Inhibition of PIKfyve by YM-201636 Dysregulates Autophagy and Leads to Apoptosis-Independent Neuronal Cell Death

The lipid phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P-2), synthesised by PIKfyve, regulates a number of intracellular membrane trafficking pathways. Genetic alteration of the PIKfyve complex, leading to even a mild reduction in PtdIns(3,5)P-2 results in marked neurodegeneration via an uncharacterised mechanism. In the present study we have shown that selectively inhibiting PIKfyve activity, using YM-201636, significantly reduces the survival of primary mouse hippocampal neurons in culture. YM-201636 treatment promoted vacuolation of endolysosomal membranes followed by apoptosis-independent cell death. Many vacuoles contained intravacuolar membranes and inclusions reminiscent of autolysosomes. Accordingly, YM-201636 treatment increased the level of the autophagosomal marker protein LC3-II, an effect that was potentiated by inhibition of lysosomal proteases, suggesting that alterations in autophagy could be a contributing factor to neuronal cell death

The Effects of Arbuscular Mycorrhizal Fungi on Direct and Indirect Defense Metabolites of Plantago lanceolata L.

Arbuscular mycorrhizal fungi can strongly influence the metabolism of their host plant, but their effect on plant defense mechanisms has not yet been thoroughly investigated. We studied how the principal direct defenses (iridoid glycosides) and indirect defenses (volatile organic compounds) of Plantago lanceolata L. are affected by insect herbivory and mechanical wounding. Volatile compounds were collected and quantified from mycorrhizal and non-mycorrhizal P. lanceolata plants that underwent three different treatments: 1) insect herbivory, 2) mechanical wounding, or 3) no damage. The iridoids aucubin and catalpol were extracted and quantified from the same plants. Emission of terpenoid volatiles was significantly higher after insect herbivory than after the other treatments. However, herbivore-damaged mycorrhizal plants emitted lower amounts of sesquiterpenes, but not monoterpenes, than herbivore-damaged non-mycorrhizal plants. In contrast, mycorrhizal infection increased the emission of the green leaf volatile (Z)-3-hexenyl acetate in untreated control plants, making it comparable to emission from mechanically wounded or herbivore-damaged plants whether or not they had mycorrhizal associates. Neither mycorrhization nor treatment had any influence on the levels of iridoid glycosides. Thus, mycorrhizal infection did not have any effect on the levels of direct defense compounds measured in P. lanceolata. However, the large decline in herbivore-induced sesquiterpene emission may have important implications for the indirect defense potential of this species

Mindfulness-based cognitive therapy in obsessive-compulsive disorder: protocol of a randomized controlled trial

BACKGROUND: Obsessive-compulsive disorder (OCD) is a very disabling condition with a chronic course, if left untreated. Though cognitive behavioral treatment (CBT) with or without selective serotonin reuptake inhibitors (SSRI) is the method of choice, up to one third of individuals with obsessive-compulsive disorder (OCD) do not respond to treatment in terms of at least 35% improvement of symptoms. Mindfulness based cognitive therapy (MBCT) is an 8-week group program that could help OCD patients with no or only partial response to CBT to reduce OC symptoms and develop a helpful attitude towards obsessions and compulsive urges. METHODS/DESIGN: This study is a prospective, bicentric, assessor-blinded, randomized, actively-controlled clinical trial. 128 patients with primary diagnosis of OCD according to DSM-IV and no or only partial response to CBT will be recruited from in- and outpatient services as well as online forums and the media. Patients will be randomized to either an MBCT intervention group or to a psycho-educative coaching group (OCD-EP) as an active control condition. All participants will undergo eight weekly sessions with a length of 120 minutes each of a structured group program. We hypothesize that MBCT will be superior to OCD-EP in reducing obsessive-compulsive symptoms as measured by the Yale-Brown-Obsessive-Compulsive Scale (Y-BOCS) following the intervention and at 6- and 12-months-follow-up. Secondary outcome measures include depressive symptoms, quality of life, metacognitive beliefs, self-compassion, mindful awareness and approach-avoidance tendencies as measured by an approach avoidance task. DISCUSSION: The results of this study will elucidate the benefits of MBCT for OCD patients who did not sufficiently benefit from CBT. To our knowledge, this is the first randomized controlled study assessing the effects of MBCT on symptom severity and associated parameters in OCD. TRIAL REGISTRATION: German Clinical Trials Register DRKS00004525. Registered 19 March 2013