TRPV1 channel in the pathophysiology of epilepsy and its potential as a molecular target for the development of new antiseizure drug candidates.

Identification of transient receptor potential cation channel, subfamily V member 1 (TRPV1), also known as capsaicin receptor, in 1997 was a milestone achievement in the research on temperature sensation and pain signalling. Very soon after it became evident that TRPV1 is implicated in a wide array of physiological processes in different peripheral tissues, as well as in the central nervous system, and thereby could be involved in the pathophysiology of numerous diseases. Increasing evidence suggests that modulation of TRPV1 may also affect seizure susceptibility and epilepsy. This channel is localized in brain regions associated with seizures and epilepsy, and its overexpression was found both in animal models of seizures and in brain samples from epileptic patients. Moreover, modulation of TRPV1 on non-neuronal cells (microglia, astrocytes, and/or peripheral immune cells) may have an impact on the neuroinflammatory processes that play a role in epilepsy and epileptogenesis. In this paper, we provide a comprehensive and critical overview of currently available data on TRPV1 as a possible molecular target for epilepsy management, trying to identify research gaps and future directions. Overall, several converging lines of evidence implicate TRPV1 channel as a potentially attractive target in epilepsy research but more studies are needed to exploit the possible role of TRPV1 in seizures/epilepsy and to evaluate the value of TRPV1 ligands as candidates for new antiseizure drugs.

Is punishment backward? On neurointerventions and forward-looking moral responsibility.

This article focuses on justified responses to "immoral" behavior and crimes committed by patients undergoing neuromodulation therapies. Such patients could be held morally responsible in the basic desert sense-the one that serves as a justification of severe practices such as backward-looking moral outrage, condemnation, and legal punishment-as long as they possess certain compatibilist capabilities that have traditionally served as the quintessence of free will, that is, reasons-responsiveness; attributability; answerability; the abilities to act in accordance with moral reasons, second-order volitions, or Deep Self. Recently leading compatibilist neuroethicists added the condition of not feeling alienated from desires motivating a person's action. This article argues against such attempts to determine conditions under which patients undergoing neuromodulation should be subject to negative reactive attitudes and legal punishment. Compatibilism should not be used to justify basic desert moral responsibility and legal punishment. Instead, a new way of thinking about the function of moral responsibility attribution is proposed for patients with neuromodulation. Their compatibilist capabilities should serve as important indicators for determining appropriate, forward-looking courses of action, such as quarantining and restorative treatment, to ensure the public safety and well-being of the patients.

To remember, or not to remember? Potential impact of memory modification on narrative identity, personal agency, mental health, and well-being.

Memory modification technologies (MMTs)-interventions within the memory affecting its functions and contents in specific ways-raise great therapeutic hopes but also great fears. Ethicists have expressed concerns that developing and using MMTs may endanger the very fabric of who we are-our personal identity. This threat has been mainly considered in relation to two interrelated concerns: truthfulness and narrative self-constitution. In this article, we propose that although this perspective brings up important matters concerning the potential aftermaths of MMT utilization, it fails to tell the whole story. We suggest that capturing more tangible potential consequences of MMT use, namely, its psychological ramifications is crucial both in ethical considerations and in making decisions regarding the permissibility of such interventions. To this end, we first examine what current MMTs are capable of and what are the prospects of emerging MMTs. Subsequently, we outline the relationship between memory and personal identity; specifically, we indicate that concepts of self-defining memories and narrative identity are crucial to considering how MMTs may influence one's psychological functioning. On this basis, we analyze potential consequences of narrative disruption that may be the result of the use of MMTs; more precisely, we consider its potential effects on mental health, well-being, and personal agency, and outline the ethical dilemmas that decision-makers face in this context. We conclude by considering the broader cultural context that may have influence on policymaking regarding permissibility of memory modification interventions.

Personality and Authenticity in Light of the Memory-Modifying Potential of Optogenetics.

There has been a growing interest in research concerning memory modification technologies (MMTs) in recent years. Neuroscientists and psychologists are beginning to explore the prospect of controllable and intentional modification of human memory. One of the technologies with the greatest potential to this end is optogenetics-an invasive neuromodulation technique involving the use of light to control the activity of individual brain cells. It has recently shown the potential to modify specific long-term memories in animal models in ways not yet possible with other MMTs. As the therapeutic potential of optogenetics has already prompted approval of the first human trials, it is especially important and timely to consider the opportunities and dangers this technology may entail. In this article, we focus on possible consequences of optogenetics as an MMT by analyzing fundamental threats potentially associated with memory modifications: the potential disruption of personality and authenticity.

Experimental Studies on 3D Printing of Automatically Designed Customized Wrist-Hand Orthoses.

The paper presents results of research conducted on a batch of additively manufactured individualized openwork wrist-hand orthoses made of thermoplastics and designed automatically based on 3D-scanned geometry of a given patient. The aim of the work was to establish an automated design process and find a reliable set of parameters for rapid and affordable manufacturing of usable orthoses on popular 3D printers, with little or no supervision of the process. The paper presents motivations, methodology of automated design, plan of manufacturing and testing, the obtained results in terms of process stability, fit and assessment by patient and strength of the obtained orthoses. Almost 100 manufacturing processes of ready-to-use orthosis parts were carried out in a controlled environment and their results were analyzed thoroughly. The results are promising, as most of the obtained products fulfil the strength criteria, although not all of them meet the economic criteria. As a result, a recommended set of process parameters was determined. These parameters were included in a prototype of the automated design and in a production system developed by the authors.

5-Keto-3-cyano-2,4-diaminothiophenes as selective maternal embryonic leucine zipper kinase inhibitors.

Maternal embryonic leucine zipper kinase (MELK) is involved in several key cellular processes and displays increased levels of expression in numerous cancer classes (colon, breast, brain, ovary, prostate and lung). Although no selective MELK inhibitors have yet been approved, increasing evidence suggest that inhibition of MELK would constitute a promising approach for cancer therapy. A weak high-throughput screening hit (17, IC50 ≈ 5 µM) with lead-like properties was optimized for MELK inhibition. The early identification of a plausible binding mode by molecular modeling offered guidance in the choice of modifications towards compound 52 which displayed a 98 nM IC50. A good selectivity profile was achieved for a representative member of the series (29) in a 486 protein kinase panel. Future elaboration of 52 has the potential to deliver compounds for further development with chemotherapeutic aims.

An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction.

A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure-activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented.