Physical interaction between MYCN oncogene and polycomb repressive complex 2 (PRC2) in neuroblastoma: Functional and therapeutic implications

This article is made available through the Brunel Open Access Publishing Fund. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.CLU (clusterin) is a tumor suppressor gene that we have previously shown to be negatively modulated by the MYCN proto-oncogene, but the mechanism of repression was unclear. Here, we show that MYCN inhibits the expression of CLU by direct interaction with the non-canonical E box sequence CACGCG in the 5′-flanking region. Binding of MYCN to the CLU gene induces bivalent epigenetic marks and recruitment of repressive proteins such as histone deacetylases and Polycomb members. MYCN physically binds in vitro and in vivo to EZH2, a component of the Polycomb repressive complex 2, required to repress CLU. Notably, EZH2 interacts with the Myc box domain 3, a segment of MYC known to be essential for its transforming effects. The expression of CLU can be restored in MYCN-amplified cells by epigenetic drugs with therapeutic results. Importantly, the anticancer effects of the drugs are ablated if CLU expression is blunted by RNA interference. Our study implies that MYC tumorigenesis can be effectively antagonized by epigenetic drugs that interfere with the recruitment of chromatin modifiers at repressive E boxes of tumor suppressor genes such as CLU.SPARKS, The Neuroblastoma Society, a Wellcome Trust grant (to A. S.), and the Italian Association for Cancer Research

Challenging inhibitory control with high- and low-calorie food: A behavioural and TMS study

Most people are often tempted by their impulses to “indulge” in high-calorie food, even if this behaviour is not consistent with their goal to control weight in the long term and might not be healthy. The outcome of this conflict is strongly dependent on inhibitory control. It has already been reported that individuals with weaker inhibitory control consume more high-calorie food, are more often unsuccessful dieters, overweight or obese compared to people with more effective inhibitory control. In the present study, we aimed at investigating inhibitory control in the context of human eating behaviour. A sample of 20 healthy normal-weight adults performed a 50% probability visual affective Go/NoGo task involving food (high- and low-calorie) and non-food images as stimuli. Single-pulse transcranial magnetic stimulation (TMS) was administered over the right primary motor cortex (M1) either 300 ms after image presentation to measure corticospinal excitability during the different stimulus categories or 300 ms after the appearance of a fixation point, as a control stimulation condition. The experimental session consisted of a food target and a non-food target block. Behavioural outcomes showed a natural implicit inclination towards high-calorie food in that participants were faster and more accurate compared to the other categories. This advantage was selectively deleted by TMS, which slowed down reaction times. MEPs did not differ according to the stimulus category, but, as expected, were bigger for Go compared to NoGo trials. Participants judged high-calorie food also as more appetising than low-calorie food images. Overall, our results point to a differential modulation when targeting inhibitory control, in favour of the more palatable food category (high-calorie). Present data suggest that the activity of the motor system is modulated by food nutritional value, being more engaged by appetising food. Future work should explore to what extent these processes are affected in patients with eating disorders and should aim to better characterise the related dynamics of cortical connectivity within the motor network

Il governo tecnocratico della moneta e i crocevia del processo di integrazione europea. Riflessioni alla luce della sentenza Weiss

The well known judgment of the German Constitutional Court in the “Weiss” case has been widely criticized under EU law, mainly because of its being in contrast with a preliminary ruling rendered by the European Court of Justice in 2018. At variance with these criticisms, it is here submitted that such a judgment brings well into focus some institutional ambiguities of the Economic and Monetary Union (EMU); namely, the powers (more and more) exercised by the European Central Bank (ECB) in the field of macroeconomic regulation and control, in spite of (its) not being provided with political legitimacy. Seen in this perspective, the “Karlsruhe” judgment objectively looks as aimed at restoring a more balanced relationship between different institutional EMU actors, in accordance with their different degree of political legitimacy. Finally, both the role so far (i.e., starting from the “whatever it takes”) played from the ECB and the respective roles played by the German Constitutional Court and the German Government in closing this affair are construed as symptoms of the current imbalances of the European integration process

Open Source evaluation of kilometric indexes of abundance.

Kilometric Abundance Index (KAI) is a common measure used in wildlife studies because it allows a straightforward comparison of species abundance in different sites or at different times. KAI expresses the ratio of the total number of individuals (or of signs of presence) observed along a transect by the total transect length covered at each site. v.transect.kia is a new tool for GRASS GIS, developed for automating the evaluation of KAI, reducing the risk of manual errors especially when handling large datasets. It can also split the transects according to one environmental variable (typically habitat type) and evaluate true 3D transect length. It calculates KAI using a point map of sightings and saves the results in the attribute table, the output can be displayed in any GIS or used for further statistical analysis. The tool has been tested on field data from Northern Italy for mountain hare (Lepus timidus), allowing a first wide-area estimate

Poly(Vinyl alcohol)/gelatin scaffolds allow regeneration of nasal tissues

Need for regeneration and repair of nasal tissues occurs as a consequence of several pathologies affecting the nose, including, but not limited to infective diseases, traumas and tumor resections. A platform for nasal tissue regeneration was set up using poly(vinyl alcohol)/gelatin sponges with 20%–30% (w/w) gelatin content to be used as scaffolds, for their intrinsic hydrophilic, cell adhesive and shape recovery properties. We propose mesodermal progenitor cells (MPCs) isolated from the bone marrow as a unique stem cell source for obtaining different connective tissues of the nose, including vascular tissue. Finally, epithelial cell immune response to these scaffolds was assessed in vitro in an environment containing inflammatory molecules. The results showed that mesenchymal stromal cells (MSCs) deriving from MPCs could be used to differentiate into cartilage and fibrous tissue; whereas, in combination with endothelial cells still deriving from MPCs, into pre-vascularized bone. Finally, the scaffold did not significantly alter the epithelial cell response to inflammatory insults derived from interaction with bacterial molecules

Cortico-cortical stimulation and robot-assisted therapy (CCS and RAT) for upper limb recovery after stroke: study protocol for a randomised controlled trial

Background: Since birth, during the exploration of the environment to interact with objects, we exploit both the motor and sensory components of the upper limb (UL). This ability to integrate sensory and motor information is often compromised following a stroke. However, to date, rehabilitation protocols are focused primarily on recovery of motor function through physical therapies. Therefore, we have planned a clinical trial to investigate the effect on functionality of UL after a sensorimotor transcranial stimulation (real vs sham) in add-on to robot-assisted therapy in the stroke population. Methods: A randomised double-blind controlled trial design involving 32 patients with a single chronic stroke (onset > 180 days) was planned. Each patient will undergo 15 consecutive sessions (5 days for 3 weeks) of paired associative stimulation (PAS) coupled with UL robot-assisted therapy. PAS stimulation will be administered using a bifocal transcranial magnetic stimulator (TMS) on the posterior-parietal cortex and the primary motor area (real or sham) of the lesioned hemisphere. Clinical, kinematics and neurophysiological changes will be evaluated at the end of protocol and at 1-month follow-up and compared with baseline. The Fugl-Meyer assessment scale will be the primary outcome. Secondly, kinematic variables will be recorded during the box-and-block test and reaching tasks using video analysis and inertial sensors. Single pulse TMS and electroencephalography will be used to investigate the changes in local cortical reactivity and in the interconnected areas. Discussion: The presented trial shall evaluate with a multimodal approach the effects of sensorimotor network stimulation applied before a robot-assisted therapy training on functional recovery of the upper extremity after stroke. The combination of neuromodulation and robot-assisted therapy can promote an increase of cortical plasticity of sensorimotor areas followed by a clinical benefit in the motor function of the upper limb. Trial registration: ClinicalTrials.gov NCT05478434. Registered on 28 Jul 2022

Regional Precuneus Cortical Hyperexcitability in Alzheimer's Disease Patients

Objective: Neuronal excitation/inhibition (E/I) imbalance is a potential cause of neuronal network malfunctioning in Alzheimer's disease (AD), contributing to cognitive dysfunction. Here, we used a novel approach combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to probe cortical excitability in different brain areas known to be directly involved in AD pathology. Methods: We performed TMS-EEG recordings targeting the left dorsolateral prefrontal cortex (l-DLPFC), the left posterior parietal cortex (l-PPC), and the precuneus (PC) in a large sample of patients with mild-to-moderate AD (n = 65) that were compared with a group of age-matched healthy controls (n = 21). Results: We found that patients with AD are characterized by a regional cortical hyperexcitability in the PC and, to some extent, in the frontal lobe, as measured by TMS-evoked potentials. Notably, cortical excitability assessed over the l-PPC was comparable between the 2 groups. Furthermore, we found that the individual level of PC excitability was associated with the level of cognitive impairment, as measured with Mini-Mental State Examination, and with corticospinal fluid levels of Aβ42 . Interpretation: Our data provide novel evidence that precuneus cortical hyperexcitability is a key feature of synaptic dysfunction in patients with AD. The current results point to the combined approach of TMS and EEG as a novel promising technique to measure hyperexcitability in patients with AD. This index could represent a useful biomarker to stage disease severity and evaluate response to novel therapies. ANN NEUROL 2022

Polymerogenic neuroserpin causes mitochondrial alterations and activates NFκB but not the UPR in a neuronal model of neurodegeneration FENIB

The neurodegenerative condition FENIB (familiar encephalopathy with neuroserpin inclusion bodies) is caused by heterozygous expression of polymerogenic mutant neuroserpin (NS), with polymer deposition within the endoplasmic reticulum (ER) of neurons. We generated transgenic neural progenitor cells (NPCs) from mouse fetal cerebral cortex stably expressing either the control protein GFP or human wild type, polymerogenic G392E or truncated (delta) NS. This cellular model makes it possible to study the toxicity of polymerogenic NS in the appropriated cell type by in vitro differentiation to neurons. Our previous work showed that expression of G392E NS in differentiated NPCs induced an adaptive response through the upregulation of several genes involved in the defence against oxidative stress, and that pharmacological reduction of the antioxidant defences by drug treatments rendered G392E NS neurons more susceptible to apoptosis than control neurons. In this study, we assessed mitochondrial distribution and found a higher percentage of perinuclear localisation in G392E NS neurons, particularly in those containing polymers, a phenotype that was enhanced by glutathione chelation and rescued by antioxidant molecules. Mitochondrial membrane potential and contact sites between mitochondria and the ER were reduced in neurons expressing the G392E mutation. These alterations were associated with a pattern of ER stress that involved the ER overload response but not the unfolded protein response. Our results suggest that intracellular accumulation of NS polymers affects the interaction between the ER and mitochondria, causing mitochondrial alterations that contribute to the neuronal degeneration seen in FENIB patients