provide a comprehensive summary of compounds aimed at one or more novel molecular targets. We also briefly describe potential pathways relevant for fungal pathogenesis that can be considered for drug development in the near future.

The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due to toxicity, a narrow spectrum of activity, and, more importantly, the consistent rise of fungal species that are intrinsically resistant or that develop resistance due to prolonged therapy. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. We previously reported a new class of potent antifungal compounds, acylhydrazones, that target the fungal sphingolipid pathway. Based upon our initial lead molecules, (E)-N′-(5-bromo-2-hydroxybenzylidene)-2-methylbenzohydrazide and D13, we performed a structure-activity relationship study, synthesizing ca. 300 new compounds. Of these, 5 compounds were identified to be the most promising for further studies, based on their broad-spectrum activity and low toxicity in mammalian cells lines. Among these top 5 lead compounds, we report here the impressive in vivo activity of 2,4-dibromo-N′-(5-bromo-2-hydroxybenzylidene)benzohydrazide (SB-AF-1002) in several models of systemic fungal infection. Our data show that SB-AF-1002 is efficacious and outperforms current standard-of-care drugs in models of invasive fungal infections, such as cryptococcosis, candidiasis, and aspergillosis. Specifically, animals treated with SB-AF-1002 not only survived the infection but also showed a clearing of fungal cells from key organs. Moreover, SB-AF-1002 was very effective in an aspergillosis model as a prophylactic therapy. SB-AF-1002 also displayed acceptable pharmacokinetic properties in mice, similar to those of the parent compound, D13. These results clearly indicate that our novel acylhydrazones constitute a new class of highly potent and efficacious antifungal agents which warrant further development for the treatment of invasive fungal infections.

Metal-organic frameworks (MOFs) interfaced with visible-light-absorbing semiconductors offer a novel approach to improve photoelectrochemical performances. When tested under 1-sun illumination, a naphthalene diimide (NDI)-based monolayer immobilized at p-type Si(111) undergoes two sequential one-electron reductions close to their thermodynamic potentials. No photovoltage is observed until the NDI monolayer is expanded in three dimensions in a PIZOF-type Zr(NDI) MOF (PIZOF = porous interpenetrated zirconium organic framework). The surface-grown MOF thin film promotes photo-induced charge separation and electron transfer across the interface and through the film, resulting in reduction of the molecular linkers at formal potentials >300 mV positive of their thermodynamic potentials. The apparent diffusion coefficient is similar to that measured at a conductive electrode (10-10 cm2 s-1), indicating that the observed photocurrent is governed by charge diffusion through the Zr(NDI) MOF film. The charges accumulated in the NDI-based MOF can be extracted by an external electron acceptor, demonstrating sufficient conductivity throughout the MOF film to power reductive transformations. When grown on GaP(100), the potentials of the NDI reductions in the MOF film are shifted anodically by >700 mV compared to those of the same MOF on conductive substrates. This photovoltage, among the highest reported for GaP in photoelectrochemical applications, illustrates the power of MOF thin films to improve photocathodic performance.

In this work the authors present the first publicly available, open-source simulation model of the Third Generation Partnership Project (3GPP) Release 14 Cellular Vehicle to Everything (C-V2X) standard. The model specifically addresses Mode 4, in which vehicles communicate directly in peer to peer mode using a distributed resource allocation algorithm. Importantly, the model is fully compliant with existing service and application layers already defined by the automotive and standards communities, providing a fully standardised cross-layer communication model spanning application layer based on the ITS-G5 standard to physical layer from the new C-V2X Mode 4 standard. This enables enhancements of the lower layers to support future vehicular use cases. The simulation model has been implemented by extending SimuLTE, an OMNeT++ cellular communication stack that enables simulation of LTE networks as well as extending and integrating Artery, an ETSI compliant ITS-G5 implementation. The developed model is validated using published 3GPP simulation evaluation scenarios and is available at www.cs.ucc.ie/cv2x.

Printing functional, metal parts for mass production using powder bed fusion additive manufacturing requires the ability to deposit more energy at the working plane to increase build rate. Conventional approaches serially add fiber lasers and scanners to create dual and quad laser machines, but scaling this strategy is limited by the size of powder bed while current scan parameters do not utilize the full output potential of available laser sources. Instead, a processing head containing an array of lower power laser sources can melt wider regions of a powder bed simultaneously to increase build rate. A 16 channel processing head comprised of fiber-coupled direct diodes capable of outputting up to 960W of combined power is presented. Fiber arrays arranged to melt widened tracks of CoCr powder demonstrated builds with >99% density at 2x the build rate of conventional, single laser systems. Details of the array layout, optical system and controls are presented along with scan strategies for melt tracks of varying widths. Most importantly, the array configuration can be scaled to multi-kW outputs spread over larger areas without requiring new parameter development as the energy per unit area remains unchanged with channel count.

The aircraft engine industry manufactures many ring-like metal parts of large diameter but small cross-sectional area. Designers of these parts require increasingly complex geometries for improved aerodynamic efficiency and cooling while manufacturers of these parts require larger and faster equipment for high productivity and low cost. The combination of these industrial requirements inspired the development of a new Direct Metal Laser Melting (DMLM) architecture, reported here, which incorporates a rotating powder bed. The system coordinates the rotational motion of the powder bed with an ascending laser scanner and recoater to build parts in a helical fashion. A single-point powder feeder delivers metal powder near the inner radius of an annular build volume, and a recoater spreads the powder to the outer radius in a “snow plow” fashion. Because the recoater and laser scanner are installed at different angular positions, they operate independently and simultaneously. Encoder feedback from both the rotational stage and the galvanometers assures accuracy of the laser scan path. A prototype system was built to demonstrate this new concept for an aircraft engine combustor liner (600-mm dia. x 150-mm ht.) and showed continuous laser utilization exceeding 97%. Build rates were shown to triple conventional DMLM systems while powder requirements were decreased by more than 4x.

Drug-drug interaction related adverse events (DIAE) signals are a major public health issue. Drug safety analysts must sift through thousands of adverse event reports submitted daily to U.S. Food and Drug Administration (FDA) to discover unexpected DIAE signals, which if addressed can lead to life-saving actions. To facilitate the DIAE discovery from these massive data sets, we design several technological innovations that together are integrated into an interactive visual analytics system called DEVES 1. First, our state- of-the-art DIAE mining algorithm efficiently infers potential DIAE signals from these reports, and then ranks them based on their significance score. For interpretability of these inferred DIAE signals, domain knowledge of adverse events and already known drug interactions is extracted from external authoritative data sources and then seamlessly integrated with the inferred signal set. Guided by this augmented signal model, DEVES supports advanced signal analytics - empowering the analyst to interact with linked visualizations offering complementary perspectives into the signal set and its supporting evidence in the form of reports. Our demonstration showcases the technological innovations of DEVES using real-world FDA datasets, demonstrating that DEVES effectively supports the core regulatory tasks from signal screening, signal prioritization to signal validation.

Hundreds of thousands of patients report adverse reactions from using one or more drugs each year. It is impossible to test every drug combination in clinical trials before a drug reaches the market. Thus, the FDA performs post-marketing surveillance to identify drug combinations that produce harmful reactions. To facilitate this surveillance, consumers and health care professionals submit drug safety reports that include the drugs a patient takes and the reactions they experience. In this research, we propose techniques to support high-fidelity rule mining of interesting drug combinations from safety reports by developing drug name matching, reaction name standardization, and known-rule matching strategies. For evaluation, we design a sensibility metric for drug name matching. We demonstrate that our technique achieves a sensibility score of 0.855, corresponding to a 91% accuracy. We compare methods for reaction name standardization and their effects on known-rule matching, identifying 427 known rules from 4652 generated signals when using our techniques as opposed to 61 known rules from 3276 generated signals without the application of our techniques.

The water chemistry and economics of a commercial-scale inland marine integrated multi-trophic aquaculture (IMTA) system was investigated. The system used a combination of a constructed wetland, sand filter followed by a constructed wetland, and geotextile bags to treat solids waste. This study is a demonstration of a zero-discharge system where commercial nursery production of wetland plants was combined with a marine RAS to treat saline solid waste. Total suspended solids (TSS), chemical oxygen demand (COD), total nitrogen (TN), and total phosphorus (TP) concentrations were measured. Plant and soil samples were analyzed for TN and TP. A significant ( p

By classifying hospital output into groups of patients with similar clinical characteristics and resource requirements, diagnosis-related groups (DRGs) are designed to be highly correlated with resource utilisation. Using a two-stage approach to control for variation within and between hospitals, we examine the ability of the diverse DRG systems in 10 European countries to explain variability in resource utilisation (costs or length of stay, LoS) for hospital patients undergoing surgical repair of inguinal hernia. Our national regression results suggest that DRGs are statistically significant in explaining cost/LoS variation in the absence of any other regressors and generally remain so in most countries when patient-level characteristics are added to the model. However patient-level characteristics, including those used in DRG assignment, are usually also statistically significant. In nine countries, where the number of relevant DRGs ranges from two (Poland) to seven (France), the inclusion of patient-level characteristics substantially improves model goodness-of-fit compared with that attained with DRGs alone. Only in Sweden is the converse true. If our analysis raises some concerns over the adequacy of DRGs to explain cost/LoS variation in inguinal hernia repair in nine of the 10 European countries, further research is required to consider whether future enhancements may be necessary. Copyright © 2012 John Wiley & Sons, Ltd.

Tree-of-heaven (Ailanthus altissima Miller [Swingle]) can be managed easily with herbicide injection. However, the potential herbicide translocation to neighboring trees must be evaluated before widespread recommendations for herbicide injections. We assessed the nontargettranslocation of imazapyr (Arsenal), an herbicide commonly used to manage woody vegetation in forests, from injected tree-of-heaven to neighboring noninjected stems. Targeted imazapyr injections not only killed all injected tree-of-heaven, but also killed 17.5% of neighboring (within 3 m) noninjected tree-of-heaven and eight other tree species 62 weeks after treatment. Nontarget mortality from herbicide translocation decreased as the distance from injected tree-of-heaven increased (up to 3 m) and as stem diameter of noninjected plants increased. The plausible modes ofinter- and intraspecific herbicide translocation include root grafts, mutually shared mycorrhizal fungi, root exudation and absorption, and/or leaf senescence. Because tree-of-heaven is clonal, patch size and vegetation heterogeneity will be an important determinant of herbicide injectionprotocols. In forest environments with many small patches (i.e., high edge to interior ratio) or mixed species stands, nontarget hardwoods are at an increased risk of mortality. In isolated large patches (with lower edge to interior ratio) or dense monospecific clones, injection risk to nontarget species will be relatively low.

Estradiol increases dendritic spine density and synaptogenesis in the CA1 region of the female hippocampus. This effect is specific to females, as estradiol-treated males fail to show increases in hippocampal spine density. Estradiol-induced spinogenesis in the female is dependent upon upregulation of the N-methyl-D-aspartic acid (NMDA) receptor as well as on non-nuclear estrogen receptors (ER), including those found in dendrites. Thus, in the male, the inability of estradiol to induce spinogenesis may be related to a failure of estradiol to increase hippocampal NMDA receptors as well as a paucity of dendritic ER. In the first experiment, we sought to investigate this possibility by assessing NMDA receptor binding, using [3H]-glutamate autoradiography, in estradiol-treated males and females. We found that while estradiol increases NMDA binding in gonadectomized females, estradiol fails to modulate NMDA binding in gonadectomized males. To further investigate sex differences in the hippocampus, we conducted a second separate, but related, ultrastructural study in which we quantified ERα-immunoreactivity (ERα-ir) in neuronal profiles in the CA1 region of the hippocampus in intact males and females in diestrus and proestrus. Consistent with previous reports in the female, we found ERα-ir in several extranuclear sites including dendrites, spines, terminals and axons. Statistical analyses revealed that females in proestrus had a 114.3% increase in ERα-labeled dendritic spines compared to females in diestrus and intact males. Taken together, these studies suggest that both the ability of estrogen to increase NMDA binding in the hippocampus and the presence of ERα in dendritic spines may contribute to the observed sex difference in estradiol-induced hippocampal spinogenesis.

The rationalisation of class sizes and subject offerings in majors, and the implementation of workloads models establishing parity in teaching hours and in student load per staff member across Faculty have created considerable challenges for tertiary foreign-language teaching over the past decade. This paper presents one way of responding to the imperatives of the new order, involving the adaptation and management of traditional class activities so that they remain valid in a group of 60 or more students, and the development and delivery of computer-based activities to allow students to receive as much (or as little) individualised instruction as they need outside of class. It reflects on principles and practices which, although not new, have assumed particular importance in the new environment, and analyses the impact of the changes on the dynamic of the class. This article is adapted from a paper entitled ‘Teaching Language in Large Groups’ presented by invitation at the National Language Workshop on ‘Teaching and Research in University Language Programs: Successful Practices, Creative Strategies’, organised by the Deans of the Faculties of Arts, Social Sciences and Humanities in Australasia (DASSH), Griffith University, Brisbane, 14-16 June, 2002) Ma n a g i n g L a rg e F o r e ig n Cla s s es a t U n iv er s i ty Br ia n McC a r th y Journal of University Teaching and Learning Practice – Vol 1/1, 35-48, 2004 36 The shift to large classes The structuro-global audio-visual approaches to foreign language teaching in the 60s and 70s were originally designed to be used in an intensive mode. Their syllabus of basic language skills was typically covered in a 10-week course of 20-25 hrs per week. These methods were conceived and developed principally in the country of the target language, and built on the dynamics of small group interactions focusing on a shared linguistic experience in the miniature world created by audio-visual materials in a teacher-managed environment. Classes were seen as ‘laboratories’ in the sense that, as with Chemistry or Music, and whether or not an actual language laboratory was used, the overall progress made by students was expected to be roughly proportional to the amount of structured, hands-on, supervised, practical experience that could be integrated into their academic training. When these approaches were first introduced into Australia, times were relatively good in the sphere of tertiary education, and there was little financial obstacle to creating structures that supported the academically driven model of discrete, ‘semi-intensive’ (6 hrs per week) classes of approximately 20 students. The past decade has seen a shift from the methodology-driven budget to the budget-driven methodology. Large-group teaching of foreign languages is essentially the result of a requirement that foreign language instruction be delivered on the same resourcing model as traditional humanities subjects. The classic pattern for Arts faculties is either 2 hours per week of plenary lectures accompanied by a 1-hour tutorial in groups of 15, or 1 hour per week in a plenary lecture with 2 hours of seminars in groups of 20. For a class of 60 students, the first of these models requires a total of 6 hours of instruction (2 hrs of lectures, 4 hrs of tutorials), and the second, 7 hours of instruction (1 hr of lectures, 6 hours of seminars). This clearly presents a challenge for foreign language departments. If the retention of discrete groups of 20 students remains the top priority, then a cohort of 60 students could only be provided with 2 or, at the outside, 3 hours per week of instruction per student (i.e. 2 hrs per week for 3 groups of 20 students requires a total of 6 hours of instruction, 3 hours per week of instruction for 3 groups of 20 students requires a total of 9 hours of instruction). It could be argued that such a model not only halves the time available to cover the formal instruction of basic language skills (i.e. the equivalent of a full secondary school foreign language syllabus), but it creates a situation in which the instruction is so ‘unintensive’ that it is impractical to persevere with the teaching approach which produced the need for discrete small groups in the first place. Different Modern Languages programs and individual foreign language coordinators around Australia have responded to the imperatives of the new order in different ways. The challenge has been met at Wollongong by adopting a radical change of approach to teaching in order to retain the same maximum contact hours (i.e. 6 hrs per week) as in other academic disciplines with a strong practical component such as Science, Informatics, Creative Arts and Engineering. In the context of a Faculty rationalisation of class sizes and subject offerings in majors, and the implementation of a workloads model establishing parity in teaching hours and student load per staff member across the Faculty, the corollary of maximising the number of hours of instruction received by each student is an increase in class size. The main planks of the new approach have been the adaptation and management of traditional class activities so that they remain valid in a class of 60 or more students, and the provision of integrated computer-based activities to allow students to receive as much (or as little) individualised instruction as they need outside of the class. These two areas are dealt with in the sections ‘Classroom principles and practices’ and ‘Computer support‘. The syllabus content and the aspects assessed are unchanged. The objective remains to cover the 6-year secondary school syllabus in one academic year, thus enabling post-secondary students to enter the language component of their major in the subject taken by beginners in their third semester. Ma n a g i n g L a rg e F o r e ig n Cla s s es a t U n iv er s i ty Br ia n McC a r th y Journal of University Teaching and Learning Practice – Vol 1/1, 35-48, 2004 37 Key elements of the syllabus are: the linguistic knowledge and skills of a contemporary commercial coursebook developed by a team of native-speaker experts in foreign language teaching methodology following a functional, communicative approach and supported by a range of audio and audio-visual resources; a thorough grounding in the grammar of the language so that students will have a tool for subsequent independent language analysis and a platform on which to build an academic specialisation in the target language; contextualisation of linguistic skills in the culture of the target language; sensitivity to the social issues and the perspective on current affairs of the foreign culture; and an initiation into the literature of the foreign language. Classroom principles and practices It is not only the syllabus and the emphasis on the communicative aspects of the language that have remained constant. The new situation has not meant the rejection of conventional activities such as explanation, question-and-answer, pairwork, information-gap activities, traditional pattern drills, and exploitation of video material, recordings and realia. A number of principles and practices, however, have assumed particular importance in the new environment. It is acknowledged that the lists that follows are not exhaustive, and, more importantly, that the principles are very definitely not exclusive to large-group teaching. In fact, most would be stock items in any compendium of sound teaching practice. But whereas they could be dealt with casually in small groups, in the context of large-group foreignlanguage teaching, student dependence on their obvious presence and clear articulation is greatly increased and the capacity of the teacher to detect and compensate for any fuzziness by one-to-one interaction with any student who may be encountering difficulty is correspondingly reduced. The challenge lies in effective management of familiar processes and activities in an unfamiliar environment. The inventory is presented in the categories: Syllabus, Assessment, Resources and Crowd Control.

A 2-year whole-farm system study compared the accumulation, utilization and nutritive value of grass in spring-calving grass-based systems differing in stocking rate (SR) and calving date (CD). Six treatments (systems) were compared over two complete grazing seasons. Stocking rates used in the study were low (2·5 cows ha−1), medium (2·9 cows ha−1) and high (3·3 cows ha−1), respectively, and mean CDs were 12 February (early) and 25 February (late). Each system had its own farmlet of eighteen paddocks and one herd that remained on the same farmlet area for the duration of the study. Stocking rate had a small effect on total herbage accumulation (11 860 kg DM ha−1 year−1), but had no effect on total herbage utilization (11 700 kg DM ha−1 year−1). Milk and milk solids (MS; fat + protein) production per ha increased by 2580 and 196 kg ha−1 as SR increased from 2·5 to 3·3 cows ha−1. Milk production per ha and net herbage accumulation and utilization were unaffected by CD. Winter feed production was reduced as SR increased. Increased SR, associated with increased grazing severity, resulted in swards of increased leaf content and nutritive value. The results indicate that, although associated with increased milk production per ha, grazed grass utilization and improved sward nutritive value, the potential benefits of increased SR on Irish dairy farms can only be realized if the average level of herbage production and utilization is increased.

It is not bold to predict that in many countries it will soon be no morepossible for education systems to be computer-free than it already is for transport systems to be motor-vehicle-free. The technology simply has too much to offer in too many areas for people to ignore it or to be content todo without it. It is therefore in the interest of any community of learnersand teachers that very careful thought be given to the integration of computers into the education process if they are to avoid situations in the classroom that are informatic equivalents of traffic jams, exhaust pollution, lunatic drivers, and road fatalities. On the road, mayhem and casualties are minimised by such things as road rules, town planning, speed limits, vehicle inspection, sign-posting, traffic lights, speed cameras and random breath testing.

This article is not intended to be either an exposition of a theory of software design or an author's review of his own software. It presents a set of reflections on pedagogical, linguistic and design considerations that emerged in the process of producing a real, innovative and classroomfriendly piece of CALL software within the limitations imposed by a HyperCard environment and by the desire to create something that could be readily transported on floppy disk and would run on virutally anyone's Macintosh.

The workspace of a mechanism is the set of positions and orientations that is reachable by its end effector. Workspaces have numerous applications, including motion planning, mechanism design, and manufacturing process planning, but their representation and computation is challenging due to high dimensionality and geometric/topological complexity. We propose a new formulation of the workspace computation problem for a large class of mechanisms represented by series-parallel constraint graphs. A wide variety of allowable constraints include all lower pair, some higher pair, and non-collision constraints. We show that the workspace of such mechanisms may be computed by a constraint propagation algorithm. After the space of all rigid body motions is discretized, these operations can be efficiently implemented using the Fast Fourier Transform and a depth first search. In contrast to algebraic formulations, the proposed method assures that all configurations in the computed workspace not only satisfy pairwise constraints but can be reached without breaking and reassembling the mechanism.

Noncanonical Pathway The textbook view of translation of messenger RNA to protein is that it is always initiated from open reading frames (ORFs) that begin with an AUG codon (encodes methionine) by an initiator methionine-bound transfer RNA (tRNA). There is evidence, however, that some polypeptides are produced from non–AUG-initiated ORFs. Starck et al. (p. 1719 ; see the Perspective by Dever ) used a variety of biochemical techniques to determine the underlying mechanism for such nontraditional translation initiation. Comparison of translation initiation from AUG-initiated ORFs with those beginning with leucine CUG-initiated ORFs revealed that cells can use an elongator Leu-tRNA to initiate translation at CUG codons. CUG-initiated peptides were presented by major histocompatibility class I molecules and could activate T cells.

Research articles on CALL frequently proceed from the general to the specific. The general can take the form of a survey of the literature, a theory or theories of language teaching, learning or acquisition, or a summarised appraisal of a number of pieces of software; the specific is usually a collection of examples from a variety of sources to illustrate a principle. The merits of such an approach are widely recognised and are in no way disputed by the present writer. It is easy, however, for lack of attention to detail to leave the reader with many unanswered questions: Wouldn't it be alright to include/omit a given feature if… or if…? How did they come up with that technique? Why did/didn't they present the information this way? Exactly who was this designed for? How and when was it intended to be used? What constraints were they working under? In this article we have chosen to proceed in the opposite direction and trace the processes involved in developing one piece of software.