Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetic–pharmacodynamic modeling in acute and chronic pain: an overview of the recent literature

In acute and chronic pain, the objective of pharmacokinetic–pharmacodynamic (PKPD) modeling is the development and application of mathematical models to describe and/or predict the time course of the pharmacokinetics (PK) and pharmacodynamics (PD) of analgesic agents and link PK to PD. Performing population PKPD modeling using nonlinear mixed effects modeling allows, apart from the estimation of fixed effects (the PK and PD model estimates), the quantification of random effects as within- and between-subject variability. Effect-compartment models and mechanism-based biophase distribution models that incorporate drug-association and -dissociation kinetics are applied in PKPD modeling of pain treatment. Mechanism-based models enable the quantification of the rate-limiting factors in drug effect owing to drug distribution versus receptor kinetics (since receptor kinetics are nonlinear they are discernable from the linear effect-compartment kinetics). It is a helpful technique in understanding the complex behavior of specific analgesics, such as buprenorphine, but also morphine and its active metabolite morphine-6-glucuronide, especially with respect to the reversal of opioid-induced side effects, most importantly life-threatening respiratory depression. One approach in chronic pain studies is the application of mixture models. Mixture models do not necessarily need to take PK data into account and allow the objective differentiation of measured responses to analgesics into specific response subgroups, and as such, may play an important role in analyzing Phase I and II analgesia studies. Appropriate application of PKPD modeling leads to the improvement of current therapeutics with respect to dose design and outcome, understanding the interaction of analgesics within complex chronic pain disease processes and may play an important role in drug development. In the current article, novel observations using the aforementioned techniques on opioids, NSAIDs, epidural analgesia, ketamine and GABA-ergic drugs in acute and chronic pain are discussed.
Low-Intensity Repetitive Transcranial Magnetic Stimulation Improves Abnormal Visual Cortical Circuit Topography and Upregulates BDNF in Mice

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used as a treatment for neurological and psychiatric disorders. Although the induced field is focused on a target region during rTMS, adjacent areas also receive stimulation at a lower intensity and the contribution of this perifocal stimulation to network-wide effects is poorly defined. Here, we examined low-intensity rTMS (LI-rTMS)-induced changes on a model neural network using the visual systems of normal (C57Bl/6J wild-type, n = 22) and ephrin-A2A5−/− (n = 22) mice, the latter possessing visuotopic anomalies. Mice were treated with LI-rTMS or sham (handling control) daily for 14 d, then fluorojade and fluororuby were injected into visual cortex. The distribution of dorsal LGN (dLGN) neurons and corticotectal terminal zones (TZs) was mapped and disorder defined by comparing their actual location with that predicted by injection sites. In the afferent geniculocortical projection, LI-rTMS decreased the abnormally high dispersion of retrogradely labeled neurons in the dLGN of ephrin-A2A5−/− mice, indicating geniculocortical map refinement. In the corticotectal efferents, LI-rTMS improved topography of the most abnormal TZs in ephrin-A2A5−/− mice without altering topographically normal TZs. To investigate a possible molecular mechanism for LI-rTMS-induced structural plasticity, we measured brain derived neurotrophic factor (BDNF) in the visual cortex and superior colliculus after single and multiple stimulations. BDNF was upregulated after a single stimulation for all groups, but only sustained in the superior colliculus of ephrin-A2A5−/− mice. Our results show that LI-rTMS upregulates BDNF, promoting a plastic environment conducive to beneficial reorganization of abnormal cortical circuits, information that has important implications for clinical rTMS.
Three essays on the non-linear dynamics of the finance-growth nexus

i Acknowledgements . ii Declaration . iii Chapter 1: Introduction . 1 1. Background to the research . 1 2. Objectives of the research . 5 3. Motivation for the research . 5 4. Contribution of the research . 8 5. Structure of the research . Error! Bookmark not defined. Chapter 2: Financial Structure and Economic Development: Evidence on the View of ‘New Structuralism’ . 11
On Cyclic Kautz Digraphs

A prominent problem in Graph Theory is to find extremal graphs or digraphs with restrictions in their diameter, degree and number of vertices. Here we obtain a new family of digraphs with minimal diameter, that is, given the number of vertices and out-degree there is no other digraph with a smaller diameter. This new family is called modified cyclic digraphs MCK(d, `) and it is derived from the Kautz digraphs K(d, `). It is well-known that the Kautz digraphs K(d, `) have the smallest diameter among all digraphs with their number of vertices and degree. We define the cyclic Kautz digraphs CK(d, `), whose vertices are labeled by all possible sequences a1 . a` of length `, such that each character ai is chosen from an alphabet containing d + 1 distinct symbols, where the consecutive characters in the sequence are different (as in Kautz digraphs), and now also requiring that a1 6= a`. The cyclic Kautz digraphs CK(d, `) have arcs between vertices a1a2 . a` and a2 . a`a`+1, with a1 6= a` and a2 6= a`+1. Unlike in Kautz digraphs K(d, `), any label of a vertex of CK(d, `) can be cyclically shifted to form again a label of a vertex of CK(d, `). We give the main parameters of CK(d, `): number of vertices, number of arcs, and diameter. Moreover, we construct the modified cyclic Kautz digraphs MCK(d, `) to obtain the same diameter as in the Kautz digraphs, and we show that MCK(d, `) are d-out-regular. Finally, we compute the number of vertices of the iterated line digraphs of CK(d, `).
Sphingosine-1-Phosphate (S1P)-Related Response of Human Conjunctival Fibroblasts After Filtration Surgery for Glaucoma.

Purpose To investigate levels of sphingosine-1-phosphate (S1P) in aqueous fluid samples taken before and after filtration surgery and S1P-induced human conjunctival fibroblast (HCF) responses. Methods Levels of S1P and its related sphingophospholipids in aqueous fluid obtained immediately before and after filtration surgery were determined by liquid chromatography-tandem mass spectrometry. HCFs were used for all in vitro experiments. The expression of five S1P receptor subtypes in HCFs was examined by quantitative real-time PCR. The effect of S1P and receptor-specific antagonists on HCF viability and cell migration was assessed by WST-1 assay and scratch migration assay, respectively. Differentiation to myofibroblasts and extracellular matrix production was evaluated by examining changes in F-actin, α-smooth muscle actin (αSMA), and collagen expression with immunocytochemistry, Western blotting, and collagen accumulation assay, respectively. Results No significant S1P levels in the aqueous fluid samples were detectable immediately before surgery, but postoperative levels of several lysophospholipids, including S1P, dehydro-S1P, and sphingosine, were significantly increased to bioactive concentrations in aqueous fluid in the blebs (P < 0.0001). mRNA expression of the three main S1P receptor subtypes was detected in HCFs. Although S1P levels did not influence HCF proliferation, S1P enhanced cell migration, which could be inhibited by the S1P2 antagonist JTE 013. F-actin, αSMA, and collagen expression was significantly increased by S1P stimulation and was reduced by JTE 013. Conclusions Bioactive S1P concentrations were present in the aqueous fluid at the end of filtration surgery. S1P activated HCFs via S1P2 receptors. These results revealed the potential of S1P2 antagonists in preventing scarring after glaucoma filtration surgery.
Leveraging Collaboration of Peer-to-Peer and Web Services

Collaborative usage of peer-to-peer and Web services has been recently paid a lot of attention. Proposed solutions, however, are mainly focused on enhancing service discovery by replacing centralized service registries with distributed peer-to-peer architectures. In this paper, we present a service environment that leverages collaboration of peer-to-peer and Web services further. Our service environment provides Web services an interface for rich interaction with a structured peer-to-peer network that is based on P2P SIP protocol implementation. In addition to service discovery and publishing, Web Services are also able to exploit communities, context information and content available in the peer-to-peer network. Finally, we evaluate how the rich Web service and peer-to-peer interaction, and especially service publishing affects the nodes' load in a structured peer-to-peer network.
Noise performance of the CrIS instrument

The Cross‐track Infrared Sounder (CrIS) is a spaceborne Fourier transform spectrometer (FTS) that was launched into orbit on 28 October 2011 onboard the Suomi National Polar‐orbiting Partnership satellite. CrIS is a sophisticated sounding sensor that accurately measures upwelling infrared radiance at high spectral resolution. Data obtained from this sensor are used for atmospheric profiles retrieval and assimilation by numerical weather prediction models. Optimum vertical sounding resolution is achieved with high spectral resolution and multiple spectral channels; however, this can lead to increased noise. The CrIS instrument is designed to overcome this problem. Noise Equivalent Differential Radiance (NEdN) is one of the key parameters of the Sensor Data Record product. The CrIS on‐orbit NEdN surpasses mission requirements with margin and has comparable or better performance when compared to heritage hyperspectral sensors currently on orbit. This paper describes CrIS noise performance through the characterization of the sensor's NEdN and compares it to calibration data obtained during ground test. In addition, since FTS sensors can be affected by vibration that leads to spectrally correlated noise on top of the random noise inherent to infrared detectors, this paper also characterizes the CrIS NEdN with respect to the correlated noise contribution to the total NEdN. Lastly, the noise estimated from the imaginary part of the complex FTS spectra is extremely useful to assess and monitor in‐flight FTS sensor health. Preliminary results on the imaginary spectra noise analysis are also presented.
Visually detected NREM Stage 2 sleep spindles in kindergarten children are associated with current and future emotional and behavioural characteristics

Sleep electroencephalogram spindles are associated with efficient cortical–subcortical connectivity, and intellectual and learning abilities. In the present study, we assessed healthy preschoolers with a twofold aim: (i) to explore associations of non‐rapid eye movement S2 spindles with emotional/behavioural characteristics cross‐sectionally; and (ii) longitudinally. A total of 43 children who were 5 years old underwent objective sleep electroencephalogram monitoring in their homes. Emotional and behavioural dimensions were assessed by parents and teachers with the Strengths & Difficulties Questionnaire at baseline and at follow‐up 1 year later. Non‐rapid eye movement S2 spindles were visually scored and compared with Strengths & Difficulties Questionnaire dimensions. High non‐rapid eye movement S2 spindle density was associated with less internalizing behaviour, more prosocial behaviour and a low total problem score. In girls, high non‐rapid eye movement S2 spindle density was related to low hyperactivity, while in boys it was associated with less internalizing behaviour, more externalizing behaviour and more hyperactivity. Longitudinally, a higher number of non‐rapid eye movement S2 spindles at 5 years old predicted fewer peer problems 12 months later. In kindergarten children, high non‐rapid eye movement S2 spindle density is associated with observable current and future favourable emotional/behavioural patterns. However, gender differences were also found, as should be taken into account in future studies.
Absorption Kinetics of Short- and Intermediate-Acting Insulins After Jet Injection With Medi-Jector II

ceptor autoantibodies in children with newly diagnosed 15. IDDM before insulin therapy. Diabetes 36:420-25, 1987 14. Vardi P, Dib SA, Tuttleman M, Connelly JE, Grinbergs M, Rabizadeh A, Riley WJ, Maclaren NK, Eisenbarth GS, Soeldner JS: Competitive insulin autoantibody assay: pro16. spective evaluation of subjects at high risk for development of type I diabetes mellitus. Diabetes 36:1286-91, 1987 Bottazzo GF, Dean BM, Gorsuch AN, Cudworth AG, Doniach D: Complement-fixing islet cell antibodies in type I diabetes: possible monitors of active beta cell damage. Lancet 1:668-72, 1980 Zancheta R, Russo V, Presotto F, Magrin L, Ledini B, Betterle C: Detection of insulin autoantibodies using an ELISA technique in first degree relatives of IDDM patients and in autoimmune patients. Diabetes Res 6:189-94, 1987
The significance of job-anxiety in a working population.

BACKGROUND Job-anxiety, as distinguished from trait-anxiety, is associated with long-term sickness absence. The prevalence of job-anxiety within a working population is not known. Identifying individuals who would benefit from intervention might be useful. AIMS To investigate job-anxiety in employees not undergoing treatment for mental health illness, firstly by assessing the level of job-anxiety and work-related avoidance tendencies in a working sample, and secondly by testing whether job-anxiety is distinguishable from trait-anxiety. METHODS Cross-sectional survey of a convenience sample obtained through personal contact distribution. Employees from different professional settings completed an anonymous questionnaire and provided information on their employment status. The State-Trait-Anxiety Inventory (STAI-T) was used to measure trait-anxiety and the Job-Anxiety-Scale (JAS) was used to assess job (state) anxiety. RESULTS There was a 69% response rate (240 responses); 188 responses were available for analysis of whom 62% were women. There were no employees with high trait-anxiety. Ten employees (5%) reported increased job-anxiety and of these nine employees reported high 'tendencies of avoidance and workplace absence'. Avoidance was most often accompanied by the comorbid job-anxieties 'job-related social anxiety', 'fear of changes at work' and 'fears of existence', 'anticipatory' and 'conditioned' job-anxiety and 'panic symptoms'. CONCLUSIONS In this sample, self-reported job-anxiety appeared as a specific type of anxiety as opposed to trait-anxiety. In the workplace job-anxiety can present as job-avoidance and sickness absence and should be distinguished from trait-anxiety. In practice, employers and occupational health practitioners should be aware of those employees prone to sickness absence.
Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer.

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and efficacy of gemcitabine combined with fluorouracil (5-FU) in patients with pancreatic cancer. PATIENTS AND METHODS Patients with measurable, locally advanced, nonresectable or metastatic pancreatic cancer were candidates for the study. 5-FU was given via protracted venous infusion (PVI) at a fixed dosage of 200 mg/m2/d, and gemcitabine was administered weekly for 3 consecutive weeks every 4 weeks. The initial dose of gemcitabine was 700 mg/m2 and was escalated in increments of 100 mg/m2/wk until the appearance of severe toxicity. Measurements of efficacy included the following: response rate; clinical benefit response, which is a composite measurement of pain, performance status, and weight loss; time to disease progression; and survival. RESULTS Twenty-six patients received a total of 109 courses. Dose-limiting toxicity, which consisted of grade 4 neutropenia with fever (one patient) and grade 4 thrombocytopenia (one patient), was observed in two of three patients treated with 1,100 mg/m2/wk of gemcitabine. On the basis of these results, the MTD of gemcitabine with 5-FU via PVI on this schedule was 1,000 mg/m2. Sixteen patients developed grade 3-4 neutropenia, and three patients developed grade 3-4 thrombocytopenia. Grade 3-4 nonhematologic toxicity consisted of diarrhea (two patients) and cutaneous toxicity, asthenia, edema, mucositis, and nausea and vomiting (one patient each). The delivered dose-intensity of gemcitabine was similar at the 1,000 mg/m2 dose level (599 mg/m2/wk) as at the 900 mg/m2 (601 mg/m2/wk) dose level. For this reason, the recommended dose of gemcitabine for phase II evaluation on this schedule was 900 mg/m2. Five patients had objective responses (one complete response and four partial responses; response rate, 19.2%; 95% confidence interval [CI], 6.5 to 39.3), and 10 patients had improvement of disease-related symptoms (45%; 95% CI, 24 to 67). After a median follow-up of 17.7 months (range, 7.8 to 24.8 months), the median progression-free survival and overall survival times were 7.4 months (95% CI, 3.3 to 11.4) and 10.3 months (95% CI, 8.1 to 12.5), respectively. CONCLUSION The MTD of gemcitabine when combined with 5-FU via PVI on this schedule was 1,000 mg/m2/ wk; however, on the basis of administered dose-intensity, the recommended dose for additional investigation is 900 mg/m2. This combination chemotherapy regimen was well tolerated and showed promising antitumor activity in the treatment of pancreatic cancer.
Inactivation of the DnaB Helicase Leads to the Collapse and Degradation of the Replication Fork: a Comparison to UV-Induced Arrest

ABSTRACT Replication forks face a variety of structurally diverse impediments that can prevent them from completing their task. The mechanism by which cells overcome these hurdles is likely to vary depending on the nature of the obstacle and the strand in which the impediment is encountered. Both UV-induced DNA damage and thermosensitive replication proteins have been used in model systems to inhibit DNA replication and characterize the mechanism by which it recovers. In this study, we examined the molecular events that occur at replication forks following inactivation of a thermosensitive DnaB helicase and found that they are distinct from those that occur following arrest at UV-induced DNA damage. Following UV-induced DNA damage, the integrity of replication forks is maintained and protected from extensive degradation by RecA, RecF, RecO, and RecR until replication can resume. By contrast, inactivation of DnaB results in extensive degradation of the nascent and leading-strand template DNA and a loss of replication fork integrity as monitored by two-dimensional agarose gel analysis. The degradation that occurs following DnaB inactivation partially depends on several genes, including recF, recO, recR, recJ, recG, and xonA. Furthermore, the thermosensitive DnaB allele prevents UV-induced DNA degradation from occurring following arrest even at the permissive temperature, suggesting a role for DnaB prior to loading of the RecFOR proteins. We discuss these observations in relation to potential models for both UV-induced and DnaB(Ts)-mediated replication inhibition.
Faculty Perceptions of Student Performance in the Online Classroom

With continually increasing enrollment, and colleges and universities struggling to meet the demand, leaders in education are turning to the web instruction to deliver instruction to students. In order to meet the needs of these online students, institutions of higher education need more data concerning the factors that influence students' decision to pursue online instruction. More importantly, factors that affect student performance in both traditional and online settings need to be understood in order to provide students with a more comprehensive educational experience. This study examines the factors that influence students' decision to seek online coursework over a traditional classroom setting. Additionally, this study explores faculty perceptions concerning the factors necessary to succeed in a web-enhanced environment, and similarly explores faculty perceptions as to whether online students' learning outcomes are the same as those of traditional students. This work correlates with the findings of previous studies, and contributes to the growing body of knowledge regarding the factors that affect student performance in both traditional and online settings.
Optimal population coding of dynamic stimuli

Organisms are routinely faced with the task of making decisions based on partial, unreliable information. Furthermore, not only is the environment noisy, but the computational units organisms employ themselves are often faulty and noisy, such as the neurons of the animal nervous system. There is a crucial difference, though: while the organism can only act indirectly on its environment, its sensory organs are under its direct control through adaptation. Here I thus consider how a population of neurons can organise itself to allow for optimal information processing at its output. I will focus on a model of a rapidly changing environment, which forces the organism to make short-time decisions. In that setting I have provided a number of novel results, extending the framework of population coding to a fully dynamic setting, where a changing environment is decoded from spike trains in an online fashion. To do so, I have drawn from the theory of stochastic filtering of doubly stochastic point processes. For a dense population of neurons, this reduces to a Gaussian process regression problem, for which I have obtained closed form relations for the error distribution. The formalism developed also lends itself to a direct extension to a control-theoretical setting. Thus I have also developed a criterion for optimal coding in the case of control problems, and have compared this to the case of estimation previously developed. Interestingly, I have been able to show that the different objective functions for control and estimation lead to different optimal encoders. The study of optimal coding in populations of neurons is an active fertile area of research. Here I have extended a number of previous findings to the case of online decoding of dynamic stimuli from point processes. Parallel to that, I have discussed the issue of optimal coding for control, and how it relates to the study of optimal coding in the estimation case.
Responses of the Peyer's Patches in Germ-Free Mice to Antigenic Stimulation

Lymph nodes, spleens, and Peyer's patches of germ-free mice are relatively inactive. The tissues are small and contain rare, small, indistinct, germinal zones. When exposed to antigenic stimuli (Salmonella paratyphi A and lymphocytic choriomeningitis virus), the tissues become larger and germinal zones appear coincident with antibodies in the blood. The Peyer's patches were activated if antigen was absorbed from the intestinal lumen into the circulation but not if the antigen was administered parenterally. There was no demonstrable immunological response by the germ-free mouse to Streptococcus faecalis.