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According to an important analogy between knowledge and action, as proposed by Timothy Williamson, intention aims at (intentional) action just as belief aims at knowledge. This paper investigates the analogy and discusses three difficulties that it has to face. The key is to distinguish between two different norms of intention and to see that the knowledge-action analogy is concerned with one of them only, namely, the realization norm: one ought to intentionally act if one intends to act in a certain way. A modification will be proposed that replaces intention by correct intention, and some work will be done with the aim of uncovering a frame for how to properly understand the analogy and what it ultimately is grounded on, namely, the normativity of capacities that are in the business of generating various states (beliefs, intentions) and of realizing one’s correct intentions. Thus, a modified knowledge-action analogy will be vindicated in the end.

In The Rationality of Perception, Susanna Siegel defends the claim that beliefs can influence our perceptions. Faulty beliefs make our experiences irrational. This explains why the biases some people hold are so tenacious. The authors point out weaknesses in Siegel’s argument.

The paper is an investigation into the prospects of an epistemology of non-conceptual knowledge. According to the orthodox view, knowledge requires concepts and belief. I present several arguments to the effect that there is non-conceptual, non-doxastic knowledge, the obvious candidate for such knowledge being non-conceptual perception. Non-conceptual perception seems to be allowed for by cognitive scientists and it exhibits the central role features of knowledge�it plays the knowledge role: it respects an anti-luck condition, it is an achievement, it enables one to act for a reason, and it provides justification. Furthermore, it makes a straightforward and elegant explanation of (doxastic) perceptual knowledge possible: doxastic perceptual knowledge builds on non-conceptual perception as non-conceptual knowledge. Three objections that might naturally arise will be discussed and answered. Thus, the prospects of an epistemology without belief seem to be much better than the orthodoxy wants to have it. We can extend knowledge into the non-conceptual realm.

I will present a problem for any externalist evidentialism that allows for accidental possession of evidence. There are Gettier cases for justification. I will describe two such cases – cases involving veridical hallucination. An analysis of the cases is given, along the lines of (reliabilist) virtue epistemology (cf. Sosa, Greco). The cases show that certain externalist evidentialist accounts of justification do not provide sufficient conditions. The reason lies in the fact that one can be luckily in possession of evidence, and then one will not have a justified belief. Justified belief requires an anti-luck condition on possession of evidence. This opens up the prospects of a unified virtue-epistemology covering both knowledge and justification.

Fred Dretske’s account of mental causation, developed in Explaining Behavior and defended in numerous articles, is generally regarded as one of the most interesting and most ambitious approaches in the field. According to Dretske, meaning facts, construed historically as facts about the indicator functions of internal states, are the structuring causes of behavior. In this article, we argue that Dretske’s view is untenable: On closer examination, the real structuring causes of behavior turn out to be markedly different from Dretske’s meaning facts. Our argument proceeds in three steps. First, we set forth the problem of meaning individuation: We argue that the proposal that meaning facts are structuring causes of behavior commits Dretske to a very fine-grained individuation of meanings that is deeply counterintuitive. In a second step, we show that even these finely individuated meaning facts cannot do the job that they are supposed to do, since information facts—which are constitutive of, but distinct from Dretske’s meaning facts—are better candidates for the role of structuring causes. Finally, we argue that it is not even information facts, but facts of co-instantiation which are the real structuring causes of behavior. In concluding, we briefly consider the options that are left for Dretske if our arguments succeed.

I distinguish between three kinds of reliabilism for epistemic justification, namely, pure reliabilism, evidential reliabilism, and reasons reliabilism, and I argue for reasons reliabilism. Pure reliabilism and evidential reliabilism are plagued, most importantly, by the generality problem, and they cannot deal adequately with defeater phenomena. One can avoid these problems only by jettisoning the idea of process reliability. The truth connection – which is essential for any kind of reliabilism – has to be provided in an altogether different way, namely, by means of facts in the world which serve as objective reasons (or evidence). So, as reasons reliabilism says, a justified belief has to be anchored in an objective reason which speaks in favor of its truth. Only in this way can intuitions about defeaters be preserved and explained. And reasons reliabilism can avoid the generality problem.

The stress distribution in a pressurized elastomer confined by a hollow cylinder is of interest in various applications of material testing and manufacturing. A relatively accurate closed form solution for the pressure distribution inside an elastomer confined by a rigid hollow cylinder was presented by Yu et al. (2001) . But in many practical applications the assumption of a rigid hollow cylinder is not appropriate, because the cylinder deformations have a significant influence on the stresses inside the elastomer. Thus in this paper a solution for an elastomer confined by a deformable hollow cylinder is derived. Both axial and radial deformations of the hollow cylinder are taken into account, while the bending stiffness of the cylinder wall is neglected, i.e. the cylinder wall is treated according to the membrane theory. The accuracy of the proposed closed form solution is verified by a parametric finite element simulation.

Creativity, the activity to construct something new and useful, is an elementary aspect of life. This article advocates the position that creative elements are also present in counselling and psychotherapy. Creativity can be found in relational, behavioural, cognitive, psychodynamic, systemic and existential approaches to counselling and psychotherapy. It is shown that the shaping of the therapeutic relationship as the basis of every successful counselling or psychotherapeutic process is a creative challenge. On the cognitive–behavioural level, creativity also plays an important role in developing and implementing new perspectives and behaviours. Psychodynamically, the verbalization of emotions and unconscious wishes and conflicts can also be considered as a creative task. Finally, on an existential level, counselling and psychotherapy appear as a means to form novel and useful constructions of reality. Recognizing and utilizing creative resources of counselling and psychotherapy correspond to a ‘creative...

In this report we present a method to identify functional artificial lantipeptides. In vitro translation coupled with an enzyme-free protocol for posttranslational modification allows preparation of more than 10(11) different lanthionine containing peptides. This diversity can be searched for functional molecules using mRNA-lantipeptide display. We validated this approach by isolating binders toward Sortase A, a transamidase which is required for virulence of Staphylococcus aureus. The interaction of selected lantipeptides with Sortase A is highly dependent on the presence of a (2S,6R)-lanthionine in the peptide and an active conformation of the protein.

Intraoperative radiotherapy (IORT) is currently being evaluated as a novel approach during breast-conserving surgery (BCS). IORT can be used either as a tumor bed boost followed by external-beam radiotherapy (EBRT) or as a single treatment. In a matched-pair study, we assessed quality of life (QoL) in 69 patients with early breast cancer treated with BCS and/or IORT and/or EBRT. Patients were matched for age and time since BCS. IORT was provided with 50 kV x-rays (Intrabeam) delivering 20 Gy at the applicator surface. EBRT (46 to 50 Gy in 2-Gy fractions in the IORT with EBRT group, and 56 Gy in 2-Gy fractions in the EBRT group) was initiated after completion of wound healing and/or chemotherapy. The mailed questionnaires included the European Organization for the Research and Treatment of Cancer QLQ-C30 and BR23, FACT-F, HADS, Body Image Scale, and Rosenberg Self-Esteem Scale. At 18 to 70 months’ follow-up (median 47 months), all patients were disease free. We found only a few differences between the three groups. There was a trend toward more pain (mean ± standard deviation; 42.8 ± 32.9 vs. 27.5 ± 34.7) and reduced QoL (57.6 ± 20.7 vs. 70.3 ± 23.9) after IORT with EBRT compared with EBRT, respectively. IORT patients reported comparable QoL (70.3 ± 23.0), and less breast symptoms and body image concerns compared to EBRT (8.6 ± 12.3 vs. 19.2 ± 23.8, and 1.7 ± 3.3 vs. 3.4 ± 4.4, respectively). IORT alone resulted in significantly fewer breast symptoms (8.6 ± 12.3; P = 0.012) and less pain (23.9 ± 24.5, P = 0.041) compared with IORT with EBRT (26.1 ± 27.6; 42.8 ± 32.9, respectively). Patients with early breast cancer after BCS and IORT with or without EBRT present with comparable QoL like patients receiving EBRT without a boost. IORT patients show the lowest rate of breast symptoms.

The paper attempts to give an account of the introspective self-knowledge of our own experiences which is in line with representationalism about phenomenal consciousness and the transparency of experience. A two-step model is presented. First, a demonstrative thought of the form ‚I am experiencing this’ is formed which refers to what one experiences, by means of attention. Plausibly, this thought is knowledge, since safe. Second, a non-demonstrative thought of the form ‚I am experiencing a pain’ occurs. This second self-ascription is justified inferentially, on the basis of the first, demonstrative thought. Thus, an account of introspective experiential self-knowledge can be developed which is richer and more adequate to the phenomena than pure reliabilism and Dretske’s displaced perception model. There is really such a thing as introspection, but no inner sense.

According to the so-called metaphysical conception of analyticity, analytic truths are true in virtue of meaning (or content) alone and independently of (extralinguistic) facts. Quine and Boghossian have tried to present a conclusive argument against the metaphysical conception of analyticity. In effect, they tried to show that the metaphysical conception inevitably leads into a highly implausible view about the truthmakers of analytic truths. We would like to show that their argument fails, since it relies on an ambiguity of the notion of ‘independence of (extralinguistic) facts’. If one distinguishes between variation independence and existence independence, the unwelcome view about the truthmakers of analytic truths no longer follows. Thus, there is at best a challenge, but no conclusive argument. The door to the metaphysical conception of analyticity is still open.1

Sydney Shoemaker has attempted to save mental causation by a new account of realization. As Brian McLaughlin argues convincingly, the account has to face two major problems. First, realization does not guarantee entailment. So even if mental properties are realized by physical properties, they need not be entailed by them. This is the first, rather general metaphysical problem. A second problem, which relates more directly to mental causation is that Shoemaker must appeal to some kind of proportionality as a constraint on causation in order to avoid redundant mental causation. I argue that, in addition, a “piling problem” arises, since causal powers seem to be bestowed twice. Then, I try to sketch an alternative view of the relation between causal powers and properties—a reductionist view—which fares better on some accounts. But it may have to face another and, perhaps, serious problem, the “problem of the natural unity of properties”. Finally, I will pose a question about the relation between causal powers and causation.

Neuroprotection can be induced by low doses of NMDA, which activate both synaptic and extrasynaptic NMDA receptors. This is in apparent contradiction with our recent findings that extrasynaptic NMDA receptor signaling exerts a dominant inhibitory effect on prosurvival signaling from synaptic NMDA receptors. Here we report that exposure to low preconditioning doses of NMDA results in preferential activation of synaptic NMDA receptors because of a dramatic increase in action potential firing. Both acute and long-lasting phases of neuroprotection in the face of apoptotic or excitotoxic insults are dependent on this firing enhancement. Key mediators of synaptic NMDA receptor-dependent neuroprotection, phosphatidylinositol 3 kinase-Akt (PI3 kinase-Akt) signaling to Forkhead box subgroup O (FOXO) export and glycogen synthase kinase 3β (GSK3β) inhibition and cAMP response element-binding protein-dependent (CREB-dependent) activation of brain-derived neurotrophic factor (BDNF), can be induced only by low doses of NMDA via this action potential-dependent route. In contrast, NMDA doses on the other side of the toxicity threshold do not favor synaptic NMDA receptor activation because they strongly suppress firing rates below baseline. The classic bell-shaped curve depicting neuronal fate in response to NMDA dose can be viewed as the net effect of two antagonizing (synaptic vs extrasynaptic) curves: via increased firing the synaptic signaling dominates at low doses, whereas firing becomes suppressed and extrasynaptic signaling dominates as the toxicity threshold is crossed.

Substrate integrated microelectrode arrays (MEAs) offer an alternative to classical electrophysiological methods like the patch clamp technique for recording the electrical activity from cells and tissue of neuronal or cardiac origin. Since its introduction 30 years ago, this technology has made possible the repeated simultaneous recording from multiple sites in a non-invasive manner. The MEA technology can be applied to any electrogenic cells or tissue (i.e., central and peripheral neurons, heart cells, and muscle cells), either as cultures or acute cell or slice preparations. The combination of culture techniques and MEAs offers the possibility to monitor the activity of a designed specimen over extended periods of time, up to several months. Furthermore, recording the electrical activity of distributed regions of a preparation yields information on spatial effects that might go undetected with other recording methods. Development, plasticity, and regeneration are examples of applications that could especially benefit from long term monitoring of neuronal activity, as they concern processes that develop over extended periods of time. Here we highlight recent MEA studies on signal regulation of neuronal network behavior and axonal regeneration. We illustrate the use of MEAs to study long term potentiation (LTP) and summarize the advantages of MEA technology over traditional electrophysiological methods for studies aimed at understanding the transcription-dependent late phase of plasticity.

The idea of truthmakers is important for doing serious metaphysics, since a truthmaker principle can give us important guidance in finding out what we would like to include into our ontology. Recently, David Lewis has argued against Armstrong’s argument that a plausible truthmaker principle requires us to accept facts. I would like to take a close look at the argument. I will argue in detail that the Humean principle of recombination on which Lewis relies is not plausible (independently of the issue of facts). Then I will show that the right truthmaker principle that vindicates facts is superior to the modified truthmaker principle that Lewis has proposed. This will lead into the topic of being and existence. It turns out that truthmaking and facts are plausible, well suited for one another, and very coherent with a plausible conception of being.

The question of what means-and-ends structure our epistemic endeavors have is an important issue in recent epistemology, and is fundamental for understanding epistemic matters in principle. Crispin Sartwell has proposed arguments for the view that knowledge is our only ultimate goal, and justification is no part of it. An important argument is his instrumentality argument which is concerned with the conditions under which something could belong to our ultimate epistemic goal. Recently, this argument has been reconstructed and criticized by Pierre Le Morvan in a clear and helpful way. It will be shown, however, that Le Morvan’s criticism is not adequate, since it misconstrues the real instrumentality argument that can be found in Sartwell’s writings.

A simplified cell culture system was developed to study neuronal plasticity. As changes in synaptic strength may alter network activity patterns, we grew hippocampal neurones on a microelectrode array (MEA) and monitored their collective behaviour with 60 electrodes simultaneously. We found that exposure of the network for 15 min to the GABAA receptor antagonist bicuculline induced an increase in synaptic efficacy at excitatory synapses that was associated with an increase in the frequency of miniature AMPA receptor-mediated EPSCs and a change in network activity from uncoordinated firing of neurones (lacking any recognizable pattern) to a highly organized, periodic and synchronous burst pattern. Induction of recurrent synchronous bursting was dependent on NMDA receptor activation and required extracellular signal-regulated kinase (ERK)1/2 signalling and translation of pre-existing mRNAs. Once induced, the burst pattern persisted for several days; its maintenance phase (> 4h )was dependent on gene transcription taking place in a critical period of 120 min following induction. Thus, cultured hippocampal neurones display a simple, transcription and protein synthesis-dependent form of plasticity. The non-invasive nature of MEA recordings provides a significant advantage over traditional assays for synaptic connectivity (i.e. long-term potentiation in brain slices) and facilitates the search fo ra ctivity-regulated genes critical for late-phase plasticity.

Hugh Mellor has proposed what appears to be a new solution to the problem of intrinsic change (Mellor 1998). Assuming endurantism and a B-theoretic, nonpresentist view of time, facts are supposed to have only enduring things and atemporal properties (or relations) as constituents, but no times. The having of properties and relations is not relativised to times. Instead, the whole of a fact is conceived of as temporally localised. It will be argued that this interesting and novel proposal does not succeed as an account of change in the intrinsic properties of things. The basic difficulty is that the view still leads into contradiction, since it makes it incomprehensible how one and the same thing can have both a property and some incompatible property. The having of these incompatible properties is treated as two facts. But to add that these facts have certain temporal locations is of no help for avoiding the contradiction.

Co-cultures of entorhinal cortex (EC) and dentate gyrus (DG) explants are a useful model system to study the formation and stabilization of axonal projections. We adapted this model system to EC-DG co-cultures on microelectrode arrays (MEA) for the characterization of axonal projections on a functional level for days and weeks. EC and DG explants were placed on MEA to allow for the reconstitution of perforant pathway projections. Connections formed were characterized by morphological and electrophysiological analyses to verify characteristic features of perforant pathway signal transmission. Morphological analysis reveals proper projection of EC neurons into the molecular layer of the DG. Examination of synaptic transmission after high frequency stimulation imply unidirectional connections that used glutamate receptors of the AMPA/kainate type as main mediators of excitatory signal transmission. The system was evaluated by the introduction of the NCAM binding peptide C3d. In accordance with in vivo and in vitro experiments C3d modulated signal transmission by NCAM-related mechanisms resulting in morphological re-arrangements.

Electrical activity of electrogenic cells in neuronal and cardiac tissue can be recorded by means of microelectrode arrays (MEAs) that offer the unique possibility for non-invasive extracellular recording from as many as 60 sites simultaneously. Since its introduction 30 years ago, the technology and the related culture methods for electrophysiological cell and tissue assays have been continually improved and have found their way into many academic and industrial laboratories. Currently, this technology is attracting increased interest owing to the industrial need to screen selected compounds against ion channel targets in their native environment at organic, cellular, and sub-cellular level. As the MEA technology can be applied to any electrogenic tissue (i.e., central and peripheral neurons, heart cells, and muscle cells), the MEA biosensor is an ideal in vitro system to monitor both acute and chronic effects of drugs and toxins and to perform functional studies under physiological or induced pathophysiological conditions that mimic in vivo damages. By recording the electrical response of various locations on a tissue, a spatial map of drug effects at different sites can be generated, providing important clues about a drug's specificity. In this survey, examples of MEA biosensor applications are described that have been developed for drug screening and discovery and safety pharmacology in the field of cardiac and neural research. Additionally, biophysical basics of recording and concepts for analysis of extracellular electrical signals are presented.

Taking into account some philosophical notionson realism a reformulation of“macro-realism” according to Leggett-Garg isput forward. A macroscopic phase dynamics based on amicroscopic SQUID-model is discussed in this context.

Background The magnitude and longevity of synaptic activity-induced changes in synaptic efficacy is quantified by measuring evoked responses whose potentiation requires gene transcription to persist for more than 2-3 hours. While miniature EPSCs (mEPSCs) are also increased in amplitude and/or frequency during long-term potentiation (LTP), it is not known how long such changes persist or whether gene transcription is required. Results We use whole-cell patch clamp recordings from dissociated hippocampal cultures to characterise for the first time the persistence and transcription dependency of mEPSC upregulation during synaptic potentiation. The persistence of recurrent action potential bursting in these cultures is transcription-, translation- and NMDA receptor-dependent thus providing an accessible model for long-lasting plasticity. Blockade of GABAA-receptors with bicuculline for 15 minutes induced action potential bursting in all neurons and was maintained in 50-60% of neurons for more than 6 hours. Throughout this period, the frequency but neither the amplitude of mEPSCs nor whole-cell AMPA currents was markedly increased. The transcription blocker actinomycin D abrogated, within 2 hours of burst induction, both action potential bursting and the increase in mEPSCs. Reversible blockade of action potentials during, but not after this 2 hour transcription period suppressed the increase in mEPSC frequency and the recovery of burst activity at a time point 6 hours after induction. Conclusion These results indicate that increased mEPSC frequency persists well beyond the 2 hour transcription-independent phase of plasticity in this model. This long-lasting mEPSC upregulation is transcription-dependent and requires ongoing action potential activity during the initial 2 hour period but not thereafter. Thus mEPSC upregulation may underlie the long term, transcription-dependent persistence of action potential bursting. This provides mechanistic insight to link gene candidates already identified by gene chip analysis to long lasting plasticity in this in vitro model.