ICM Partners

About: ICM Partners is a based out in . It is known for research contribution in the topics: Population & Breast cancer. The organization has 1311 authors who have published 1521 publications receiving 33745 citations. The organization is also known as: International Creative Management Partners.

The PINK1 kinase-driven ubiquitin ligase Parkin promotes mitochondrial protein import through the presequence pathway in living cells.

Abstract: Most of over a thousand mitochondrial proteins are encoded by nuclear genes and must be imported from the cytosol. Little is known about the cytosolic events regulating mitochondrial protein import, partly due to the lack of appropriate tools for its assessment in living cells. We engineered an inducible biosensor for monitoring the main presequence-mediated import pathway with a quantitative, luminescence-based readout. This tool was used to explore the regulation of mitochondrial import by the PINK1 kinase-driven Parkin ubiquitin ligase, which is dysfunctional in autosomal recessive Parkinson’s disease. We show that mitochondrial import was stimulated by Parkin, but not by disease-causing Parkin variants. This effect was dependent on Parkin activation by PINK1 and accompanied by an increase in the abundance of K11 ubiquitin chains on mitochondria and by ubiquitylation of subunits of the translocase of outer mitochondrial membrane. Mitochondrial import efficiency was abnormally low in cells from patients with PINK1- and PARK2-linked Parkinson’s disease and was restored by phosphomimetic ubiquitin in cells with residual Parkin activity. Altogether, these findings uncover a role of ubiquitylation in mitochondrial import regulation and suggest that loss of this regulatory loop may underlie the pathophysiology of Parkinson’s disease, providing novel opportunities for therapeutic intervention.

Effect of cigarette smoke on gustatory sensitivity, evaluation of the deficit and of the recovery time-course after smoking cessation.

Abstract: Study results have shown that chronic exposure to cigarette smoke affects the taste function in humans. However, neither the quantitative impact on taste sensitivity nor the time-course of taste recovery on stopping smoking have been precisely examined. The experimental design included 2 phases, (i) a case–control phase comparing the taste sensitivity level measured by Electrogustometric (EGM) thresholds from various parts of the tongue (locus) between smokers (n = 83) and non-smokers (n = 48), (ii) a follow-up study looking at the taste sensitivity recovery in smokers after smoking cessation (n = 24) and compared with non-smokers. Smokers exhibited significantly lower taste sensitivity than non-smokers - the higher the nicotine dependence (Fagerstrom scores), the lower the taste sensitivity. After smoking cessation, EGM thresholds decreased progressively, and reached the taste sensitivity range of non-smokers depending on locus and time. After 2 weeks a recovery could be observed on the 3 Tip and the 2 edge loci; the recovery in the posterior loci was complete after 9 weeks, and in the dorsal loci recovery was observed only after 2 months or more. Smoking cessation does lead to a rapid recovery of taste sensitivity among smokers, with recovery time found to differ based on the sensitivity of loci of the tongue. The use of EGM could potentially be explored as a motivational tool for smoking cessation.

Combined behavioral and electrophysiological evidence for a direct cortical effect of prefrontal tDCS on disorders of consciousness.

Abstract: Severe brain injuries can lead to long-lasting disorders of consciousness (DoC) such as vegetative state/unresponsive wakefulness syndrome (VS/UWS) or minimally conscious state (MCS). While behavioral assessment remains the gold standard to determine conscious state, EEG has proven to be a promising complementary tool to monitor the effect of new therapeutics. Encouraging results have been obtained with invasive electrical stimulation of the brain, and recent studies identified transcranial direct current stimulation (tDCS) as an effective approach in randomized controlled trials. This non-invasive and inexpensive tool may turn out to be the preferred treatment option. However, its mechanisms of action and physiological effects on brain activity remain unclear and debated. Here, we stimulated 60 DoC patients with the anode placed over left-dorsolateral prefrontal cortex in a prospective open-label study. Clinical behavioral assessment improved in twelve patients (20%) and none deteriorated. This behavioral response after tDCS coincided with an enhancement of putative EEG markers of consciousness: in comparison with non-responders, responders showed increases of power and long-range cortico-cortical functional connectivity in the theta-alpha band, and a larger and more sustained P300 suggesting improved conscious access to auditory novelty. The EEG changes correlated with electric fields strengths in prefrontal cortices, and no correlation was found on the scalp. Taken together, this prospective intervention in a large cohort of DoC patients strengthens the validity of the proposed EEG signatures of consciousness, and is suggestive of a direct causal effect of tDCS on consciousness.

The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines.

Abstract: Classic psychedelics are substances of paramount cultural and neuroscientific importance. A distinctive feature of psychedelic drugs is the wide range of potential subjective effects they can elicit, known to be deeply influenced by the internal state of the user ("set") and the surroundings ("setting"). The observation of cross-tolerance and a series of empirical studies in humans and animal models support agonism at the serotonin (5-HT)2A receptor as a common mechanism for the action of psychedelics. The diversity of subjective effects elicited by different compounds has been attributed to the variables of "set" and "setting," to the binding affinities for other 5-HT receptor subtypes, and to the heterogeneity of transduction pathways initiated by conformational receptor states as they interact with different ligands ("functional selectivity"). Here we investigate the complementary (i.e., not mutually exclusive) possibility that such variety is also related to the binding affinity for a range of neurotransmitters and monoamine transporters including (but not limited to) 5-HT receptors. Building on two independent binding affinity datasets (compared to "in silico" estimates) in combination with natural language processing tools applied to a large repository of reports of psychedelic experiences (Erowid's Experience Vaults), we obtained preliminary evidence supporting that the similarity between the binding affinity profiles of psychoactive substituted phenethylamines and tryptamines is correlated with the semantic similarity of the associated reports. We also showed that the highest correlation was achieved by considering the combined binding affinity for the 5-HT, dopamine (DA), glutamate, muscarinic and opioid receptors and for the Ca+ channel. Applying dimensionality reduction techniques to the reports, we linked the compounds, receptors, transporters and the Ca+ channel to distinct fingerprints of the reported subjective effects. To the extent that the existing binding affinity data is based on a low number of displacement curves that requires further replication, our analysis produced preliminary evidence consistent with the involvement of different binding sites in the reported subjective effects elicited by psychedelics. Beyond the study of this particular class of drugs, we provide a methodological framework to explore the relationship between the binding affinity profiles and the reported subjective effects of other psychoactive compounds.

Optic Disc Drusen in Children: The Copenhagen Child Cohort 2000 Eye Study.

Abstract: BACKGROUND Optic disc drusen (ODD) are seen in up to 2.4% of the general population, but the etiology and pathophysiology of the condition is still unknown. The purpose of this study was to determine the prevalence of ODD in a population-based child cohort and to determine if scleral canal diameter and fetal birth and pubertal parameters are associated with the presence of ODD. METHODS This observational, longitudinal population-based birth cohort study, with a nested case-control, included 1,406 children. Eye examinations were performed when the children were between 11 and 12 years of age. Assessment was performed of optical coherence tomography (OCT) scans from 1,304 children with gradable enhanced depth imaging scans of the optic disc. RESULTS ODD in one or both eyes were found in 13 (1.0%) of all children. All but one of the cases were found in children with scleral canal diameter in the lowest quartile (1,182-1,399 μm) in the nested case-control study. Children with ODD had a mean disc diameter of 1,339 μm (interquartile range, 30 μm), whereas it was 1,508 μm (interquartile range, 196 μm) in the 130 controls without ODD (P < 0.001). No differences in sex, birth weight, refractive error, and Tanner stages (of puberty) were found between children with and without ODD. CONCLUSIONS The prevalence of ODD was 1% in a large child cohort examined by OCT. ODD was found only in eyes with a narrow scleral canal, which is consistent with the hypothesis that ODD might arise as a consequence of retinal nerve fiber congestion in the scleral canal.