Full Time Course Research Articles

Epidemic Spread on Weighted Networks

The contact structure between hosts shapes disease spread. Most network-based models used in epidemiology tend to ignore heterogeneity in the weighting of contacts between two individuals. However, this assumption is known to be at odds with the data for many networks (e.g. sexual contact networks) and to have a critical influence on epidemics' behavior. One of the reasons why models usually ignore heterogeneity in transmission is that we currently lack tools to analyze weighted networks, such that most studies rely on numerical simulations. Here, we present a novel framework to estimate key epidemiological variables, such as the rate of early epidemic expansion () and the basic reproductive ratio (), from joint probability distributions of number of partners (contacts) and number of interaction events through which contacts are weighted. These distributions are much easier to infer than the exact shape of the network, which makes the approach widely applicable. The framework also allows for a derivation of the full time course of epidemic prevalence and contact behaviour, which we validate with numerical simulations on networks. Overall, incorporating more realistic contact networks into epidemiological models can improve our understanding of the emergence and spread of infectious diseases.

Full Time Course Kinetics of the Streptokinase-Plasminogen Activation Pathway

Our previously hypothesized mechanism for the pathway of plasminogen (Pg) activation by streptokinase (SK) was tested by the use of full time course kinetics. Three discontinuous chromogenic substrate initial rate assays were developed with different quenching conditions that enabled quantitation of the time courses of Pg depletion, plasmin (Pm) formation, transient formation of the conformationally activated SK·Pg* catalytic complex intermediate, formation of the SK·Pm catalytic complex, and the free concentrations of Pg, Pm, and SK. Analysis of full time courses of Pg activation by five concentrations of SK along with activity-based titrations of SK·Pg* and SK·Pm formation yielded rate and dissociation constants within 2-fold of those determined previously by continuous measurement of parabolic chromogenic substrate hydrolysis and fluorescence-based equilibrium binding. The results obtained with orthogonal assays provide independent support for a mechanism in which the conformationally activated SK·Pg* complex catalyzes an initial cycle of Pg proteolytic conversion to Pm that acts as a trigger. Higher affinity binding of the formed Pm to SK outcompetes Pg binding, terminating the trigger cycle and initiating the bullet catalytic cycle by the SK·Pm complex that converts the residual Pg into Pm. The new assays can be adapted to quantitate SK-Pg activation in the context of SK- or Pg-directed inhibitors, effectors, and SK allelic variants. To support this, we show for the first time with an assay specific for SK·Pg* that fibrinogen forms a ternary SK·Pg*·fibrinogen complex, which assembles with 200-fold enhanced SK·Pg* affinity, signaled by a perturbation of the SK·Pg* active site.

Academic Quality Assurance in the Colleges of Education: Challenges and Ways Forward for Future Development

Colleges of education encompassed the production of professional teachers who are equipped with skills and methodologies of teaching in our primary and junior secondary levels of education in Nigeria. Essentially, colleges of education are to provide full-time courses in teaching, instruction and training and to conduct courses in education for qualified teachers. In order to achieve this objective, academic quality assurance is required. Against this background, the paper examines academic quality assurance and determines the general opinion on academic quality assurance in the colleges of education. It equally highlights some challenges to academic quality assurance in the colleges of education. Finally, the paper proffered some solution required by the colleges of education to stamp out the challenges for future development. Finally, the paper recommends that there should be regular monitoring and evaluation of all the units concern with the certification of colleges of education graduates.

Quantitative full time course analysis of nonlinear enzyme cycling kinetics

Enzyme inhibition due to the reversible binding of reaction products is common and underlies the origins of negative feedback inhibition in many metabolic and signaling pathways. Product inhibition generates non-linearity in steady-state time courses of enzyme activity, which limits the utility of well-established enzymology approaches developed under the assumption of irreversible product release. For more than a century, numerous attempts to find a mathematical solution for analysis of kinetic time courses with product inhibition have been put forth. However, no practical general method capable of extracting common enzymatic parameters from such non-linear time courses has been successfully developed. Here we present a simple and practical method of analysis capable of efficiently extracting steady-state enzyme kinetic parameters and product binding constants from non-linear kinetic time courses with product inhibition and/or substrate depletion. The method is general and applicable to all enzyme systems, independent of reaction schemes and pathways.

Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome.

BackgroundRare genetic variation is an important class of autism spectrum disorder (ASD) risk factors and can implicate biological networks for investigation. Altered serotonin (5-HT) signaling has been implicated in ASD, and we and others have discovered multiple, rare, ASD-associated variants in the 5-HT transporter (SERT) gene leading to elevated 5-HT re-uptake and perturbed regulation. We hypothesized that loci encoding SERT regulators harbor variants that impact SERT function and/or regulation and therefore could contribute to ASD risk. The adenosine A3 receptor (A3AR) regulates SERT via protein kinase G (PKG) and other signaling pathways leading to enhanced SERT surface expression and catalytic activity.MethodsTo test our hypothesis, we asked whether rare variants in the A3AR gene (ADORA3) were increased in ASD cases vs. controls. Discovery sequencing in a case-control sample and subsequent analysis of comparison exome sequence data were conducted. We evaluated the functional impact of two variants from the discovery sample on A3AR signaling and SERT activity.ResultsSequencing discovery showed an increase of rare coding variants in cases vs. controls (P=0.013). While comparison exome sequence data did not show a significant enrichment (P=0.071), combined analysis strengthened evidence for association (P=0.0025). Two variants discovered in ASD cases (Leu90Val and Val171Ile) lie in or near the ligand-binding pocket, and Leu90Val was enriched individually in cases (P=0.040). In vitro analysis of cells expressing Val90-A3AR revealed elevated basal cGMP levels compared with the wildtype receptor. Additionally, a specific A3AR agonist increased cGMP levels across the full time course studied in Val90-A3AR cells, compared to wildtype receptor. In Val90-A3AR/SERT co-transfections, agonist stimulation elevated SERT activity over the wildtype receptor with delayed 5-HT uptake activity recovery. In contrast, Ile171-A3AR was unable to support agonist stimulation of SERT. Although both Val90 and Ile171 were present in greater numbers in these ASD cases, segregation analysis in families showed incomplete penetrance, consistent with other rare ASD risk alleles.ConclusionsOur results validate the hypothesis that the SERT regulatory network harbors rare, functional variants that impact SERT activity and regulation in ASD, and encourages further investigation of this network for other variation that may impact ASD risk.

GABA UPTAKE BY GAT1 MODULATES LONG-TERM OPTICAL CHANGES FOLLOWING ELECTRICAL STIMULATION OF THE PITUITARY GLAND NEUROINTERMEDIATE LOBE

Intrinsic optical changes that follow infundibular stalk stimulation of the neurointermediate lobe of the mouse pituitary gland exhibit three different phases that reflect three distinct physiological events. The first (E-wave) is the rapid light-scattering increase that is associated with a nerve terminal volume increase (mechanical spike), and that accompanies excitation of the neurohypophysial terminals by the invading action potential; the second (S-wave) is the slower light-scattering decrease that is tightly correlated with the secretion of the peptide hormones oxytocin and arginine vasopressin, and the third is the long-duration response (R-wave) that reflects cell volume changes in the pars intermedia. We have studied the E-wave and the S-wave in earlier publications. The R-wave, considered here, is sensitive to chloride replacement as well as to blockade of chloride channels. By blocking GABAAreceptors (which are ligand-gated chloride channels) with pharmacological agents, and by applying GABA directly into the bathing solution, or evoking its release from GABAergic inputs, we have demonstrated that this long-duration optical response is sensitive to chloride movements and reflects GABA-induced changes in the intrinsic optical properties of the pars intermedia. The full time-course of this optical response takes minutes and, therefore, has to embody some other process (or processes) related to the restoration of resting physiological chloride concentrations, following the opening and closing of GABAA-receptor channels. Here we demonstrate that the shape of the R-wave, the long-lasting light-scattering signal, is indeed affected by the activity of GAT1, one of the sodium- and chloride-dependent GABA transporters.

How Students Perceive Professional Courses with Special Reference to Part Time and Full Time Courses in Kolkata and its Suburbs

The paper focuses on the behavioural aspect of undergraduate students who want to pursue higher educational especially professional courses and deals with how students perceive full time and part time courses along with course fee structures. This also shows the perception of students regarding job guarantee along with course duration. The finding in the paper gives a clear idea that job guarantee is an important factor while opting for professional courses irrespective of gender. The investigation here finds that if students were offered a professional course that would actualize their dreams, they were even willing to migrate to other cities. The paper also investigates preference order of sample students' career options in some selected sector among FMCG/CD, Retail, Manufacturing, IT, and BPO.

Pathophysiology of Exercise Heart Rate Recovery: A Comprehensive Analysis

Expanded use of exercise heart rate recovery (HRR) has renewed interest in the pathophysiology of heart rate control. This study uses basic physiologic principles to construct a unique model capable of describing the full time course of sympathetic and parasympathetic activity during HRR. The model is tested in a new study of 22 diverse subjects undergoing both maximal and submaximal treadmill exercise. Based on this analysis, prolongation of HRR involves changes within the sinus node, changes in sympathetic function, in parasympathetic function, and in the central mechanisms regulating autonomic balance. The methods may provide unique insight into alterations in autonomic control in health and disease.

Quantitative analysis of the time course of Aβ oligomerization and subsequent growth steps using tetramethylrhodamine-labeled Aβ

Although amyloid β (Aβ) is a critical player in the pathology of Alzheimer's disease, there is currently little Information on the rate and extent of formation of oligomers that lead to the presence of Aβ fibrils observed in amyloid plaques. Here we describe a unique method to monitor the full time course of Aβ aggregation. In this method, Aβ is labeled with tetramethylrhodamine at a lysine residue on the N-terminal end. During aggregation, the fluorescence is quenched in a time-dependent manner in three distinct phases: an early oligomerization phase, an intermediate phase, and a growth phase. The oligomerization phase can be characterized as a monomer-dimer-trimer process for which we have determined the rate and equilibrium constants. The rate constants differ markedly between Aβ(1-42) and Aβ(1-40), with Aβ(1-42) showing a greater oligomerization propensity. The intermediate phase reflects slow clustering and reorganization of the oligomers, whereas the growth phase ultimately results in the formation of fibrillar material. The data are consistent with a conformational change being an important rate-limiting step in the overall aggregation process. The rates of all phases are highly sensitive to temperature and pH, with the pH-dependent data indicating important roles for lysine and histidine residues. From the temperature-dependent data, activation energies of oligomerization and fibrillization are estimated to be 5.5 and 12.1 kCal/mol, respectively. The methodologies presented here are simple and can be applied to other amyloidogenic peptides or proteins.

What is Tropical Medicine?

Copyright: © 2013 Miller A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. At first sight this seems a question with an obvious response and not one that requires debate in the editorial columns of a tropical medicine journal. However, the answer may be more complex than appears at first sight and perhaps it may therefore benefit from a more detailed exploration. The obvious response is that the discipline of “Tropical Medicine” refers to the practice of medicine in the tropics. But does it refer to all medical practice that takes place within the Tropics, does it refer to the practice of medicine within resource poor settings or does it refer to the diagnosis and treatment of infectious and parasitic diseases found in a tropical environment? There is no standard definition of Tropical Medicine. In the UK, doctors who wish to specialize in Tropical Medicine (TM) must first train in General Internal Medicine (GIM) and secure their exam to gain Membership of the Royal College of Physicians (MRCP). They then follow the training pathway for specialists in Infectious Disease (ID) with the addition of doing a full time course of study for the Diploma of Tropical Medicine & Hygiene (DTM&H). Study is carried out at either the London or Liverpool Schools of Tropical Medicine and the diploma is conferred either by the Royal College of Physicians of London or the Liverpool School of Tropical Medicine. Additionally trainees who wish to be certified in TM must spend at least 2 years of their training at the UK centre approved for TM training (currently Liverpool, London and Birmingham) and spend a year working overseas in a resource poor setting. In many other countries, TM does not exist as a distinct specialty but is incorporated into the practice of Infectious Disease. In the US, it is not a board certified specialty but there are several credentialed courses available. These days, Tropical Medicine is often referred to as global/geographical health or international health and it encompasses a number of sub specialties such as refugee healthcare, travel medicine and expedition or remote/wilderness medicine.

2257 – Family interventions for the severe mentally ill in portugal: a country-level project of training and implementation

Introduction Psychiatric deinstitutionalization has been frequently associated with an increase in family burden in most Western countries. Research shows that notwithstanding of evidence of its usefulness, family interventions for psychotic disorders are not routinely applied in most public mental health services. This applies especially to countries where family issues are not so well documented, such as Portugal. To address that issue, the Ministry of Health hurled a training program on family interventions for the severe mentally ill, ensuing the recommendations of the National Mental Health Plan. Objectives a) to launch a family intervention training program on a national level, and b) to identify the obstacles to implementation in routine settings. Methods Professionals from public mental health services throughout Portugal attended a 3 days full-time course in which they were trained in the family intervention, consisting in guidelines presentation and discussion, demonstrative audios/videos and role-playing sessions. Results The trainees' acquisition of competences was found rather encouraging. Perceived obstacles to the implementation of the family intervention in routine practice comprised work overload, the nuisance to integrate weekly family sessions with other professional tasks, and the stunted availability of time to run the intervention on a regular basis. Conclusions Arrangements need to be envisaged in order to overcome deal with barriers limiting the implementation of family interventions in routine settings. Amelioration have to focus on changing the organisation of the mental health facilities, like greater handiness of dedicated hours and career inducements for professionals working with the families of psychotic patients.

COMPLETION EFFICIENCY AND ITS INFLUENCING FACTORS OF STATISTICS I. COMPULSORY COURSE

In the Budapest Business School College of Finance and Accountancy 989 students attended the compulsory course unit Statistics I. in the Spring semester of 2011/2012 in full-time courses on bachelor level. During the semester two tests – a midterm and a final test, 50 points each – had to be written. The results, the points obtained in the two written tests, the total points and the factors influencing the results are investigated in this paper. In our opinion the accomplishment of the course on an acceptable level depends on several factors. The studies before the college provide very important information, since the completion of high school studies on a better level significantly influences the results at the college. We investigate how the performance is affected by the fact whether the students graduated at grammar- or technical school, which subjects of the school-leaving exam were taken into account and how many points were reached when they applied for admission to the college. It was also a question for us whether knowledge of languages and its level influences the level of completion of the Statistics course or not.

GABA Uptake by GAT-1 Modulates Long-Term Optical Changes following Secretion in the Mouse Neurohypophysis

Intrinsic optical changes in the mouse pituitary gland associated with secretion exhibit three phases (waves) that reflect three distinct physiological events. The first (E-wave) is the rapid light scattering change that is associated with a nerve terminal volume increase (mechanical spike) that accompanies excitation of the neurohypophysial terminals by the invading action potential (Kim et al., Biophys. J. 92(9) 3122-3129 (2007)); the second (S-wave) is the slower, opposite change in light scattering that reflects the secretion of the peptide hormones, oxytocin and arginine vasopressin, and the third is the long duration response (recovery phase or R-wave) that reflects cell volume changes in the pars intermedia. This recovery phase is sensitive to chloride replacement and to blockade of chloride channels. Experiments that employ pharmacological blockers of GABAA receptors (chloride channels), as well as direct bath application of GABA, alter the R-wave in a manner that reflects GABA-induced changes in the intrinsic optical properties of the pars intermedia (Kosterin et al., Neuroendocrinology 92, 158-167 (2010)). Because the full time-course of this optical response takes minutes, we suggested that, in addition to chloride-channel opening / closing, some additional processes related to the restoration of resting physiological chloride concentrations may occur. Indeed, we demonstrate here that the time-course of this long term light scattering signal is also affected by the turnover of GAT-1, the sodium- and chloride-dependent GABA-transporter.Supported by RO1 040966.

Membrane Cholesterol Strongly Influences Confined Diffusion of Prestin

Prestin is the membrane motor protein that drives outer hair cell (OHC) electromotility, a process that is essential for mammalian hearing. Prestin function is sensitive to membrane cholesterol levels, and numerous studies have suggested that prestin localizes in cholesterol-rich membrane microdomains. Previously, fluorescence recovery after photobleaching experiments were performed in HEK cells expressing prestin-GFP after cholesterol manipulations, and revealed evidence of transient confinement. To further characterize this apparent confined diffusion of prestin, we conjugated prestin to a photostable fluorophore (tetramethylrhodamine) and performed single-molecule fluorescence microscopy. Using single-particle tracking, we determined the microscopic diffusion coefficient from the full time course of the mean-squared deviation. Our results indicate that prestin undergoes diffusion in confinement regions, and that depletion of membrane cholesterol increases confinement size and decreases confinement strength. By interpreting the data in terms of a mathematical model of hop-diffusion, we quantified these cholesterol-induced changes in membrane organization. A complementary analysis of the distribution of squared displacements confirmed that cholesterol depletion reduces prestin confinement. These findings support the hypothesis that prestin function is intimately linked to membrane organization, and further promote a regulatory role for cholesterol in OHC and auditory function.

Problem-based Learning for Design and Engineering Activities in Virtual Worlds

There are a growing number of problem-based learning (PBL) studies in virtual worlds (VWs); however, the suitability of these approaches is still unknown for particular knowledge domains and in full-time courses. In this paper, we argue that VWs can support a constructionist approach to PBL for blended-practice-based courses of design and engineering, and we describe an instructional design framework and its application at an HCI (human–computer interaction) design course. The approach places emphasis on learning by doing, and enables students to collaboratively work in authentic and ill-defined situations, follow self-directed routes to address problems, and construct digital artifacts as candidate solutions. The proposed approach translates the principles of PBL into guidelines for setting up a VW as a learning environment, building supporting tools, and implementing learning activities that require that students create digital models that reflect their understanding about their learning. We have applied the framework in a blended postgraduate course in HCI design that involved various PBL activities and the application of methods related to the lifecycle of interactive product development (including user research, conceptual design, prototyping, and usability evaluation). The results were encouraging with respect to the applicability of the approach, students' acceptance, as well as perceived usability of the VW environment and tools in the long term.

Analytical Integrate-and-Fire Neuron Models with Conductance-Based Dynamics and Realistic Postsynaptic Potential Time Course for Event-Driven Simulation Strategies

In a previous paper (Rudolph & Destexhe, 2006), we proposed various models, the gIF neuron models, of analytical integrate-and-fire (IF) neurons with conductance-based (COBA) dynamics for use in event-driven simulations. These models are based on an analytical approximation of the differential equation describing the IF neuron with exponential synaptic conductances and were successfully tested with respect to their response to random and oscillating inputs. Because they are analytical and mathematically simple, the gIF models are best suited for fast event-driven simulation strategies. However, the drawback of such models is they rely on a nonrealistic postsynaptic potential (PSP) time course, consisting of a discontinuous jump followed by a decay governed by the membrane time constant. Here, we address this limitation by conceiving an analytical approximation of the COBA IF neuron model with the full PSP time course. The subthreshold and suprathreshold response of this gIF4 model reproduces remarkably well the postsynaptic responses of the numerically solved passive membrane equation subject to conductance noise, while gaining at least two orders of magnitude in computational performance. Although the analytical structure of the gIF4 model is more complex than that of its predecessors due to the necessity of calculating future spike times, a simple and fast algorithmic implementation for use in large-scale neural network simulations is proposed.

Mechanism‐based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV

To assess the pharmacokinetics of vildagliptin at different doses and build a mechanism-based population model that simultaneously describes vildagliptin pharmacokinetics and its effects on DPP-4 activity based on underlying physiology and biology. Vildagliptin concentrations and DPP-4 activity vs. time from 13 type 2 diabetic patients after oral vildagliptin 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. NONMEM VI and S-ADAPT were utilized for population modelling. A target-mediated drug disposition (TMDD) model accounting for capacity-limited high affinity binding of vildagliptin to DPP-4 in plasma and tissues had good predictive performance. Modelling the full time course of the vildagliptin-DPP-4 interaction suggested parallel vildagliptin dissociation from DPP-4 by a slow first-order process and hydrolysis by DPP-4 to an inactive metabolite as a disposition mechanism. Due to limited amounts of DPP-4, vildagliptin concentrations increased slightly more than dose proportionally. This newly proposed model and the parameter estimates are supported by published in vitro studies. Mean parameter estimates (inter-individual coefficient of variation) were: non-saturable clearance 36 l h−1 (25%), central volume of distribution 22 l (37%), half-life of dissociation from DPP-4 1.1 h (94%) and half-life of hydrolysis 6.3 h (81%). Vildagliptin is both an inhibitor and substrate for DPP-4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP-4 was found in patients and the half-life of hydrolysis by DPP-4 estimated. This model can be used to predict DPP-4 inhibition effects of other dosage regimens and be modified for other DPP-4 inhibitors to differentiate their properties.

Use of a wiki as an interactive teaching tool in pathology residency education: Experience with a genomics, research, and informatics in pathology course

Background: The need for informatics and genomics training in pathology is critical, yet limited resources for such training are available. In this study we sought to critically test the hypothesis that the incorporation of a wiki (a collaborative writing and publication tool with roots in “Web 2.0”) in a combined informatics and genomics course could both (1) serve as an interactive, collaborative educational resource and reference and (2) actively engage trainees by requiring the creation and sharing of educational materials. Materials and Methods: A 2-week full-time course at our institution covering genomics, research, and pathology informatics (GRIP) was taught by 36 faculty to 18 second- and third-year pathology residents. The course content included didactic lectures and hands-on demonstrations of technology (e.g., whole-slide scanning, telepathology, and statistics software). Attendees were given pre- and posttests. Residents were trained to use wiki technology (MediaWiki) and requested to construct a wiki about the GRIP course by writing comprehensive online review articles on assigned lectures. To gauge effectiveness, pretest and posttest scores for our course were compared with scores from the previous 7 years from the predecessor course (limited to informatics) given at our institution that did not utilize wikis. Results: Residents constructed 59 peer-reviewed collaborative wiki articles. This group showed a 25% improvement (standard deviation 12%) in test scores, which was greater than the 16% delta recorded in the prior 7 years of our predecessor course (P = 0.006). Conclusions: Our use of wiki technology provided a wiki containing high-quality content that will form the basis of future pathology informatics and genomics courses and proved to be an effective teaching tool, as evidenced by the significant rise in our resident posttest scores. Data from this project provide support for the notion that active participation in content creation is an effective mechanism for mastery of content. Future residents taking this course will continue to build on this wiki, keeping content current, and thereby benefit from this collaborative teaching tool.

Mapping of nutrition teaching and training initiatives in India: the need for Public Health Nutrition.

India spans the spectrum of under- and overnutrition disorders and does so in generous proportions. India also tops the charts globally in the prevalence of risk factors for several chronic diseases. Although Public Health Nutrition (PHN) - both as an academic field as well as a means to improved health - has been around for two centuries in developed countries, it is only now coming to the fore as a conduit for tackling nutrition-related disorders in developing countries. In the light of these issues, we undertook an exercise to map the existing educational initiatives for nutrition, and in particular PHN, in India. This situational analysis of PHN across India was conducted using a combination of Internet search, telephone calls as well as interviews with experts. Information collected was pooled and tabulated using a snowball approach. India. Not applicable. Currently, there are nearly 190 institutes in India that offer one or more nutrition courses, with the majority offering full-time courses. Of these, PHN was offered in less than five institutes across India and opportunities were confined to specialization options/modules. This situational analysis reveals the huge gap in existing nutrition ventures and points towards the urgent need to undertake newer academic initiatives especially in the field of PHN in India. Reforms in the education and employment sector need to be brought in which may include working towards making the field of nutrition attractive for career pursuit. The focus of this discipline needs to be broadened to, but not limited to, span the entire spectrum from dietetics to research and teaching. Strong synergistic collaborations and academic partnerships with other developed countries should be encouraged to catalyse finding solutions to emerging and/or existing threats to public health problems.

Comprehension of Linguistic Dependencies: Speed‐Accuracy Tradeoff Evidence for Direct‐Access Retrieval From Memory

Comprehenders can rapidly and efficiently interpret expressions with various types of non-adjacent dependencies. In the sentence The boy that the teacher warned fell, boy is readily interpreted as the subject of the verb fall despite the fact that a relative clause, that the teacher warned, intervenes between the two dependent elements. We review research investigating three memory operations proposed for resolving this and other types of non-adjacent dependencies: serial search retrieval, in which the dependent constituent is recovered by a search process through representations in memory, direct-access retrieval in which the dependent constituent is recovered directly by retrieval cue operations without search, and active maintenance of the dependent constituent in focal attention. Studies using speed-accuracy tradeoff methodology to examine the full timecourse of interpreting a wide range of non-adjacent dependencies indicate that comprehenders retrieve dependent constituents with a direct-access operation, consistent with the claim that representations formed during comprehension are accessed with a cue-driven, content-addressable retrieval process. The observed timecourse profiles are inconsistent with a broad class of models based on several search operations for retrieval. The profiles are also inconsistent with active maintenance of a constituent while concurrently processing subsequent material, and suggest that, with few exceptions, direct-access retrieval is required to process non-adjacent dependencies.