The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species

Mitochondrial fission mediated by the GTPase dynamin-related protein 1 (Drp1) is an attractive drug target in numerous maladies that range from heart disease to neurodegenerative disorders. The compound mdivi-1 is widely reported to inhibit Drp1-dependent fission, elongate mitochondria, and mitigate brain injury. Here, we show that mdivi-1 reversibly inhibits mitochondrial complex I-dependent O2 consumption and reverse electron transfer-mediated reactive oxygen species (ROS) production at concentrations (e.g., 50 μM) used to target mitochondrial fission. Respiratory inhibition is rescued by bypassing complex I using yeast NADH dehydrogenase Ndi1. Unexpectedly, respiratory impairment by mdivi-1 occurs without mitochondrial elongation, is not mimicked by Drp1 deletion, and is observed in Drp1-deficient fibroblasts. In addition, mdivi-1 poorly inhibits recombinant Drp1 GTPase activity (Ki > 1.2 mM). Overall, these results suggest that mdivi-1 is not a specific Drp1 inhibitor. The ability of mdivi-1 to reversibly inhibit complex I and modify mitochondrial ROS production may contribute to effects observed in disease models. © 2017 Elsevier Inc

Direction and magnitude of nicotine effects on the fMRI BOLD response are related to nicotine effects on behavioral performance

Considerable variability across individuals has been reported in both the behavioral and fMRI blood oxygen level-dependent (BOLD) response to nicotine. We aimed to investigate (1) whether there is a heterogeneous effect of nicotine on behavioral and BOLD responses across participants and (2) if heterogeneous BOLD responses are associated with behavioral performance measures. In this double-blind, placebo-controlled, cross-over study, 41 healthy participants (19 smokers)—drawn from a larger population-based sample—performed a visual oddball task after acute challenge with 1 mg nasal nicotine. fMRI data and reaction time were recorded during performance of the task. Across the entire group of subjects, we found increased activation in the anterior cingulate cortex, middle frontal gyrus, superior temporal gyrus, post-central gyrus, planum temporal and frontal pole in the nicotine condition compared with the placebo condition. However, follow-up analyses of this difference in activation between the placebo and nicotine conditions revealed that some participants showed an increase in activation while others showed a decrease in BOLD activation from the placebo to the nicotine condition. A reduction of BOLD activation from placebo to nicotine was associated with a decrease in reaction time and reaction time variability and vice versa, suggesting that it is the direction of BOLD response to nicotine which is related to task performance. We conclude that the BOLD response to nicotine is heterogeneous and that the direction of response to nicotine should be taken into account in future pharmaco-fMRI research on the central action of nicotine

The Cytosolic Domain of Fis1 Binds and Reversibly Clusters Lipid Vesicles

Every lipid membrane fission event involves the association of two apposing bilayers, mediated by proteins that can promote membrane curvature, fusion and fission. We tested the hypothesis that Fis1, a tail-anchored protein involved in mitochondrial and peroxisomal fission, promotes changes in membrane structure. We found that the cytosolic domain of Fis1 alone binds lipid vesicles, which is enhanced upon protonation and increasing concentrations of anionic phospholipids. Fluorescence and circular dichroism data indicate that the cytosolic domain undergoes a membrane-induced conformational change that buries two tryptophan side chains upon membrane binding. Light scattering and electron microscopy data show that membrane binding promotes lipid vesicle clustering. Remarkably, this vesicle clustering is reversible and vesicles largely retain their original shape and size. This raises the possibility that the Fis1 cytosolic domain might act in membrane fission by promoting a reversible membrane association, a necessary step in membrane fission

Localization of arabidopsis SYP125 syntaxin in the plasma membrane sub-apical and distal zones of growing pollen tubes

Tip growth in pollen tubes occurs by continuous vesicle secretion and delivery of new wall material, but the exact sub-cellular location of endocytic and exocytic domains remains unclear. Here we studied the localization of the Arabidopsis thaliana pollen specific syntaxin SYP125 using GFP-fusion constructs expressed in Nicotiana tobaccum pollen tubes. In agreement with the predicted role for syntaxins, SYP125 was found to be associated with the plasma membrane and apical vesicles in growing cells. At the plasma membrane, SYP125 was asymmetrically localized with a higher labeling 20–35 µm behind the apex, a distribution which is distinct from SYP124, another pollen-specific syntaxin. Competition with a related dominant negative mutant affected the specific distribution of SYP125 but not tip growth. Co-expression of the phosphatidylinositol-4-monophosphate-5-kinase 4 (PIP5K4) or of the small GTPase Rab11 perturbed polarity and the normal distribution of GFP-SYP but did not inhibit the accumulation in vesicles or at the plasma membrane

Objective measures of neural processing of interaural time differences

We assessed neural sensitivity to interaural time differences (ITDs) conveyed in the temporal fine structure (TFS) of low-frequency sounds and ITDs conveyed in the temporal envelope of amplitude-modulated (AM’ed) high-frequency sounds. Using electroencephalography (EEG), we recorded brain activity to sounds in which the interaural phase difference (IPD) of the TFS (or the modulated temporal envelope) was repeatedly switched between leading in one ear or the other. When the amplitude of the tones is modulated equally in the two ears at 41 Hz, the interaural phase modulation (IPM) evokes an IPM following-response (IPM-FR) in the EEG signal. For low-frequency signals, IPM-FRs were reliably obtained, and largest for an IPM rate of 6.8 Hz and when IPD switches (around 0°) were in the range 45–90°. IPDs conveyed in envelope of high-frequency tones also generated IPM-FRs; response maxima occurred for IPDs switched between 0° and 180° IPD. This is consistent with the interpretation that distinct binaural mechanisms generate the IPM-FR at low and high frequencies, and with the reported physiological responses of medial superior olive (MSO) and lateral superior olive (LSO) neurons in other mammals. Low-frequency binaural neurons in the MSO are considered maximally activated by IPDs in the range 45–90°, consistent with their reception of excitatory inputs from both ears. High-frequency neurons in the LSO receive excitatory and inhibitory input from the two ears receptively—as such maximum activity occurs when the sounds at the two ears are presented out of phase.9 page(s

Avaliação auditiva objetiva através de potenciais evocados

Analisaram-se 1300 exames de Potencial Evocado Auditivo. Classificaram-se os pacientes segundo faixa de idade, apresentação clínica, relato de fatores de risco que levam a deficiência auditiva e limiar auditivo determinado pelo exame. Distribuíram-se os resultados em 5 faixas de limiar auditivo: audição normal (até 25 dBHL); perda auditiva moderada (25-50 dBHL); perda acentuada (50-70 dBHL); perda severa (70-90 dRHL); e sem resposta ao estímulo auditivo. Estudaram-se os fatores de risco relativos a gestação, parto e período neonatal, história familiar de deficiência auditiva, malformações do aparelho auditivo, anomalias crânio-faciais, síndromes associadas a deficiência auditiva, certas modalidades de doenças infecciosas e uso de determinadas drogas. Investigaram-se também os itens Retardo do Desenvolvimento Neuropsicomotor, Paralisia Cerebral e os casos sem antecedentes conhecidos. Entre as conclusões destacam-se: 82,8% dos pacientes eram portadores de alguma forma de deficiência auditiva; o encaminhamento é tardio, evidenciado pelo fato de 54,1% dos pacientes situarem-se entre 1 e 3 anos de idade; 54,0% da totalidade dos casos apresentavam-se sem linguagem; o fator de risco «Rubéola Congênita» possui a elevada incidência de 14,8%, e este percentual distribuído nas faixas de limiar auditivo revelou um crescimento exponencial, demonstrando inequívoca e acentuada correlação da moléstia com deficiência auditiva