Indirect Response Research Articles

Obra de arte e verdade: Sobre a inversão de Heidegger da estética de Platão

According to the doctrine set out in Book X of the Republic, art is for Plato three degrees far from truth. This doctrine is based on the representative character of art: in his productions, the artist takes sensible things and not the ideas as his model, and ignores the use of the objects that the craftsman produces. In the essay The Origin of the Work of Art, Heidegger completely reverses this Platonic hierarchy. The essay seems to be an indirect response to Plato, as it discusses exactly the distinctions Plato draws, between natural object (the idea, which is “by nature”), object of use and work of art. The work of art – even when it imitates an object of use, as in the case of van Gogh’s painting of a pair of shoes – is for Heidegger the “setting-itself-to-work of truth”, because it shows the primarily ontological character of every work: its fabrication, that is, its historical being. The truth of the work of art lies in its historical character, and the work of art is the happening of truth because, more than any other object, its essence consists precisely in showing the temporal character as the essence of every object, even the natural ones.

Population pharmacokinetic/pharmacodynamic modelling of eplontersen, an antisense oligonucleotide in development for transthyretin amyloidosis.

Transthyretin-mediated amyloidosis is a progressive and fatal disease caused by the build-up of misfolded transthyretin (TTR) protein. Eplontersen is a triantennary N-acetyl galactosamine (GalNAc3)-conjugated antisense oligonucleotide targeting TTR messenger ribonucleic acid (mRNA) to inhibit production of both variant and wild-type TTR. We aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for eplontersen and to evaluate the impact of covariates on exposure and response. Plasma eplontersen and serum TTR concentration data were obtained from two phase 1 studies in healthy volunteers (ClinicalTrials.gov: NCT03728634, NCT04302064). Model development was conducted using a nonlinear mixed-effects approach. Eplontersen PK was well described by a two-compartment model. Evaluation of demographics identified significant covariates of lean body mass on clearance and body weight on intercompartmental clearance and volumes of distribution. Population PK modelling showed the absorption rate was 29.6% greater with injection into the abdomen versus the arm. The typical population terminal elimination half-life was 25.5days. Serum TTR was well described by an indirect response model with inhibition of TTR production by eplontersen. Maximum fractional inhibition (Imax ) was 0.970 (0.549%RSE) and the half maximal inhibitory concentration (IC50 ) was 0.0283 ng/ml (13.3%RSE). Simulations showed subjects with lower weight had higher exposure (AUC, Cmax ), while higher Cmax was observed when comparing site of administration (ratio abdomen/arm = 1.18), but differences in exposure did not significantly impact response at evaluated doses. The exposure-response relationship of eplontersen was well characterised by the PKPD model. Weight and injection site were found to affect systemic exposure, but this effect does not seem to result in clinically relevant variation in response.

Agronomical evaluation of low dormancy alfalfa populations selected by an indoor screening method

AbstractFall dormancy is a vital component of alfalfa (Medicago sativa L.) yield in northern climates, but selection for the trait is often done at the expense of winter survival. We performed one cycle of selection to reduce fall dormancy in two winter hardy cultivars (Yellowhead and Peace) using a new indoor screening method. We compared the reduced dormancy populations with their respective initial cultivars for fall dormancy, yield, and winter survival at four sites across Canada. During the establishment and the first production years, plants of the reduced dormancy populations were generally taller in the fall than their respective cultivar, which resulted in a one unit increase of their fall dormancy class. Under field conditions, plants of the reduced dormancy populations had a similar winter survival than those of the initial cultivars. Under simulated winter conditions, freezing tolerance was not affected by selection for reduced dormancy in Peace, whereas a decrease from −24.0 to −21.5 °C was observed in Yellowhead. However, in this cultivar, we noted a 37% yield increase under field conditions and a 40% more vigorous regrowth under simulated winter conditions in the reduced dormancy population. These results showed that the indoor selection method effectively reduced fall dormancy and that indirect responses for yield and winter survival were dependent on the genetic background used as selection material. This selection method could therefore be promising to develop alfalfa cultivars adapted to northern latitudes with high winter hardiness and improved late season yield.

Pharmacokinetic/pharmacodynamic modeling of ketoprofen and flunixin at piglet castration and tail-docking.

This study performed population‐pharmacokinetic/pharmacodynamic (pop‐PK/PD) modeling of ketoprofen and flunixin in piglets undergoing routine castration and tail‐docking, utilizing previously published data. Six‐day‐old male piglets (8/group) received either ketoprofen (3.0 mg/kg) or flunixin (2.2 mg/kg) intramuscularly. Two hours post‐dose, piglets were castrated and tail docked. Inhibitory indirect response models were developed utilizing plasma cortisol or interstitial fluid prostaglandin E2 (PGE2) concentration data. Plasma IC50 for ketoprofen utilizing PGE2 as a biomarker was 1.2 μg/ml, and ED50 for was 5.83 mg/kg. The ED50 calculated using cortisol was 4.36 mg/kg; however, the IC50 was high, at 2.56 μg/ml. A large degree of inter‐individual variability (124.08%) was also associated with the cortisol IC50 following ketoprofen administration. IC50 for flunixin utilizing cortisol as a biomarker was 0.06 μg/ml, and ED50 was 0.51 mg/kg. The results show that the currently marketed doses of ketoprofen (3.0 mg/kg) and flunixin (2.2 mg/kg) correspond to drug responses of 33.97% (ketoprofen‐PGE2), 40.75% (ketoprofen‐cortisol), and 81.05% (flunixin‐cortisol) of the maximal possible responses. Given this information, flunixin may be the best NSAID to use in mitigating castration and tail‐docking pain at the current label dose.

Conversational partners’ interactions in response to co-present mobile phone usage

ABSTRACT The goals of the two studies were to identify common communicative responses to co-present mobile phone usage and conversational partners’ reactions to that communication, and to determine whether individuals perceive their communicative responses as effective. Study 1 identified common participant responses and partner (i.e., phone user) reactions to those responses. In Study 2, researchers coded data from a new sample for these same responses and reactions and measured participants’ perceived effectiveness and likelihood to use the same responses again. The most frequent responses were demanding/requesting to stop, asking partner about their phone use, and using humor/sarcasm. Stopping, apologizing and stopping, justifying the use, and continuing to use the phone were the most common partner reactions. Directness of communicative responses was unrelated to reaction valence. Most conversational partner reactions were positive, but when negative, participants rated direct responses as significantly less effective than indirect responses.

Temperature and doping-dependent interplay between the direct and indirect optical response in buffer-mediated epitaxial germanium

The structural and optical properties of buffer mediated epitaxial germanium (Ge) layer were investigated and compared with bulk n-type and p-type Ge substrates. An interconnected dual-chamber molecular beam epitaxy (MBE) system was used to grow a 280 nm thin Ge epilayer on (100)GaAs substrate with an intermediate AlAs buffer layer. The lattice-matched, abrupt Ge/AlAs heterointerface was analyzed using cross-sectional transmission electron microscopic analysis, and no elemental interdiffusion was detected via secondary ion mass spectrometry. A strong direct gap transition, compared to the indirect gap transition, and a series of phonon-assisted transitions was observed by photoluminescence (PL) spectroscopy. In addition, the intensity of the direct gap recombination decreases with decreasing PL measurement temperatures, which was ascribed to the reduced density of Γ-valley electrons available for recombination at lower temperature. Furthermore, the intensity ratio between the direct and indirect optical transition drastically decreases with decreasing temperature in both n-type epitaxial and p-type bulk Ge. An empirical relation in both direct and indirect peak position with temperature was established. The observed strong luminescence in 280 nm thick epitaxial Ge at room temperature is vital for Ge-based photonic devices. In addition, the quality of the epitaxial Ge layer grown via MBE is on par with bulk Ge substrates.

Delayed concentration effect models for dabigatran anticoagulation.

IntroductionDabigatran is an anticoagulant with potential use during cardiopulmonary bypass in children and adults. The pharmacokinetic–pharmacodynamic relationship for dabigatran anticoagulation effect was investigated in an intact animal model using rabbits.MethodsTen male New Zealand white rabbits were given a novel preparation of intravenous dabigatran 15 mg.kg−1. Blood samples were collected for activated clotting time, thromboelastometric reaction time, and drug assay at 5, 15, 30, 60, 120, 180, 300, and 420 min. Plasma dabigatran concentrations and coagulation measures were analyzed using an integrated pharmacokinetic–pharmacodynamic model using nonlinear mixed effects. Effects (activated clotting and thromboelastometric reaction times) were described using a sigmoidal EMAX model. Pharmacokinetic parameters were scaled using allometry and standardized to a 70 kg size standard. Pharmacodynamics were investigated using both an effect compartment model and an indirect response (turnover) model.ResultsA two‐compartment model described dabigatran pharmacokinetics with a clearance (CL 0.135 L.min−1.70 kg−1), intercompartment clearance (Q 0.33 L.min−1.70 kg−1), central volume of distribution (V1 12.3 L.70 kg−1), and peripheral volume of distribution (V2 30.1 L.70 kg−1). The effect compartment model estimates for a sigmoid EMAX model with activated clotting time had an effect site concentration (Ce50 20.1 mg.L−1) eliciting half of the maximal effect (EMAX 899 s) and a Hill coefficient (N 0.66). The equilibration half time (T1/2keo) was 1.4 min. Results for the reaction time were plasma concentration (Cp50 65.3 mg.L−1), EMAX 34 min, N 0.80 with a baseline thromboelastometric reaction time of 0.4 min. The equilibration half time (T1/2keo) was 2.04 min.ConclusionsDabigatran reversibly binds to the active site on the thrombin molecule, preventing thrombin‐mediated activation of coagulation factors. The effect compartment model performed slightly better than the turnover model and was able to adequately capture pharmacodynamics for both activated clotting and thromboelastometric reaction times. The equilibration half time was short (<2 min). These data can be used to inform future animal preclinical studies for those undergoing cardiopulmonary bypass. These preclinical data also demonstrate the magnitude of parameter values for a delayed effect compartment model that are applicable to humans.

A Simulation Study of the Comparative Performance of Partial Area under the Curve (pAUC) and Partial Area under the Effect Curve (pAUEC) Metrics in Crossover Versus Replicated Crossover Bioequivalence Studies for Concerta and Ritalin LA.

Concerta and Ritalin LA are methylphenidate (MPH) drugs with different release mechanisms. Generic bioequivalence (BE) to these conventionally uses pAUC (partial area under the curve) as metrics in addition to Cmax (maximum concentration), AUC0-t (area from time 0 to time t), and AUC0-infinity. The recommended BE design was a standard two-formulation, two-sequence, and two-period crossover; however, the currently recommended design is a replicated crossover to better define subject-by-formulation interaction variance. The current purpose was to compare via simulation, using literature MPH models, the performance of the pAUC metrics in establishing BE via the standard crossover design versus a replicated design, and the relationship of the pAUC metrics to PD (pharmacodynamics) metrics, e.g., SKAMP (Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale) composite scores pAUEC (partial area under the effect curve). One-thousand, 40-subject studies were simulated with model literature parameters. An indirect response model described the SKAMP composite scores corrected for placebo. Performance of the pAUC metrics was demonstrated by the calculation of 90% confidence intervals (CIs) for each k0fast (fast absorption rate constant) and kaslow (slow absorption rate constant) test/reference (T/R) ratio. The 90% CIs resulting from changes in the k0fast and kaslow ratios, e.g., T/R, showed greater sensitivity to changes in the ratios at quotients below 0.8 than above for both Concerta and Ritalin LA. Ritalin LA pAUC values were insensitive to increases in either ratio once the ratio exceeded 1.0 and the study design. Correlations between least squares means (LSM) for pAUC and the SKAMP pAUEC for the composite scores were near 90%.

B Effects: Bonds of Form and Time in Barthes, Blanchot and Beckett

Starting from Nicholas Zurbrugg’s dismissal of the negative ‘B-Effect’ in postmodernism, which he associates with ‘Benjamin, Brecht, Beckett, Barthes, Baudrillard, and Bourdieu’, this essay examines the common rationale behind convergent affirmations of a neutrality or minimalism, often mistaken for nihilism, at key junctures in the works of Samuel Beckett and Roland Barthes, adding Maurice Blanchot as a critical link. The argument unfolds along a double axis: it first considers the formal role of ‘chatter’ or ‘idle speech’ and the fragment(ary in writing) in the three ‘B-writers’ before relating them to different constructions of temporality, such as the ‘future anterior’ and the après-coup, in their thematizations of ‘catastrophe’ and ‘disaster’ as indirect responses to personal or historical trauma and death. A brief concluding paragraph highlights how time’s suspensiveness leads to different forms of waiting across Barthes, Blanchot and Beckett.

A high-throughput study of visceral organs in CT-scanned pigs

It has been debated whether intensive selection for growth and carcass yield in pig breeding programmes can affect the size of internal organs, and thereby reduce the animal’s ability to handle stress and increase the risk of sudden deaths. To explore the respiratory and circulatory system in pigs, a deep learning based computational pipeline was built to extract the size of lungs and hearts from CT-scan images. This pipeline was applied on CT images from 11,000 boar selection candidates acquired during the last decade. Further, heart and lung volumes were analysed genetically and correlated with production traits. Both heart and lung volumes were heritable, with h2 estimated to 0.35 and 0.34, respectively, in Landrace, and 0.28 and 0.4 in Duroc. Both volumes were positively correlated with lean meat percentage, and lung volume was negatively genetically correlated with growth (rg = − 0.48 ± 0.07 for Landrace and rg = − 0.44 ± 0.07 for Duroc). The main findings suggest that the current pig breeding programs could, as an indirect response to selection, affect the size of hearts- and lungs. The presented methods can be used to monitor the development of internal organs in the future.

Indirect Response in Egg Production and Egg Quality Traits Due to Selection for Body Weight at 8 Weeks of Age in Dandarawi Chicken

Indirect Response in Egg Production and Egg Quality Traits Due to Selection for Body Weight at 8 Weeks of Age in Dandarawi Chicken

MO364: Population Pharmacodynamic Dose-Response Analysis of Serum Potassium Following Dosing With Sodium Zirconium Cyclosilicate

Abstract BACKGROUND AND AIMS Sodium zirconium cyclosilicate (SZC, LOKELMA®) is an orally administered suspension for treating hyperkalemia that permits selective, monovalent cation exchange and has a high exchange capacity for potassium cations in the gut leading to a net reduction in systemic potassium. The goals of the analysis were to describe the population pharmacodynamic response of serum potassium concentration (S-K) in hyperkalemic subjects treated with SZC; specifically, the longitudinal dose response of SZC for S-K in correction (0–48 h) and maintenance (&amp;gt;48 h) phases of treatment, and the differences in S-K response among populations identified by their intrinsic and extrinsic factors. METHOD A population pharmacodynamic model was developed using serum potassium, dose timing/amount, and patient demographic and medical history data pooled from 7 phase 2 and 3 clinical studies consisting of 2369 subjects with hyperkalemia (screening S K &amp;gt;5 mmol/L) with a total of 25 764 S-K observations. A virtual pharmacokinetic-pharmacodynamic model (K-PD) model was used to mimic a drug exposure without any measurements (none were available, drug was not absorbed). S-K over time was described by an indirect response model where potassium enters/leaves a compartment corresponding to serum potassium measurements. The impact of SZC exposure was modeled as an inhibition of the potassium production rate, consistent with the SZC mechanism of action to bind potassium and lower its absorption and appearance in circulation. RESULTS Diagnostics indicated good agreement between the observed data and the model, for mean S-K and change from baseline, and overall qualified the model as appropriate for predicting S-K changes following SZC dosing. The sigmoid exposure response on Kin was characterized by a high value for the EC50 (32.8 g) and a hill coefficient of 1.36. Not surprisingly, within the range of doses studied (0–15 g), the dose response appeared nearly linear. The placebo adjusted S-K change from baseline for QD maintenance treatment was 0.37 (95% CI –0.42 to –0.32) for 5 g, –0.75 (95% CI –0.82 to –0.65) for 10 g, and –1.06 (95% CI –1.17 to –0.89) for 15 g. Greater treatment response was associated with high S-K at baseline, more advanced age, lower body weight and lower eGFR. Furthermore, greater treatment response was also predicted for Black or African American and Asian patients, compared with Caucasian individuals, but they remained unworthy of dose adjustment. Lastly, dose-response simulations show no clinically meaningful difference between maintenance regimens of 5 g QOD and 2.5 g QD in the studied patient groups. CONCLUSION The population K-PD model of SZC adequately described the changes in serum potassium concentration during correction and maintenance phase dosing in the seven clinical studies. Greater treatment response was associated with high S-K at baseline, more advanced age, lower body weight, lower eGFR, Black or African American race and Asian race; however, the impact of each covariate was modest. The overall results of this analysis support the conclusion that no dose adjustment is needed for SZC based on any of the tested covariates.

Experimental evolution of a pheromone signal.

Sexual signals are important in speciation, but understanding their evolution is complex as these signals are often composed of multiple, genetically interdependent components. To understand how signals evolve, we thus need to consider selection responses in multiple components and account for the genetic correlations among components. One intriguing possibility is that selection changes the genetic covariance structure of a multicomponent signal in a way that facilitates a response to selection. However, this hypothesis remains largely untested empirically. In this study, we investigate the evolutionary response of the multicomponent female sex pheromone blend of the moth Heliothis subflexa to 10 generations of artificial selection. We observed a selection response of about three‐quarters of a phenotypic standard deviation in the components under selection. Interestingly, other pheromone components that are biochemically and genetically linked to the components under selection did not change. We also found that after the onset of selection, the genetic covariance structure diverged, resulting in the disassociation of components under selection and components not under selection across the first two genetic principle components. Our findings provide rare empirical support for an intriguing mechanism by which a sexual signal can respond to selection without possible constraints from indirect selection responses.

An insight to the incidence of acute pancreatitis, and co-morbidity of diabetes in SARS-COV2 infection

Since the emergence of SARS-COV2 infection, accumulating reports as well as evidences have been reported to the complex disease-disease interactions between this viral infection and the pre-existing diabetes co-morbidity. Hyperglycemia accompanied the onset of infection is repeatedly reported to be associated with the disease severity, prognosis and mortality rate elevation. Various mechanism has been speculated to lay behind the reported hyperglycemia including direct pancreatic tissues tropism besides the indirect cytokine storm overwhelming inflammatory immune response. In another perspective, other collection of studies has reported and emphasized the involvement of SARS-COV2 infection in the development of acute pancreatitis as one of this infection complications during the onset of infection, hence increasing the morbidity of such infection including the admission of the patients to the intensive care unit. Some have related the diagnosis of acute pancreatitis to the serum amylase and lipase levels manifested with the experienced GI symptoms, while, others consider CT scan images to confirm diagnosis. Finally, some reporters has hypothesized that SARS-COV2 infection may develop autoantibodies that probably precipitate type I diabetes mellitus long after infection. Therefore, due to significance of hyperglycemia/ diabetes to fate / severity of the infection as well as long term complications of SARS-COV2 this survey have covered aspects related to these issues.

Pharmacokinetic/pharmacodynamic modeling of roxadustat's effect on LDL cholesterol in patients in Japan with dialysis-dependent chronic kidney disease and anemia

AimsThe objective of this analysis was to develop and evaluate a pharmacokinetic/pharmacodynamic (PK/PD) model of the effect of roxadustat on low-density lipoprotein cholesterol (LDL-C) in Japanese patients with anemia of dialysis-dependent chronic kidney disease while considering the impact of covariates on model parameters. MethodsA total of 2330 LDL-C measurements from 275 patients in 3 clinical studies were analyzed using a nonlinear-mixed effects modeling approach in NONMEM software. ResultsThe PK/PD relationship between roxadustat exposure and LDL-C was well described by a kinetic-pharmacodynamic model with a physiological indirect response model as the PD component. Co-administered statin usage, sevelamer usage, type of dialysis (hemodialysis or peritoneal dialysis), and sex were selected as covariates for LDLbaseline. Weight was selected as a covariate for ID50. Imax and ID50 were estimated as 0.661 and 1.51 mg/h, respectively. ConclusionRoxadustat can decrease LDL-C independent of statins and sevelamer. Further study of the ability of roxadustat to lower LDL-C and any potential effects on outcomes is needed.

Turn-Taking Model for Filipinos’ High-Context Communication Style from No-Answered and Non-Answered Questions in Faculty Meetings

Interrogativity is a linguistic property in all world languages. It is inherently related to the ‘question-answer’ tandem of turn-taking. One notable feature of turn-taking is the adjacency pairs, where the question-and-answer sequences are part of. The canonical turn-taking model by Sacks et al. (1974) highlights the obligation to answer the questions. In this paper, however, we report the many cases of no-answered and non-answered questions in faculty meetings using the analytical framework of Conversation Analysis. We show that the Filipinos’ high-context communication style has impinged on the occurrences of these types of answers. We then illustrate a turn-taking model for this type of communication, wherein a straightforward answer is no longer obligatory, but becomes optional within the frame of high-context communication style of the Filipino context. The questioning party can just “let it go” and accept the indirect response as a legitimate and true answer to the question. Towards the end, we argue that the results may convey that the faculty meeting, which is considered as an institutional talk, has resembled ordinary mundane conversations, where questions are oftentimes taken for granted. Keywords: Conversation Analysis; faculty meeting; Filipino communication style; high-context communication; question-answer system

Characterisation of individual ferritin response in patients receiving chelation therapy.

AimsTo develop a drug–disease model describing iron overload and its effect on ferritin response in patients affected by transfusion‐dependent haemoglobinopathies and investigate the contribution of interindividual differences in demographic and clinical factors on chelation therapy with deferiprone or deferasirox.MethodsIndividual and mean serum ferritin data were retrieved from 13 published studies in patients affected by haemoglobinopathies receiving deferiprone or deferasirox. A nonlinear mixed effects modelling approach was used to characterise iron homeostasis and serum ferritin production taking into account annual blood consumption, baseline demographic and clinical characteristics. The effect of chelation therapy was parameterised as an increase in the iron elimination rate. Internal and external validation procedures were used to assess model performance across different study populations.ResultsAn indirect response model was identified, including baseline ferritin concentrations and annual blood consumption as covariates. The effect of chelation on iron elimination rate was characterised by a linear function, with different slopes for each drug (0.0109 [90% CI: 0.0079–0.0131] vs. 0.0013 [90% CI: 0.0008–0.0018] L/mg mo). In addition to drug‐specific differences in the magnitude of the ferritin response, simulation scenarios indicate that ferritin elimination rates depend on ferritin concentrations at baseline.ConclusionModelling of serum ferritin following chronic blood transfusion enabled the evaluation of drug‐induced changes in iron elimination rate and ferritin production. The use of a semi‐mechanistic parameterisation allowed us to disentangle disease‐specific factors from drug‐specific properties. Despite comparable chelation mechanisms, deferiprone appears to have a significantly larger effect on the iron elimination rate than deferasirox.

A Pragmatic Analysis of Responses in Malaysian Parliamentary Discourse

This study employs the framework of responses proposed by Harris (1991), the notion of implicature as defined by Thomas (1995), and the dimensions of resistance introduced by Clayman (2001) to examine the types of responses in Malaysian Parliamentary Question Time. Analysis revealed the tendency of using direct, indirect, and evasive responses to specific questions for various reasons. Direct answers were observed in questions that could reflect positively on the government’s image. On the contrary, indirect answers were employed in questions that suggest clashing of goals between responders and questioners that could subsequently threaten the image of the government whereas negative presuppositions and the way questions are structured in parliament influence the production of evasion.Keywords: direct answer, evasive response, indirect answer, parliamentary discourse, political discourse

Adenosinergic Pathway and Linked Suppression: Two Critical Suppressive Mechanisms of Human Donor Antigen Specific Regulatory T Cell Lines Expanded Post Transplant.

Regulatory T cells are an important component of an immune response shaping the overall behavior to potential antigens including alloantigens. Multiple mechanisms have been shown to contribute towards developing and sustaining a immunological regulatory response. One of the described contact dependent suppressive mechanisms regulatory cells have been shown to utilize is through the production of adenosine from extracellular ATP mediated by CD39 and CD73. In this study we demonstrate that the adenosinergic pathway plays a major role in the suppressive/regulatory effects antigen specific regulatory T cell enriched lines (ASTRLs) that have been of expanded ex vivo from stable kidney transplant patients. We have previously shown that these ASTRL cells are capable of suppressing alloimmune responses in vitro and significantly prolonging allograft survival in an animal model of kidney transplantation. For this study nineteen ASTRLs were expanded from 17 kidney transplant patients by repeated stimulation of recipient peripheral blood mononuclear cells with donor specific HLA-DR peptides. All 19 ASTRLs showed upregulation of numerous markers associated with regulatory cells and were able to inhibit donor antigen specific T cell proliferation in a dose dependent fashion. ASTRLs suppressed indirect and direct alloimmune responses compatible with our previous animal study findings. Upregulation of both CD39 and CD73 was observed post expansion and ASTRLs demonstrated extracellular hydrolysis of ATP, indicating functionality of the upregulated proteins. We also showed that inhibition of the adenosinergic pathway using inhibitors of CD39 resulted in abrogation of suppression and increased antigen specific T cell proliferation. This demonstrates that the main mechanism of action of the suppressive activity donor peptide driven ASTRLs generated from kidney transplant patients is the adenosinergic pathway. Furthermore this suggests the possibility that combining infusion of Tregs with other treatments, such as adenosine receptor agonists or increasing CD39 expression in the grafts may further enhance a regulatory response to the allograft and possibly achieve transplantation tolerance.

A Lexicogrammar Approach to Analyze Response Strategies to Apology in English Conversations

The acts of apologizing and responding to apology are common activities in communication since using only either of these two crucial speech acts cannot itself establish fully effective communication. This article aims to examine response strategies to apology that are used in English romance and family films and find out the lexico-grammatical realizations of response utterances in English conversations. This article was qualitatively designed with the support of the researchers’ observation of the films' scripts extracted from English films, subsequently the researchers’ description of the data collection into separate categories. The results of this study revealed that English film characters were more likely to accept than reject apologies. Direct positive comments were favoured by the English, with indirect positive responses coming in second.