Beyond Covariation: Cues to Causal Structure

Causal induction has two components: learning about the structure of causal models and learning about causal strength and other quantitative parameters. This chapter argues for several interconnected theses. First, people represent causal knowledge qualitatively, in terms of causal structure; quantitative knowledge is derivative. Second, people use a variety of cues to infer causal structure aside from statistical data (e.g. temporal order, intervention, coherence with prior knowledge). Third, once a structural model is hypothesized, subsequent statistical data are used to confirm, refute, or elaborate the model. Fourth, people are limited in the number and complexity of causal models that they can hold in mind to test, but they can separately learn and then integrate simple models, and revise models by adding and removing single links. Finally, current computational models of learning need further development before they can be applied to human learning

The tight coupling between category and causal learning

The main goal of the present research was to demonstrate the interaction between category and causal induction in causal model learning. We used a two-phase learning procedure in which learners were presented with learning input referring to two interconnected causal relations forming a causal chain (Experiment 1) or a common-cause model (Experiments 2a, b). One of the three events (i.e., the intermediate event of the chain, or the common cause) was presented as a set of uncategorized exemplars. Although participants were not provided with any feedback about category labels, they tended to induce categories in the first phase that maximized the predictability of their causes or effects. In the second causal learning phase, participants had the choice between transferring the newly learned categories from the first phase at the cost of suboptimal predictions, or they could induce a new set of optimally predictive categories for the second causal relation, but at the cost of proliferating different category schemes for the same set of events. It turned out that in all three experiments learners tended to transfer the categories entailed by the first causal relation to the second causal relation

Perturbative Construction of Models of Algebraic Quantum Field Theory

We review the construction of models of algebraic quantum field theory by renormalized perturbation theory.Comment: 38 page

Tumor-Targeted Delivery of IL-2 by NKG2D Leads to Accumulation of Antigen-Specific CD8+ T Cells in the Tumor Loci and Enhanced Anti-Tumor Effects

Interleukin-2 (IL-2) has been shown to promote tumor-specific T-cell proliferation and differentiation but systemic administration of IL-2 results in significant toxicity. Therefore, a strategy that can specifically deliver IL-2 to the tumor location may alleviate concerns of toxicity. Because NKG2D ligands have been shown to be highly expressed in many cancer cells but not in healthy cells, we reason that a chimeric protein consisting of NKG2D linked to IL-2 will lead to the specific targeting of IL-2 to the tumor location. Therefore, we created chimeric proteins consisting of NKG2D linked to Gaussia luciferase (GLuc; a marker protein) or IL-2 to form NKG2D-Fc-GLuc and NKG2D-Fc-IL2, respectively. We demonstrated that NKG2D linked to GLuc was able to deliver GLuc to the tumor location in vivo. Furthermore, we showed that TC-1 tumor-bearing mice intramuscularly injected with DNA encoding NKG2D-Fc-IL2, followed by electroporation, exhibited an increased number of luciferase-expressing E7-specific CD8+ T cells at the tumor location. More importantly, treatment with the DNA construct encoding NKG2D-Fc-IL2 significantly enhanced the therapeutic anti-tumor effects generated by intradermal vaccination with therapeutic HPV DNA in tumor-bearing mice. Therefore, by linking NKG2D to IL2, we are able to specifically deliver IL-2 to the tumor location, enhancing antigen-specific T-cell immune response and controlling tumor growth. Our approach represents a platform technology to specifically deliver proteins of interest to tumor loci

Inherent Dynamics of the Acid-Sensing Ion Channel 1 Correlates with the Gating Mechanism

A combination of computational and experimental approaches reveals the dynamics of ASIC1 gating, involving a deformation of the channel that triggers “twist-to-open” motions of the channel pore

The male fetal biomarker INSL3 reveals substantial hormone exchange between fetuses in early pig gestation

The peptide hormone INSL3 is uniquely produced by the fetal testis to promote the transabdominal phase of testicular descent. Because it is fetal sex specific, and is present in only very low amounts in the maternal circulation, INSL3 acts as an ideal biomarker with which to monitor the movement of fetal hormones within the pregnant uterus of a polytocous species, the pig. INSL3 production by the fetal testis begins at around GD30. At GD45 of the ca.114 day gestation, a time at which testicular descent is promoted, INSL3 evidently moves from male to female allantoic compartments, presumably impacting also on the female fetal circulation. At later time-points (GD63, GD92) there is less inter-fetal transfer, although there still appears to be significant INSL3, presumably of male origin, in the plasma of female fetuses. This study thus provides evidence for substantial transfer of a peptide hormone between fetuses, and probably also across the placenta, emphasizing the vulnerability of the fetus to extrinsic hormonal influences within the uterus

Responsiveness of the EQ-5D in breast cancer patients in their first year after treatment

<p>Abstract</p> <p>Background/aim</p> <p>The EQ-5D is a generic health-related quality of life (HRQoL) measure that is used for the purpose of economic evaluations of health interventions. Therefore, it has to be responsive to meaningful changes in health in the patient population under investigation. The aim of this study was to investigate the responsiveness of the EQ-5D in breast cancer patients in their first year after treatment.</p> <p>Methods</p> <p>The subscale global health of the disease-specific HRQoL measure EORTC QLQ-C30 was used as a reference instrument to determine meaningful changes in health and identify subgroups of patients: patients reporting a moderate-large deterioration, small deterioration, a small improvement, moderate-large improvement, or no change in health status. Responsiveness was evaluated by calculating standardized response means (SRMs) in the five subgroups of patients and performing analysis of variance procedures. The two HRQoL measures were filled out two weeks and one year after finalizing curative treatment for breast cancer (n = 192).</p> <p>Results</p> <p>The EQ-5D was able to capture both improvements and deteriorations in HRQoL. SRMs of the EQ VAS and EQ-5D Index were close to zero in the subgroup reporting no change and increased and decreased adequately in the subgroups reporting small and moderate changes. Additional analysis of variance procedures showed that the EQ-5D was able to differentiate between subgroups of patients with no change and moderate-large deterioration or improvement in health.</p> <p>Conclusion</p> <p>The EQ-5D seems an appropriate measure for the purpose of economic evaluations of health intervention in breast cancer patients after treatment.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN74071417.</p

Acid-evoked Ca2+ signalling in rat sensory neurones: effects of anoxia and aglycaemia

Ischaemia excites sensory neurones (generating pain) and promotes calcitonin gene-related peptide release from nerve endings. Acidosis is thought to play a key role in mediating excitation via the activation of proton-sensitive cation channels. In this study, we investigated the effects of acidosis upon Ca2+ signalling in sensory neurones from rat dorsal root ganglia. Both hypercapnic (pHo 6.8) and metabolic–hypercapnic (pHo 6.2) acidosis caused a biphasic increase in cytosolic calcium concentration ([Ca2+]i). This comprised a brief Ca2+ transient (half-time approximately 30 s) caused by Ca2+ influx followed by a sustained rise in [Ca2+]i due to Ca2+ release from caffeine and cyclopiazonic acid-sensitive internal stores. Acid-evoked Ca2+ influx was unaffected by voltage-gated Ca2+-channel inhibition with nickel and acid sensing ion channel (ASIC) inhibition with amiloride but was blocked by inhibition of transient receptor potential vanilloid receptors (TRPV1) with (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide (AMG 9810; 1 μM) and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl) tetrahydropryazine-1(2H)-carbox-amide (BCTC; 1 μM). Combining acidosis with anoxia and aglycaemia increased the amplitude of both phases of Ca2+ elevation and prolonged the Ca2+ transient. The Ca2+ transient evoked by combined acidosis, aglycaemia and anoxia was also substantially blocked by AMG 9810 and BCTC and, to a lesser extent, by amiloride. In summary, the principle mechanisms mediating increase in [Ca2+]i in response to acidosis are a brief Ca2+ influx through TRPV1 followed by sustained Ca2+ release from internal stores. These effects are potentiated by anoxia and aglycaemia, conditions also prevalent in ischaemia. The effects of anoxia and aglycaemia are suggested to be largely due to the inhibition of Ca2+-clearance mechanisms and possible increase in the role of ASICs