Free will and mental disorder: Exploring the relationship

A link between mental disorder and freedom is clearly present in the introduction of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). It mentions “an important loss of freedom” as one of the possible defining features of mental disorder. Meanwhile, it remains unclear how “an important loss of freedom” should be understood. In order to get a clearer view on the relationship between mental disorder and (a loss of) freedom, in this article, I will explore the link between mental disorder and free will. I examine two domains in which a connection between mental disorder and free will is present: the philosophy of free will and forensic psychiatry. As it turns out, philosophers of free will frequently refer to mental disorders as conditions that compromise free will and reduce moral responsibility. In addition, in forensic psychiatry, the rationale for the assessment of criminal responsibility is often explained by referring to the fact that mental disorders can compromise free will. Yet, in both domains, it remains unclear in what way free will is compromised by mental disorders. Based on the philosophical debate, I discuss three senses of free will and explore their relevance to mental disorders. I conclude that in order to further clarify the relationship between free will and mental disorder, the accounts of people who have actually experienced the impact of a mental disorder should be included in future research

HIV-1 Inhibits Autophagy in Bystander Macrophage/Monocytic Cells through Src-Akt and STAT3

Autophagy is a homeostatic mechanism of lysosomal degradation. Defective autophagy has been linked to various disorders such as impaired control of pathogens and neurodegeneration. Autophagy is regulated by a complex array of signaling pathways that act upstream of autophagy proteins. Little is known about the role of altered regulatory signaling in disorders associated with defective autophagy. In particular, it is not known if pathogens inhibit autophagy by modulation of upstream regulatory pathways. Cells infected with HIV-1 blocked rapamycin-induced autophagy and CD40-induced autophagic killing of Toxoplasma gondii in bystander (non-HIV-1 infected) macrophage/monocytic cells. Blockade of autophagy was dependent on Src-Akt and STAT3 triggered by HIV-1 Tat and IL-10. Neutralization of the upstream receptors VEGFR, β-integrin or CXCR4, as well as of HIV-1 Tat or IL-10 restored autophagy in macrophage/monocytic cells exposed to HIV-1-infected cells. Defective autophagic killing of T. gondii was detected in monocyte-derived macrophages from a subset of HIV-1+ patients. This defect was also reverted by neutralization of Tat or IL-10. These studies revealed that a pathogen can impair autophagy in non-infected cells by activating counter-regulatory pathways. The fact that pharmacologic manipulation of cell signaling restored autophagy in cells exposed to HIV-1-infected cells raises the possibility of therapeutic manipulation of cell signaling to restore autophagy in HIV-1 infection

Flavianate, an amino acid precipitant, is a competitive inhibitor of trypsin at pH 3.0

Textile dyes bind to proteins leading to selective co-precipitation of a complex involving one protein molecule and more than one dye molecule of opposite charge in acid solutions, in a process of reversible denaturation that can be utilized for protein fractionation. In order to understand what occurs before the co-precipitation, a kinetic study using bovine ß-trypsin and sodium flavianate was carried out based on reaction progress curve techniques. The experiments were carried out using <FONT FACE="Symbol">a</font>-CBZ-L-Lys-p-nitrophenyl ester as substrate which was added to 50 mM sodium citrate buffer, pH 3.0, containing varying concentrations of ß-trypsin and dye. The reaction was recorded spectrophotometrically at 340 nm for 30 min, and the families of curves obtained were analyzed simultaneously by fitting integrated Michaelis-Menten equations. The dye used behaved as a competitive inhibitor of trypsin at pH 3.0, with Ki = 99 µM; kinetic parameters for the substrate hydrolysis were: Km = 32 µM, and kcat = 0.38/min. The competitive character of the inhibition suggests a specific binding of the first dye molecule to His-57, the only positively charged residue at the active site of the enzyme

Studies on the Glutathione-Dependent Formaldehyde-Activating Enzyme from Paracoccus denitrificans.

Formaldehyde is a toxin and carcinogen that is both an environmental pollutant and an endogenous metabolite. Formaldehyde metabolism, which is probably essential for all aerobic cells, likely proceeds via multiple mechanisms, including via a glutathione-dependent pathway that is widely conserved in bacteria, plants and animals. However, it is unclear whether the first step in the glutathione-dependent pathway (i.e. formation of S-hydroxymethylglutathione (HMG)) is enzyme-catalysed. We report studies on glutathione-dependent formaldehyde-activating enzyme (GFA) from Paracoccus denitrificans, which has been proposed to catalyse HMG formation from glutathione and formaldehyde on the basis of studies using NMR exchange spectroscopy (EXSY). Although we were able to replicate the EXSY results, time course experiments unexpectedly imply that GFA does not catalyse HMG formation under standard conditions. However, GFA was observed to bind glutathione using NMR and mass spectrometry. Overall, the results reveal that GFA binds glutathione but does not directly catalyse HMG formation under standard conditions. Thus, it is possible that GFA acts as a glutathione carrier that acts to co-localise glutathione and formaldehyde in a cellular context

Neuroscientists in Court

Neuroscientific evidence is increasingly being offered in court cases. Consequently, the legal system needs neuroscientists to act as expert witnesses who can explain the limitations and interpretations of neuroscientific findings so that judges and jurors can make informed and appropriate inferences. The growing role of neuroscientists in court means that neuroscientists should be aware of important differences between the scientific and legal fields, and, especially, how scientific facts can be easily misunderstood by non-scientists,including judges and jurors. This article describes similarities, as well as key differences, of legal and scientific cultures. And it explains six key principles about neuroscience that those in law need to know