Publications by authors named "Felice D"

39 Publications

Magnetic resonance features and cranial nerve involvement in pediatric head and neck rhabdomyosarcomas.

Neuroradiology 2021 Jul 25. Epub 2021 Jul 25.

Neuroradiology Department, Great Ormond Street Hospital for Children, London, UK.

Purpose: Rhabdomyosarcoma (RMS) is a malignant tumor frequent in children. The frequency and characteristics of cranial nerve involvement in pediatric head and neck (H&N) RMS have been scarcely reported. The aim of this study is to review a large cohort of pediatric head and neck RMS with an emphasis on cranial nerve involvement.

Methods: We retrospectively reviewed H&N RMS cases from 3 tertiary hospitals over a 10-year period. Cranial nerve involvement was defined as radiologically apparent tumor extension along a nerve and/or the presence of secondary signs. Scans were reviewed by two pediatric neuroradiologists, blinded to clinical data.

Results: A total of 52 patients met the inclusion criteria. Histologically, 39/52 were embryonal RMS, while 13/52 were alveolar RMS. Regional lymph nodes metastases were present in 19.2%. Cranial nerve involvement was present in 36.5%. Nerves were mainly involved as a direct extension of the mass through skull base foramina or after invasion of cavernous sinus, Meckel's cave, orbital apex, or stylomastoid foramen.

Conclusion: Cranial nerve involvement is frequent in pediatric head and neck RMS and occurs secondary to "geographic" invasion due to direct extension through skull base foramina or cavernous sinus. These tumors never showed distant perineural metastatic disease as is seen in cases of adult head and neck carcinomas. This implies a different biological interaction between the nerves and these tumors in comparison to adult H&N tumors.
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http://dx.doi.org/10.1007/s00234-021-02765-0DOI Listing
July 2021

Dissecting the contribution of host genetics and the microbiome in complex behaviors.

Cell 2021 Apr 10;184(7):1740-1756.e16. Epub 2021 Mar 10.

Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

The core symptoms of many neurological disorders have traditionally been thought to be caused by genetic variants affecting brain development and function. However, the gut microbiome, another important source of variation, can also influence specific behaviors. Thus, it is critical to unravel the contributions of host genetic variation, the microbiome, and their interactions to complex behaviors. Unexpectedly, we discovered that different maladaptive behaviors are interdependently regulated by the microbiome and host genes in the Cntnap2 model for neurodevelopmental disorders. The hyperactivity phenotype of Cntnap2 mice is caused by host genetics, whereas the social-behavior phenotype is mediated by the gut microbiome. Interestingly, specific microbial intervention selectively rescued the social deficits in Cntnap2 mice through upregulation of metabolites in the tetrahydrobiopterin synthesis pathway. Our findings that behavioral abnormalities could have distinct origins (host genetic versus microbial) may change the way we think about neurological disorders and how to treat them.
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http://dx.doi.org/10.1016/j.cell.2021.02.009DOI Listing
April 2021

Calcium cytotoxicity sensitizes prostate cancer cells to standard-of-care treatments for locally advanced tumors.

Cell Death Dis 2020 12 7;11(12):1039. Epub 2020 Dec 7.

Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.

Therapy resistance is a major roadblock in oncology. Exacerbation of molecular dysfunctions typical of cancer cells have proven effective in twisting oncogenic mechanisms to lethal conditions, thus offering new therapeutic avenues for cancer treatment. Here, we demonstrate that selective agonists of Transient Receptor Potential cation channel subfamily M member 8 (TRPM8), a cation channel characteristic of the prostate epithelium frequently overexpressed in advanced stage III/IV prostate cancers (PCa), sensitize therapy refractory models of PCa to radio, chemo or hormonal treatment. Overall, our study demonstrates that pharmacological-induced Ca cytotoxicity is an actionable strategy to sensitize cancer cells to standard therapies.
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http://dx.doi.org/10.1038/s41419-020-03256-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721710PMC
December 2020

The Organoid Era Permits the Development of New Applications to Study Glioblastoma.

Cancers (Basel) 2020 Nov 9;12(11). Epub 2020 Nov 9.

Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy.

Glioblastoma (GB) is the most frequent and aggressive type of glioma. The lack of reliable GB models, together with its considerable clinical heterogeneity, has impaired a comprehensive investigation of the mechanisms that lead to tumorigenesis, cancer progression, and response to treatments. Recently, 3D cultures have opened the possibility to overcome these challenges and cerebral organoids are emerging as a leading-edge tool in GB research. The opportunity to easily engineer brain organoids via gene editing and to perform co-cultures with patient-derived tumor spheroids has enabled the analysis of cancer development in a context that better mimics brain tissue architecture. Moreover, the establishment of biobanks from GB patient-derived organoids represents a crucial starting point to improve precision medicine therapies. This review exemplifies relevant aspects of 3D models of glioblastoma, with a specific focus on organoids and their involvement in basic and translational research.
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http://dx.doi.org/10.3390/cancers12113303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695252PMC
November 2020

GABA Receptors: Anxiety and Mood Disorders.

Curr Top Behav Neurosci 2020 Aug 30. Epub 2020 Aug 30.

Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.

Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, acts at the ionotropic GABA and GABA receptors, and the metabotropic GABA receptor. This chapter summarizes the studies that have investigated the role of the GABA receptor in stress-related psychiatric disorders including anxiety and mood disorders. Overall, clinical and preclinical evidences strongly suggest that the GABA receptor is a therapeutic candidate for depression and anxiety disorders. However, the clinical development of GABA receptor-based drugs to treat these disorders has been hampered by their potential side-effects, particularly those of agonists. Nevertheless, the discovery of novel GABA receptor allosteric modulators, and increasing understanding of the influence of specific intracellular GABA receptor-associated proteins on GABA receptor activity, may now pave the way towards GABA receptor therapeutics in the treatment of mood and anxiety disorders.
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http://dx.doi.org/10.1007/7854_2020_171DOI Listing
August 2020

Mechanosensitive Piezo Channels in Cancer: Focus on altered Calcium Signaling in Cancer Cells and in Tumor Progression.

Cancers (Basel) 2020 Jul 3;12(7). Epub 2020 Jul 3.

Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Povo (Tn), Italy.

Mechanotransduction, the translation of mechanical stimuli into biological signals, is a crucial mechanism involved in the function of fundamentally all cell types. In many solid tumors, the malignant transformation is often associated with drastic changes in cell mechanical features. Extracellular matrix stiffness, invasive growth, and cell mobility are just a few hallmarks present in cancer cells that, by inducing mechanical stimuli, create positive feedbacks promoting cancer development. Among the molecular players involved in these pathophysiological processes, the mechanosensitive Ca-permeable Piezo channels have emerged as major transducers of mechanical stress into Ca dependent signals. Piezo channels are overexpressed in several cancers, such as in breast, gastric, and bladder, whereas their downregulation has been described in other cancers. Still, the roles of mechanosensitive Piezos in cancer are somewhat puzzling. In this review, we summarize the current knowledge on the pathophysiological roles of these Ca-permeable channels, with special emphasis on their functional involvement in different cancer types progression.
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http://dx.doi.org/10.3390/cancers12071780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407875PMC
July 2020

Region-Specific Transcriptional Control of Astrocyte Function Oversees Local Circuit Activities.

Neuron 2020 06 21;106(6):992-1008.e9. Epub 2020 Apr 21.

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Astrocytes play essential roles in brain function by supporting synaptic connectivity and associated circuits. How these roles are regulated by transcription factors is unknown. Moreover, there is emerging evidence that astrocytes exhibit regional heterogeneity, and the mechanisms controlling this diversity remain nascent. Here, we show that conditional deletion of the transcription factor nuclear factor I-A (NFIA) in astrocytes in the adult brain results in region-specific alterations in morphology and physiology that are mediated by selective DNA binding. Disruptions in astrocyte function following loss of NFIA are most pronounced in the hippocampus, manifested by impaired interactions with neurons, coupled with diminution of learning and memory behaviors. These changes in hippocampal astrocytes did not affect basal neuronal properties but specifically inhibited synaptic plasticity, which is regulated by NFIA in astrocytes through calcium-dependent mechanisms. Together, our studies reveal region-specific transcriptional dependencies for astrocytes and identify astrocytic NFIA as a key transcriptional regulator of hippocampal circuits.
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http://dx.doi.org/10.1016/j.neuron.2020.03.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879989PMC
June 2020

Behavioural characterization of ghrelin ligands, anamorelin and HM01: Appetite and reward-motivated effects in rodents.

Neuropharmacology 2020 05 14;168:108011. Epub 2020 Feb 14.

Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Food for Health Ireland, University College Cork, Cork, Ireland; APC Microbiome Ireland, University College Cork, Cork, Ireland. Electronic address:

The ghrelinergic system has been steadily investigated as a therapeutic target in the treatment of metabolic disorders and modulation of appetite. While endogenous ghrelin activates the full complement of the growth hormone secretagogue receptor (GHSR-1a) pathways, synthetic GHSR-1a ligands display biased signalling and functional selectivity, which have a significant impact on the intended and indeed, unintended, therapeutic effects. The widespread expression of the GHSR-1a receptor in vivo also necessitates an imperative consideration of the biodistribution of GHSR-1a ligands. Here, we investigate anamorelin and HM01, two recently described synthetic GHSR-1a ligands which have shown promising effects on food intake in preclinical and clinical studies. We compare the downstream signalling pathways in cellular in vitro assays, including calcium mobilization, IP-one, internalization and β-arrestin recruitment assays. We describe a novel divergent activation of central reward circuitry by anamorelin and HM01 using c-Fos immunostaining as well as behavioural effects in food intake and reward paradigms. Interestingly, we found a paradoxical reduction in reward-related behaviour for anamorelin and HM01 treated animals in our chosen paradigms. The work highlights the critical importance to consider signalling bias in relation to future ghrelin-based therapies. In addition, central access of GHSR-1a ligands, particularly to reward areas of the brain, remains a crucial factor in eliciting potent appetite-stimulating effects. The precise characterization of downstream ghrelinergic signalling and biodistribution of novel GHSR-1a ligands will be decisive in their successful development and will allow predictive modelling and design of future synthetic ligands to combat metabolic and appetite disorders involving the ghrelinergic system. This article is part of the special issue on 'Neuropeptides'.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108011DOI Listing
May 2020

Canonical Divergence for Measuring Classical and Quantum Complexity.

Entropy (Basel) 2019 Apr 24;21(4). Epub 2019 Apr 24.

Max Planck Institute for Mathematics in the Sciences, Inselstrasse 22, 04103 Leipzig, Germany.

A new canonical divergence is put forward for generalizing an information-geometric measure of complexity for both classical and quantum systems. On the simplex of probability measures, it is proved that the new divergence coincides with the Kullback-Leibler divergence, which is used to quantify how much a probability measure deviates from the non-interacting states that are modeled by exponential families of probabilities. On the space of positive density operators, we prove that the same divergence reduces to the quantum relative entropy, which quantifies many-party correlations of a quantum state from a Gibbs family.
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http://dx.doi.org/10.3390/e21040435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7514924PMC
April 2019

2D vertical field-effect transistor.

Nanotechnology 2018 Dec 25;29(50):505708. Epub 2018 Sep 25.

Service de Physique de l'Etat Condensé, DSM/IRAMIS/SPEC, CNRS UMR 3680, CEA Saclay, Université Paris-Saclay, F-91191 Gif-Sur-Yvette, France.

Within the framework of 2D materials, we present four theoretical models of a vertical field-effect transistor (FET) composed of simple alternate graphene and MoS layers. The electronic transport properties at a specific graphene/MoS interface in each configuration are investigated by focusing in particular on the current as a function of the gate voltage. The gate voltage, simulated with a shift of the bands of a specific layer, allows us to tune the current at the interface and the charge transfer between the planes. This analysis of the charge transfer as a function of the gate voltage reveals a strong connection with the transport characteristics as the slope of the current curve. The analysis of physical phenomena at the graphene/MoS interface can further improve the 2D vertical FET performance and contribute to the development of new 2D nanotechnology.
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http://dx.doi.org/10.1088/1361-6528/aae406DOI Listing
December 2018

Information geometric methods for complexity.

Chaos 2018 Mar;28(3):032101

School of Science and Technology, University of Camerino, 62032 Camerino, Italy.

Research on the use of information geometry (IG) in modern physics has witnessed significant advances recently. In this review article, we report on the utilization of IG methods to define measures of complexity in both classical and, whenever available, quantum physical settings. A paradigmatic example of a dramatic change in complexity is given by phase transitions (PTs). Hence, we review both global and local aspects of PTs described in terms of the scalar curvature of the parameter manifold and the components of the metric tensor, respectively. We also report on the behavior of geodesic paths on the parameter manifold used to gain insight into the dynamics of PTs. Going further, we survey measures of complexity arising in the geometric framework. In particular, we quantify complexity of networks in terms of the Riemannian volume of the parameter space of a statistical manifold associated with a given network. We are also concerned with complexity measures that account for the interactions of a given number of parts of a system that cannot be described in terms of a smaller number of parts of the system. Finally, we investigate complexity measures of entropic motion on curved statistical manifolds that arise from a probabilistic description of physical systems in the presence of limited information. The Kullback-Leibler divergence, the distance to an exponential family and volumes of curved parameter manifolds, are examples of essential IG notions exploited in our discussion of complexity. We conclude by discussing strengths, limits, and possible future applications of IG methods to the physics of complexity.
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http://dx.doi.org/10.1063/1.5018926DOI Listing
March 2018

Vortioxetine Improves Context Discrimination in Mice Through a Neurogenesis Independent Mechanism.

Front Pharmacol 2018 12;9:204. Epub 2018 Mar 12.

Université Paris-Saclay, Univ. Paris-Sud, Faculté de Pharmacie, CESP, INSERM UMRS1178, Chatenay-Malabry, France.

Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive function. In addition, VORT treatment increases adult hippocampal neurogenesis (AHN) in rodents, a candidate mechanism for antidepressant activity. Pattern separation (PS) is the ability to discriminate between two similar contexts/events generating two distinct and non-overlapping representations. Impaired PS may lead to overgeneralization and anxiety disorders. If PS impairments were described in depressed patients, the consequences of antidepressant treatment on context discrimination (CD) are still in its infancy. We hypothesized that VORT-increased AHN may improve CD. Thus, in an attempt to elucidate the molecular mechanism underpinning VORT treatment effects on CD, a rodent model of PS, the role of AHN and stress-induced c-Fos activation was evaluated in the adult mouse hippocampus. Chronic treatment with VORT (1.8 g/kg of food weight; corresponding to a daily dose of 10 mg/kg, 3 weeks) improved CD in mice. Interestingly, chronic treatment with VORT reversed ablation of AHN-induced delay in CD and freezing behavior. VORT treatment decreased stress-induced c-Fos activation in the dorsal but not ventral dentate gyrus. VORT treatment did not affect c-Fos activity in the hippocampus of mice with ablated neurogenesis. This study highlights a role of VORT in CD, which may be independent from AHN and hippocampal c-Fos activation. Further studies elucidating the mechanisms underlying VORT's effects in CD could contribute to future strategies for alleviating the disease burden for individuals suffering from depression and/or anxiety disorders.
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http://dx.doi.org/10.3389/fphar.2018.00204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857583PMC
March 2018

Forces and electronic transport in a contact formed by a graphene tip and a defective MoS monolayer: a theoretical study.

Nanotechnology 2018 Jun 12;29(22):225704. Epub 2018 Mar 12.

SPEC, CEA, CNRS, Université Paris-Saclay, CEA Saclay, 91191 Gif-Sur-Yvette, France.

A theoretical study of a graphene-like tip used in atomic force microscopy (AFM) is presented. Based on first principles simulations, we proved the low reactivity of this kind of tip, using a MoS monolayer as the testing sample. Our simulations show that the tip-MoS interaction is mediated through weak van der Waals forces. Even on the defective monolayer, the interaction is reduced by one order of magnitude with respect to the values obtained using a highly reactive metallic tip. On the pristine monolayer, the S atoms were imaged for large distances together with the substitutional defects which should be observed as brighter spots in non-contact AFM measurements. This result is in contradiction with previous simulations performed with Cu or Si tips where the metallic defects were imaged for much larger distances than the S atoms. For shorter distances, the Mo sites will be brighter even though a vacancy is formed. On the other hand, the largest conductance value is obtained over the defect formed by two Mo atoms occupying a S divacancy when the half-occupied p -states of the graphene-like tip find a better coupling with d-orbitals of the highest substitutional atom. Due to the weak interaction, no conductance plateau is formed in any of the sites. A great advantage of this tip lies in the absence of atomic transfer between the tip and the sample leading to a more stable AFM measurement. Finally, and as previously shown, we confirm the atomic resolution in a scanning tunneling microscopy simulation using this graphene-based tip.
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http://dx.doi.org/10.1088/1361-6528/aab5fcDOI Listing
June 2018

The Volume of Two-Qubit States by Information Geometry.

Entropy (Basel) 2018 Feb 24;20(2). Epub 2018 Feb 24.

School of Science and Technology, University of Camerino, 62032 Camerino, Italy.

Using the information geometry approach, we determine the volume of the set of two-qubit states with maximally disordered subsystems. Particular attention is devoted to the behavior of the volume of sub-manifolds of separable and entangled states with fixed purity. We show that the usage of the classical Fisher metric on phase space probability representation of quantum states gives the same qualitative results with respect to different versions of the quantum Fisher metric.
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http://dx.doi.org/10.3390/e20020146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512640PMC
February 2018

Strain differences in the susceptibility to the gut-brain axis and neurobehavioural alterations induced by maternal immune activation in mice.

Behav Pharmacol 2018 04;29(2 and 3-Spec Issue):181-198

APC Microbiome Institute.

There is a growing realization that the severity of the core symptoms of autism spectrum disorders and schizophrenia is associated with gastrointestinal dysfunction. Nonetheless, the mechanisms underlying such comorbidities remain unknown. Several genetic and environmental factors have been linked to a higher susceptibility to neurodevelopmental abnormalities. The maternal immune activation (MIA) rodent model is a valuable tool for elucidating the basis of this interaction. We induced MIA with polyinosinic-polycytidylic acid (poly I:C) at gestational day 12.5 and assessed behavioural, physiological and molecular aspects relevant to the gut-brain axis in the offspring of an outbred (NIH Swiss) and an inbred (C57BL6/J) mouse strain. Our results showed that the specific MIA protocol employed induces social deficits in both strains. However, alterations in anxiety and depression-like behaviours were more pronounced in NIH Swiss mice. These strain-specific behavioural effects in the NIH Swiss mice were associated with marked changes in important components of gut-brain axis communication: the endocrine response to stress and gut permeability. In addition, MIA-induced changes in vasopressin receptor 1a mRNA expression in the hypothalamus were observed in NIH Swiss mice only. Taken together, these data suggest that genetic background is a critical factor in susceptibility to the gut-brain axis effects induced by MIA.
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http://dx.doi.org/10.1097/FBP.0000000000000374DOI Listing
April 2018

The vagus nerve modulates BDNF expression and neurogenesis in the hippocampus.

Eur Neuropsychopharmacol 2018 02;28(2):307-316

Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland.

Accumulating evidence suggests that certain gut microbiota have antidepressant-like behavioural effects and that the microbiota can regulate neurogenesis and the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. The precise mechanisms underlying these effects are not yet clear. However, the vagus nerve is one of the primary bidirectional routes of communication between the gut and the brain and thus may represent a candidate mechanism. Yet, relatively little is known about the direct influence of vagus nerve activity on hippocampal function and plasticity. Thus, the aim of the present study was to determine whether constitutive vagus nerve activity contributes to the regulation of neurogenesis and BDNF mRNA expression in the hippocampus. To this end, we examined the impact of subdiaphragmatic vagotomy in adult mice on these parameters. We found that vagotomy decreased BDNF mRNA in all areas of the hippocampus. Vagotomy also reduced the proliferation and survival of newly born cells and decreased the number of immature neurons, particularly those with a more complex dendritic morphology. Taken together, these findings suggest that vagal nerve activity influences neurogenesis and BDNF mRNA expression in the adult hippocampus.
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http://dx.doi.org/10.1016/j.euroneuro.2017.12.004DOI Listing
February 2018

Beyond van der Waals Interaction: The Case of MoSe Epitaxially Grown on Few-Layer Graphene.

ACS Nano 2018 03 6;12(3):2319-2331. Epub 2018 Feb 6.

Université Grenoble Alpes , CEA, CNRS, Grenoble INP, INAC-SPINTEC, 38000 Grenoble , France.

Van der Waals heterojunctions composed of graphene and transition metal dichalcogenides have gain much attention because of the possibility to control and tailor band structure, promising applications in two-dimensional optoelectronics and electronics. In this report, we characterized the van der Waals heterojunction MoSe/few-layer graphene with a high-quality interface using cutting-edge surface techniques scaling from atomic to microscopic range. These surface analyses gave us a complete picture of the atomic structure and electronic properties of the heterojunction. In particular, we found two important results: the commensurability between the MoSe and few-layer graphene lattices and a band-gap opening in the few-layer graphene. The band gap is as large as 250 meV, and we ascribed it to an interface charge transfer that results in an electronic depletion in the few-layer graphene. This conclusion is well supported by electron spectroscopy data and density functional theory calculations. The commensurability between the MoSe and graphene lattices as well as the band-gap opening clearly show that the interlayer interaction goes beyond the simple van der Waals interaction. Hence, stacking two-dimensional materials in van der Waals heterojunctions enables us to tailor the atomic and electronic properties of individual layers. It also permits the introduction of a band gap in few-layer graphene by interface charge transfer.
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http://dx.doi.org/10.1021/acsnano.7b07446DOI Listing
March 2018

Riemannian-geometric entropy for measuring network complexity.

Phys Rev E 2016 Jun 27;93(6):062317. Epub 2016 Jun 27.

Aix-Marseille University, Marseille, France.

A central issue in the science of complex systems is the quantitative characterization of complexity. In the present work we address this issue by resorting to information geometry. Actually we propose a constructive way to associate with a-in principle, any-network a differentiable object (a Riemannian manifold) whose volume is used to define the entropy. The effectiveness of the latter in measuring network complexity is successfully proved through its capability of detecting a classical phase transition occurring in both random graphs and scale-free networks, as well as of characterizing small exponential random graphs, configuration models, and real networks.
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http://dx.doi.org/10.1103/PhysRevE.93.062317DOI Listing
June 2016

When ageing meets the blues: Are current antidepressants effective in depressed aged patients?

Neurosci Biobehav Rev 2015 Aug 6;55:478-97. Epub 2015 Jun 6.

Institut National de la Santé et de la recherche Médicale UMR-S 1178 Santé Mentale et Santé Publique, Université Paris-Sud, Fac Pharmacie, Université Paris Saclay, Châtenay-Malabry, France. Electronic address:

"I had to wait 110 years to become famous. I wanted to enjoy it as long as possible.", Jeanne Louise Calment (1875-1997). This review summarizes current knowledge of the effects of antidepressant drugs in elderly patients (double-blind placebo (n=27) or active comparator-controlled clinical trials (n=21) indexed in Pubmed in depressed patients aged ≥60) and in aged mice (≥9 months) and middle-aged rats (≥14 months) on depression-related symptoms and cognitive performances. Finally, other potential therapeutic targets for treating depression-related disorders in elderly patients are also addressed (neurogenesis, GABAB receptor, 5-HT4 receptor, mTOR signaling). Overall, the very few published preclinical studies (n=12 in total) in middle-aged and aged rodents seem to suggest that selective serotonin reuptake inhibitors (SSRIs) may be less effective than tricyclic antidepressant drugs (TCAs) in ameliorating depression-like behavior and cognitive functions. On the other hand, results from clinical trials suggest that there is not a marked difference in efficacy and safety profiles of current marketed classes of antidepressant drugs.
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http://dx.doi.org/10.1016/j.neubiorev.2015.06.005DOI Listing
August 2015

GABAB(1) receptor subunit isoforms differentially regulate stress resilience.

Proc Natl Acad Sci U S A 2014 Oct 6;111(42):15232-7. Epub 2014 Oct 6.

Departments of Anatomy and Neuroscience and Alimentary Pharmabiotic Centre, and

Stressful life events increase the susceptibility to developing psychiatric disorders such as depression; however, many individuals are resilient to such negative effects of stress. Determining the neurobiology underlying this resilience is instrumental to the development of novel and more effective treatments for stress-related psychiatric disorders. GABAB receptors are emerging therapeutic targets for the treatment of stress-related disorders such as depression. These receptors are predominantly expressed as heterodimers of a GABAB(2) subunit with either a GABAB(1a) or a GABAB(1b) subunit. Here we show that mice lacking the GABAB(1b) receptor isoform are more resilient to both early-life stress and chronic psychosocial stress in adulthood, whereas mice lacking GABAB(1a) receptors are more susceptible to stress-induced anhedonia and social avoidance compared with wild-type mice. In addition, increased hippocampal expression of the GABAB(1b) receptor subunit is associated with a depression-like phenotype in the helpless H/Rouen genetic mouse model of depression. Stress resilience in GABAB(1b)(-/-) mice is coupled with increased proliferation and survival of newly born cells in the adult ventral hippocampus and increased stress-induced c-Fos activation in the hippocampus following early-life stress. Taken together, the data suggest that GABAB(1) receptor subunit isoforms differentially regulate the deleterious effects of stress and, thus, may be important therapeutic targets for the treatment of depression.
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http://dx.doi.org/10.1073/pnas.1404090111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210293PMC
October 2014

Vortioxetine for the treatment of major depressive disorder.

Expert Rev Clin Pharmacol 2014 Nov 28;7(6):731-45. Epub 2014 Aug 28.

Univ Paris Sud, EA3544, Faculté de Pharmacie, 5, rue JB Clement, 92296 Châtenay-Malabry Cedex, France.

Vortioxetine (Brintellix(®), 1-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]-piperazine) is a multimodal antidepressant targeting the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT3, 5-HT7 receptors and the serotonin (5-HT) transporter (5-HTT). Vortioxetine administration induces antidepressant- and anxiolytic-like effects, and can enhance cognitive performance in rodents. Several clinical trials have reported the efficiency and a satisfactory tolerability of vortioxetine treatment in depressed patients. Remarkably, vortioxetine has a specific positive impact on cognitive symptoms in depressed patients. Overall, vortioxetine is an efficacious antidepressant drug for the treatment of patients with a major depressive episode and has a unique mechanism of action offering a new therapeutic option.
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http://dx.doi.org/10.1586/17512433.2014.950655DOI Listing
November 2014

Growth hormone potentiates 17β-estradiol-dependent breast cancer cell proliferation independently of IGF-I receptor signaling.

Endocrinology 2013 Sep 19;154(9):3219-27. Epub 2013 Jun 19.

Department of Physiology and Biophysics, University of Illinois at Chicago, 835 South Wolcott Avenue, MC 901, Chicago, Illinois 60612, USA.

Estrogen action in mammary gland development and breast cancer progression is tightly linked to the GH/IGF-I axis. Although many of the effects of GH on mammary gland growth and development require IGF-I, the extent to which GH action in breast cancer depends on IGF-I is not known. We examined GH action in a panel of estrogen receptor-positive breast cancer cell lines and found that T47D cells express significant levels of GH receptor and that GH significantly enhances 17β-estradiol (E2)-stimulated proliferation in these cells. GH action in the T47D cells was independent of changes in IGF-I and IGF-I receptor (IGF-IR) expression and IGF-IR signaling, suggesting that GH can exert direct effects on breast cancer cells. Although E2-dependent proliferation required IGF-IR signaling, the combination of GH+E2 overcame inhibition of IGF-IR activity to restore proliferation. In contrast, GH required both Janus kinase 2 and epidermal growth factor receptor signaling for subsequent ERK activation and potentiation of E2-dependent proliferation. Downstream of these pathways, we identified a number of immediate early-response genes associated with proliferation that are rapidly and robustly up-regulated by GH. These findings demonstrate that GH can have important effects in breast cancer cells that are distinct from IGF-IR activity, suggesting that novel drugs or improved combination therapies targeting estrogen receptor and the GH/IGF axis may be beneficial for breast cancer patients.
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http://dx.doi.org/10.1210/en.2012-2208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749474PMC
September 2013

Environmental factors affect the activity of biocontrol agents against ochratoxigenic Aspergillus carbonarius on wine grape.

Int J Food Microbiol 2012 Sep 31;159(1):17-24. Epub 2012 Jul 31.

Dipartimento di Agricoltura, Ambiente e Alimenti, Università degli Studi del Molise, Via F. De Sanctis snc, 86100 Campobasso, Italy.

The influence of temperature and relative humidity (RH) on the activity of three biocontrol agents-the yeast Metschnikowia pulcherrima LS16 and two strains of the yeast-like fungus Aureobasidium pullulans LS30 and AU34-2-against infection by A. carbonarius and ochratoxin A (OTA) accumulation in wine grape berries was investigated in lab-scale experiments. The presence of wounds on grape skin dramatically favored infection of berries by A. carbonarius strain A1102, since unwounded berries showed very low levels of infection at all conditions of RH and temperature tested. Artificially wounded berries pre-treated with the biocontrol agents were inoculated with the ochratoxigenic A. carbonarius strain A1102 and were incubated for 5 days at two levels of RH (60% and 100%) and three different temperatures (20, 25 and 30 °C). The three biocontrol agents were able to prevent infections at 60% RH and 20 °C. At 60% RH and 25 °C only strain AU34-2 achieved some protection on day 5, whereas at 30 °C a limited biocontrol efficacy was evident only up to day 2. At 100% RH, LS16, LS30 and AU34-2 showed effective protection of grape berries at 20 °C until the 5th day of incubation. The three biocontrol agents achieved significant protection at higher temperatures only until the 2nd day after the beginning of the experiment: all three strains at 25 °C, and only strain LS16 at 30 °C. After 5 days, the three biocontrol agents were able to significantly reduce the level of OTA in berries at all the conditions tested. This occurred even when protection from infection was not significant, except at 30 °C and 100% of RH for all the three strains, and at 25 °C and 100% of RH for strain LS16. The biocontrol agents displayed a higher rate of colonization on grape berries at 20 and 25 °C than at 30 °C. The higher value of RH (100%) appeared to increase the rate of colonization, in particular at 20 and 25 °C. Taken together, our results emphasize the significant influence of environmental factors on the effectiveness of biocontrol against A. carbonarius as well as on OTA contamination in wine grape berries, and the need for biocontrol agents that can cope with the environmental conditions that are conducive to attack by A. carbonarius.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2012.07.023DOI Listing
September 2012

Blockade of the GABA(B) receptor increases neurogenesis in the ventral but not dorsal adult hippocampus: relevance to antidepressant action.

Neuropharmacology 2012 Dec 1;63(8):1380-8. Epub 2012 Aug 1.

Molecular & Behavioural Neuroscience Group, Department of Anatomy and Neuroscience, University College Cork, Ireland.

GABA(B) receptor antagonists have been shown to have antidepressant-like properties in animal models and thus, could represent a novel approach for the treatment of depression. The neurobiological mechanisms underlying these effects are currently unknown. Adult hippocampal neurogenesis (the birth of new neurons) is thought to play a role in antidepressant drug action. However, the ability of GABA(B) receptors to modulate the proliferation and survival of newly-born cells in the adult hippocampus remains unexplored. Therefore, we investigated whether the GABA(B) receptor antagonist, CGP 52432, can induce antidepressant-like behaviour and increase hippocampal neurogenesis in the stress-sensitive mouse strain, BALB/c. Male mice were treated with CGP 52432 either acutely (one injection, 3; 10; 30 mg/kg, i.p.), subchronically (7 days, 3; 10 mg/kg, i.p.) or chronically (21 days, 3; 10 mg/kg, i.p.) and antidepressant-like behaviour was assessed using the forced swim test (FST). The effects of CGP 52432 on the proliferation and survival of newly-born cells in the hippocampus were assessed using BrdU immunohistochemistry. Acute, subchronic and chronic treatment with CGP 52432 induced antidepressant-like behavioural effects in the FST. Moreover, chronic but not acute or subchronic treatment with CGP 52432 increased hippocampal cell proliferation but had no effect on the survival of newly-born cells. This temporal effect is consistent with the time course for the therapeutic action of antidepressants. Interestingly, CGP 52432-induced increases in cell proliferation occurred in the ventral but not in the dorsal hippocampus. This topographical segregation concurs with the hypothesis that the ventral hippocampus is primarily involved in the regulation of stress and emotionality. Taken together, our data suggest that increased hippocampal cell proliferation is a plausible mechanism for the antidepressant-like effects of GABA(B) receptor antagonists following chronic but not acute treatments. Moreover, altered behavioural effects in the FST does not correlate with changes in neurogenesis.
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http://dx.doi.org/10.1016/j.neuropharm.2012.06.066DOI Listing
December 2012

Early-life stress induces visceral hypersensitivity in mice.

Neurosci Lett 2012 Mar 6;512(2):99-102. Epub 2012 Feb 6.

Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Ireland.

Early-life stress is a risk factor for irritable bowel syndrome (IBS), a common and debilitating functional gastrointestinal disorder that is often co-morbid with stress-related psychiatric disorders. In the rat, maternal separation (MS) stress has been shown to induce visceral hypersensitivity in adulthood and thus has become a useful model of IBS. However, development of mouse models of maternal separation has been difficult. Given the advent of transgenic mouse technology, such models would be useful to further our understanding of the pathophysiology of IBS and to develop new pharmacological treatments. Thus, the present study aimed to develop a mouse model of MS stress-induced visceral hyperalgesia as measured using manometric recordings of colorectal distension (CRD). Moreover, since the GABA(B) receptor has been reported to play a role in pain processes, we also assessed its role in visceral nociception using novel GABA(B(1b)) receptor subunit knockout mice. CRD was performed in adult male wildtype and GABA(B(1b)) receptor knockout mice that had undergone unpredictable MS combined with unpredictable maternal stress (MSUS) from postnatal day 1 through 14 (PND 1-14). MSUS induced visceral hypersensitivity in both wildtype and GABA(B(1b)) receptor knockout mice when compared with non-stressed mice. Wildtype and GABA(B(1b)) receptor knockout mice did not differ in baseline or stress-induced visceral sensitivity. To the best of our knowledge, this is the first study to show that early-life stress induces visceral hypersensitivity in a mouse model. These findings may provide a novel mouse model of visceral hypersensitivity which may aid our understanding of its underlying mechanisms in future studies.
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http://dx.doi.org/10.1016/j.neulet.2012.01.066DOI Listing
March 2012

Conversion of the mycotoxin patulin to the less toxic desoxypatulinic acid by the biocontrol yeast Rhodosporidium kratochvilovae strain LS11.

J Agric Food Chem 2011 Nov 10;59(21):11571-8. Epub 2011 Oct 10.

Dipartimento di Scienze Animali, Vegetali e dell'Ambiente, Università degli Studi del Molise, Via F. De Sanctis snc, 86100 Campobasso, Italy.

The infection of stored apples by the fungus Penicillium expansum causes the contamination of fruits and fruit-derived products with the mycotoxin patulin, which is a major issue in food safety. Fungal attack can be prevented by beneficial microorganisms, so-called biocontrol agents. Previous time-course thin layer chromatography analyses showed that the aerobic incubation of patulin with the biocontrol yeast Rhodosporidium kratochvilovae strain LS11 leads to the disappearance of the mycotoxin spot and the parallel emergence of two new spots, one of which disappears over time. In this work, we analyzed the biodegradation of patulin effected by LS11 through HPLC. The more stable of the two compounds was purified and characterized by nuclear magnetic resonance as desoxypatulinic acid, whose formation was also quantitated in patulin degradation experiments. After R. kratochvilovae LS11 had been incubated in the presence of (13)C-labeled patulin, label was traced to desoxypatulinic acid, thus proving that this compound derives from the metabolization of patulin by the yeast. Desoxypatulinic acid was much less toxic than patulin to human lymphocytes and, in contrast to patulin, did not react in vitro with the thiol-bearing tripeptide glutathione. The lower toxicity of desoxypatulinic acid is proposed to be a consequence of the hydrolysis of the lactone ring and the loss of functional groups that react with thiol groups. The formation of desoxypatulinic acid from patulin represents a novel biodegradation pathway that is also a detoxification process.
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http://dx.doi.org/10.1021/jf203098vDOI Listing
November 2011

Early pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for Down syndrome.

J Neurosci 2010 Jun;30(26):8769-79

Department of Human and General Physiology, University of Bologna, I-40126 Bologna, Italy.

Down syndrome (DS) is a genetic pathology characterized by intellectual disability and brain hypotrophy. Widespread neurogenesis impairment characterizes the fetal and neonatal DS brain, strongly suggesting that this defect may be a major determinant of mental retardation. Our goal was to establish, in a mouse model for DS, whether early pharmacotherapy improves neurogenesis and cognitive behavior. Neonate Ts65Dn mice were treated from postnatal day (P) 3 to P15 with fluoxetine, an antidepressant that inhibits serotonin (5-HT) reuptake and increases proliferation in the adult Ts65Dn mouse (Clark et al., 2006). On P15, they received a BrdU injection and were killed after either 2 h or 1 month. Results showed that P15 Ts65Dn mice had notably defective proliferation in the hippocampal dentate gyrus, subventricular zone, striatum, and neocortex and that proliferation was completely rescued by fluoxetine. In the hippocampus of untreated P15 Ts65Dn mice, we found normal 5-HT levels but a lower expression of 5-HT1A receptors and brain-derived neurotrophic factor (BDNF). In Ts65Dn mice, fluoxetine treatment restored the expression of 5-HT1A receptors and BDNF. One month after cessation of treatment, there were more surviving cells in the dentate gyrus of Ts65Dn mice, more cells with a neuronal phenotype, more proliferating precursors, and more granule cells. These animals were tested for contextual fear conditioning, a hippocampus-dependent memory task, and exhibited a complete recovery of memory performance. Results show that early pharmacotherapy with a drug usable by humans can correct neurogenesis and behavioral impairment in a model for DS.
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http://dx.doi.org/10.1523/JNEUROSCI.0534-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632890PMC
June 2010

Strains of Aureobasidium pullulans can lower ochratoxin A contamination in wine grapes.

Phytopathology 2008 Dec;98(12):1261-70

Dipartimento di Scienze Animali, Vegetali e dell'Ambiente, Università del Molise, Via F. De Sanctis, Campobasso, Italy.

Wine contamination with ochratoxin A (OTA) is due to the attack of wine grapes by ochratoxigenic Aspergillus carbonarius and Aspergillus spp. section Nigri. Four A. pullulans strains, AU14-3-1, AU18-3B, AU34-2, and LS30, are resistant to and actively degrade ochratoxin A in vitro. The less toxic ochratoxin alpha and the aminoacid L-beta-phenylalanine were the major degradation products, deriving from the cleavage of the amide bond linking these two moieties of OTA. The same strains were studied further as biocontrol agents of A. carbonarius on wine grapes in laboratory experiments. Three of the four strains significantly prevented infections by A. carbonarius. Berries pretreated with the biocontrol agents and infected with A. carbonarius contained lower amounts of OTA as compared to the untreated infected control berries. Two of these strains were shown to degrade OTA to ochratoxin alpha in fresh grape must, but the mechanisms of the decrease of OTA accumulation in infected berries pretreated with the biocontrol agents remain to be elucidated. Assessment of one strain carried out in the vineyard during the growing season of 2006 showed that the tested strain was an effective biocontrol agent, reducing both severity of Aspergillus rots and OTA accumulation in wine grapes. To our knowledge this is the first report describing the positive influence of biocontrol agents on OTA accumulation in this crop species.
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http://dx.doi.org/10.1094/PHYTO-98-12-1261DOI Listing
December 2008
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