Experience and the Pacemaker- Accumulator Model

The pacemaker-accumulator model provides a framework in which the results of different duration estimation tasks are commonly accounted for. Nevertheless, the model remains abstract and it does not provide proper explanations nor predictions for duration estimations in various experimental set-ups. This paper aims to address these shortcomings by explicating an experiential pacemaker-accumulator model that supplements the standard pacemaker-accumulator model with two claims. Both of them concern the role that experiences play in duration estimation tasks and are also partly supported by studies not directly related to duration estimation. First, the internal responses based on which the switch between the pacemaker and the accumulator operates are the same as the neural processes that realize conscious access to experiences. Second, the processes that realize the experiences of stimuli realize the function of the pacemaker. By supplementing the standard pacemaker-accumulator model with these claims, the model affords proper explanations for the systematic errors and empirically testable predictions in duration estimations tasks. One likely consequence of the model is that the experience of duration and the duration of experience can differ

Ni+-irradiated InGaAs/GaAs quantum wells: picosecond carrier dynamics

Room-temperature carrier dynamics as functions of heavy-ion implantation and subsequent thermal annealing were investigated for technologically important InGaAs/GaAs quantum wells (QWs) by means of a time-resolved up-conversion method. Sub-picosecond lifetimes were achieved at 10 MeV Ni+ doses of (20-50) x 1010 ions cm-2. The decay rates reached a maximum at the highest irradiation dose, yielding the shortest lifetime of the confined QW states of 600 fs. A simple theoretical model is proposed for the photodynamics of the carriers. The relaxation rate depended on the irradiation dose according to a power law of 1.2, while the irradiated and subsequently annealed samples exhibited a power law of 0.35. The results are qualitatively interpreted.Room-temperature carrier dynamics as functions of heavy-ion implantation and subsequent thermal annealing were investigated for technologically important InGaAs/GaAs quantum wells (QWs) by means of a time-resolved up-conversion method. Sub-picosecond lifetimes were achieved at 10 MeV Ni+ doses of (20-50) x 1010 ions cm-2. The decay rates reached a maximum at the highest irradiation dose, yielding the shortest lifetime of the confined QW states of 600 fs. A simple theoretical model is proposed for the photodynamics of the carriers. The relaxation rate depended on the irradiation dose according to a power law of 1.2, while the irradiated and subsequently annealed samples exhibited a power law of 0.35. The results are qualitatively interpreted.Room-temperature carrier dynamics as functions of heavy-ion implantation and subsequent thermal annealing were investigated for technologically important InGaAs/GaAs quantum wells (QWs) by means of a time-resolved up-conversion method. Sub-picosecond lifetimes were achieved at 10 MeV Ni+ doses of (20-50) x 1010 ions cm-2. The decay rates reached a maximum at the highest irradiation dose, yielding the shortest lifetime of the confined QW states of 600 fs. A simple theoretical model is proposed for the photodynamics of the carriers. The relaxation rate depended on the irradiation dose according to a power law of 1.2, while the irradiated and subsequently annealed samples exhibited a power law of 0.35. The results are qualitatively interpreted.Peer reviewe

Temporal binding and the perception/cognition boundary

Temporal binding occurs when people observe two events that they believe to be causally connected: They underestimate the length of the interval between those two events, when compared with their estimates of the length of intervals between events they believe to be causally unrelated. I discuss temporal binding in the context of Dennett and Kinsbourne’s (1992) influential argument levelled at what they call ‘Cartesian Materialism’. In particular, I argue that Dennett and Kinsbourne’s argument trades on a representational conception of perceptual experience, which blurs the boundary between perception and judgement, and that temporal binding can serve as a case study for developing an alternative, relational, conception of perceptual experience and of its relation to judgement. Based on research on the mechanisms underlying temporal binding, I provide an explanation of the phenomenon in which perception and judgement play clearly distinct roles

Identification of errors introduced during high throughput sequencing of the T cell receptor repertoire

<p>Abstract</p> <p>Background</p> <p>Recent advances in massively parallel sequencing have increased the depth at which T cell receptor (TCR) repertoires can be probed by >3log10, allowing for saturation sequencing of immune repertoires. The resolution of this sequencing is dependent on its accuracy, and direct assessments of the errors formed during high throughput repertoire analyses are limited.</p> <p>Results</p> <p>We analyzed 3 monoclonal TCR from TCR transgenic, Rag^-/-mice using Illumina^®sequencing. A total of 27 sequencing reactions were performed for each TCR using a trifurcating design in which samples were divided into 3 at significant processing junctures. More than 20 million complementarity determining region (CDR) 3 sequences were analyzed. Filtering for lower quality sequences diminished but did not eliminate sequence errors, which occurred within 1-6% of sequences. Erroneous sequences were pre-dominantly of correct length and contained single nucleotide substitutions. Rates of specific substitutions varied dramatically in a position-dependent manner. Four substitutions, all purine-pyrimidine transversions, predominated. Solid phase amplification and sequencing rather than liquid sample amplification and preparation appeared to be the primary sources of error. Analysis of polyclonal repertoires demonstrated the impact of error accumulation on data parameters.</p> <p>Conclusions</p> <p>Caution is needed in interpreting repertoire data due to potential contamination with mis-sequence reads. However, a high association of errors with phred score, high relatedness of erroneous sequences with the parental sequence, dominance of specific nt substitutions, and skewed ratio of forward to reverse reads among erroneous sequences indicate approaches to filter erroneous sequences from repertoire data sets.</p

The Blood of Healthy Individuals Exhibits CD8 T Cells with a Highly Altered TCR Vb Repertoire but with an Unmodified Phenotype

CD8 T cell clonal expansions (TCE) have been observed in elderly, healthy individuals as well in old mice, and have been associated with the ageing process. Both chronic latent and non-persistent viral infections have been proposed to drive the development of distinct non-functional and functional TCE respectively. Biases in TCR Vβ repertoire diversity are also recurrently observed in patients that have undergone strong immune challenge, and are preferentially observed in the CD8 compartment. Healthy adults can also exhibit CD8 T cells with strong alterations of their CDR3 length distribution. Surprisingly, no specific investigations have been conducted to analyze the CD8 T cell repertoire in normal adults, to determine if such alterations in TCR Vβ repertoire share the features of TCE. In this study, we characterized the phenotype and function of the CD8 population in healthy individuals of 25–52 years of age. All but one of the EBV-positive HLA-B8 healthy volunteers that were studied were CMV-negative. Using a specific unsupervised statistical method, we identified Vβ families with altered CDR3 length distribution and increased TCR Vβ/HPRT transcript ratios in all individuals tested. The increase in TCR Vβ/HPRT transcript ratio was more frequently associated with an increase in the percentage of the corresponding Vβ+ T cells than with an absence of modification of their percentage. However, in contrast with the previously described TCE, these CD8+ T cells were not preferentially found in the memory CD8 subset, they exhibited normal effector functions (cytokine secretion and cytotoxic molecule expression) and they were not reactive to a pool of EBV/CMV/Flu virus peptides. Taken together, the combined analysis of transcripts and proteins of the TCR Vβ repertoire led to the identification of different types of CD8+ T cell clone expansion or contraction in healthy individuals, a situation that appears more complex than previously described in aged individuals

Temporal Accumulation and Decision Processes in the Duration Bisection Task Revealed by Contingent Negative Variation

The duration bisection paradigm is a classic task used to examine how humans and other animals perceive time. Typically, participants first learn short and long anchor durations and are subsequently asked to classify probe durations as closer to the short or long anchor duration. However, the specific representations of time and the decision rules applied in this task remain the subject of debate. For example, researchers have questioned whether participants actually use representations of the short and long anchor durations in the decision process rather than merely a response threshold that is derived from those anchor durations. Electroencephalographic (EEG) measures, like the contingent negative variation (CNV), can provide information about the perceptual and cognitive processes that occur between the onset of the timing stimulus and the motor response. The CNV has been implicated as an electrophysiological marker of interval timing processes such as temporal accumulation, representation of the target duration, and the decision that the target duration has been attained. We used the CNV to investigate which durations are involved in the bisection categorization decision. The CNV increased in amplitude up to the value of the short anchor, remained at a constant level until about the geometric mean (GM) of the short and long anchors, and then began to resolve. These results suggest that the short anchor and the GM of the short and long anchors are critical target durations used in the bisection categorization decision process. In addition, larger mean N1P2 amplitude differences were associated with larger amplitude CNVs, which may reflect the participant’s precision in initiating timing on each trial across a test session. Overall, the results demonstrate the value of using scalp-recorded EEG to address basic questions about interval timing

Altered Thymic Function during Interferon Therapy in HCV-Infected Patients

Interferon alpha (IFNα) therapy, despite good efficacy in curing HCV infection, leads to major side effects, in particular inducement of a strong peripheral T-cell lymphocytopenia. We here analyze the early consequences of IFNα therapy on both thymic function and peripheral T-cell homeostasis in patients in the acute or chronic phase of HCV-infection as well as in HIV/HCV co-infected patients. The evolution of T-cell subsets and T-cell homeostasis were estimated by flow cytometry while thymic function was measured through quantification of T-cell receptor excision circles (TREC) and estimation of intrathymic precursor T-cell proliferation during the first four months following the initiation of IFNα therapy. Beginning with the first month of therapy, a profound lymphocytopenia was observed for all T-cell subsets, including naïve T-cells and recent thymic emigrants (RTE), associated with inhibition of intrathymic precursor T-cell proliferation. Interleukin (IL)-7 plasma concentration rapidly dropped while lymphocytopenia progressed. This was neither a consequence of higher consumption of the cytokine nor due to its neutralization by soluble CD127. Decrease in IL-7 plasma concentration under IFNα therapy correlated with the decline in HCV viral load, thymic activity and RTE concentration in blood. These data demonstrate that IFNα-based therapy rapidly impacts on thymopoiesis and, consequently, perturbs T-cell homeostasis. Such a side effect might be detrimental for the continuation of IFNα therapy and may lead to an increased level of infectious risk, in particular in HIV/HCV co-infected patients. Altogether, this study suggests the therapeutic potential of IL-7 in the maintenance of peripheral T-cell homeostasis in IFNα-treated patients

Structural, thermal and dissolution properties of MgO- and CaO-containing borophosphate glasses: effect of Fe2O3 addition

This paper investigated manufacture of high-durability phosphate glass fibres for biomedical applications. Five different borophosphate glass formulations in the systems of 45P2O5–5B2O3–5Na2O–(29 − x)CaO–16MgO–(x)Fe2O3 and 45P2O5–5B2O3–5Na2O–24CaO–(21 − x)MgO–(x)Fe2O3 where x = 5, 8 and 11 mol% were produced via melt quenching. The compositions and amorphous nature of the glasses were confirmed by ICP-MS and XRD, respectively. FTIR results indicated depolymerisation of the phosphate chains with a decrease in Q2 units with increasing Fe2O3 content. DSC analyses showed an increase in Tg by ~5 °C with an increment of 3 mol% in Fe2O3 content. The thermal properties were also used to calculate processing window (i.e. Tc,ons—Tg) and another parameter, Kgl, to determine the suitability for fibre drawing directly from melt, which equals (Tc,ons—Tg)/(Tl—Tc,ons). The degradation study conducted in PBS solution at 37 °C showed a decrease of 25–47% in degradation rate with increasing Fe2O3 content. This confirmed that the chemical durability of the glasses had increased, which was suggested to be due to Fe2O3 addition. Furthermore, the density measured via Archimedes method revealed a linear increase with increasing Fe2O3 content

Genetic and Structural Basis for Selection of a Ubiquitous T Cell Receptor Deployed in Epstein-Barr Virus Infection

Despite the ∼1018 αβ T cell receptor (TCR) structures that can be randomly manufactured by the human thymus, some surface more frequently than others. The pinnacles of this distortion are public TCRs, which exhibit amino acid-identical structures across different individuals. Public TCRs are thought to result from both recombinatorial bias and antigen-driven selection, but the mechanisms that underlie inter-individual TCR sharing are still largely theoretical. To examine this phenomenon at the atomic level, we solved the co-complex structure of one of the most widespread and numerically frequent public TCRs in the human population. The archetypal AS01 public TCR recognizes an immunodominant BMLF1 peptide, derived from the ubiquitous Epstein-Barr virus, bound to HLA-A*0201. The AS01 TCR was observed to dock in a diagonal fashion, grasping the solvent exposed peptide crest with two sets of complementarity-determining region (CDR) loops, and was fastened to the peptide and HLA-A*0201 platform with residue sets found only within TCR genes biased in the public response. Computer simulations of a random V(D)J recombination process demonstrated that both TCRα and TCRβ amino acid sequences could be manufactured easily, thereby explaining the prevalence of this receptor across different individuals. Interestingly, the AS01 TCR was encoded largely by germline DNA, indicating that the TCR loci already comprise gene segments that specifically recognize this ancient pathogen. Such pattern recognition receptor-like traits within the αβ TCR system further blur the boundaries between the adaptive and innate immune systems

The Dynamics of T-Cell Receptor Repertoire Diversity Following Thymus Transplantation for DiGeorge Anomaly

T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after thymus transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective roles of TCR-specific vs. TCR-nonspecific regulatory signals in the growth of these emerging T-cell populations. During the course of the study, we measured peripheral blood T-cell concentrations, TCRβ V gene-segment usage and CDR3-length spectratypes over two years or more for each of the subjects. We find, through statistical analysis based on a novel stochastic population-dynamic T-cell model, that the carrying capacity corresponding to TCR-specific resources is approximately 1000-fold larger than that of TCR-nonspecific resources, implying that the size of the peripheral T-cell pool at steady state is determined almost entirely by TCR-nonspecific mechanisms. Nevertheless, the diversity of the TCR repertoire depends crucially on TCR-specific regulation. The estimated strength of this TCR-specific regulation is sufficient to ensure rapid establishment of TCR repertoire diversity in the early phase of T cell population growth, and to maintain TCR repertoire diversity in the face of substantial clonal expansion-induced perturbation from the steady state