Stochastic model of solvent exchange in the first coordination shell of aqua Ions

Ion microsolvation is a basic, yet fundamental, process of ionic solutions underlying many relevant phenomena in either biological or nanotechnological applications, such as solvent reorganization energy, ion transport, catalytic activity, and so on. As a consequence, it is a topic of extensive investigations by various experimental techniques, ranging from X-ray diffraction to NMR relaxation and from calorimetry to vibrational spectroscopy, and theoretical approaches, especially those based on molecular dynamics (MD) simulations. The conventional microscopic view of ion solvation is usually provided by a "static" cluster model representing the first ion-solvent coordination shell. Despite the merits of such a simple model, however, ion coordination in solution should be better regarded as a complex population of dynamically interchanging molecular configurations. Such a more comprehensive view is more subtle to characterize and often elusive to standard approaches. In this work, we report on an effective computational strategy aiming at providing a detailed picture of solvent coordination and exchange around aqua ions, thus including the main structural, thermodynamic, and dynamic properties of ion microsolvation, such as the most probable first-shell complex structures, the corresponding free energies, the interchanging energy barriers, and the solvent-exchange rates. Assuming the solvent coordination number as an effective reaction coordinate and combining MD simulations with enhanced sampling and master-equation approaches, we propose a stochastic model suitable for properly describing, at the same time, the thermodynamics and kinetics of ion-water coordination. The model is successfully tested toward various divalent ions (Ca2+, Zn2+, Hg2+, and Cd2+) in aqueous solution, considering also the case of a high ionic concentration. Results show a very good agreement with those issuing from brute-force MD simulations, when available, and support the reliable prediction of rare ion-water complexes and slow water exchange rates not easily accessible to usual computational methods

Cytoprotective Effect of Idebenone through Modulation of the Intrinsic Mitochondrial Pathway of Apoptosis in Human Retinal Pigment Epithelial Cells Exposed to Oxidative Stress Induced by Hydrogen Peroxide

Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of Leber’s hereditary optic neuropathy. Mitochondria of retinal pigment epithelium (RPE) are particularly vulnerable to oxidative damage associated with cellular senescence. Therefore, the aim of this study was to explore idebenone’s cytoprotective effect and its underlying mechanism. We used a human-RPE cell line (ARPE-19) exposed to idebenone pre-treatment for 24 h followed by conditions inducing H2O2 oxidative damage for a further 24 h. We found that idebenone: (a) ameliorated H2O2-lowered cell viability in the RPE culture; (b) activated Nrf2 signaling pathway by promoting Nrf2 nuclear translocation; (c) increased Bcl-2 protein levels, leaving unmodified those of Bax, thereby reducing the Bax/Bcl-2 ratio; (d) maintained the mitochondrial membrane potential (ΔΨm) at physiological levels, preserving the functionality of mitochondrial respiratory complexes and counteracting the excessive production of ROS; and (e) reduced mitochondrial cytochrome C-mediated caspase-3 activity. Taken together, our findings show that idebenone protects RPE from oxidative damage by modulating the intrinsic mitochondrial pathway of apoptosis, suggesting its possible role in retinal epitheliopathies associated with mitochondrial dysfunction

Cannabidiol tempers alcohol intake and neuroendocrine and behavioural correlates in alcohol binge drinking adolescent rats. Focus on calcitonin gene-related peptide's brain levels

: Alcohol binge drinking is common among adolescents and may challenge the signalling systems that process affective stimuli, including calcitonin gene-related peptide (CGRP) signalling. Here, we employed a rat model of adolescent binge drinking to evaluate reward-, social- and aversion-related behaviour, glucocorticoid output and CGRP levels in affect-related brain regions. As a potential rescue, the effect of the phytocannabinoid cannabidiol was explored. Adolescent male rats underwent the intermittent 20% alcohol two-bottle choice paradigm; at the binge day (BD) and the 24 h withdrawal day (WD), we assessed CGRP expression in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, hypothalamus and brainstem; in addition, we evaluated sucrose preference, social motivation and drive, nociceptive response, and serum corticosterone levels. Cannabidiol (40 mg/kg, i.p.) was administered before each drinking session, and its effect was measured on the above-mentioned readouts. At BD and WD, rats displayed decreased CGRP expression in mPFC, NAc and amygdala; increased CGRP levels in the brainstem; increased response to rewarding- and nociceptive stimuli and decreased social drive; reduced serum corticosterone levels. Cannabidiol reduced alcohol consumption and preference; normalised the abnormal corticolimbic CGRP expression, and the reward and aversion-related hyper-responsivity, as well as glucocorticoid levels in alcohol binge-like drinking rats. Overall, CGRP can represent both a mediator and a target of alcohol binge-like drinking and provides a further piece in the intricate puzzle of alcohol-induced behavioural and neuroendocrine sequelae. CBD shows promising effects in limiting adolescent alcohol binge drinking and rebalancing the bio-behavioural abnormalities

Psychological assessment in pathological gamblers treated with escitalopram

Pathological Gambling (PG) is classified as a "Disorder of Impulse Control", but due to similarities with drug addiction is frequently described as a drug-free addiction (Potenza et al., 2012). PG is conceptualized as a behavioural addiction because of its neurobiologic, neurophysiologic and psychological features. Current therapeutical approaches seem unsatisfactory as they do not achieve definitive positive outcomes. Considering the well known psycopathological comorbidities, PG represents both a social (impact on relatives money/life) and a sanitary cost, in terms of pharmacological and psychological support. The compulsive behaviour detectable in PG, is a disease with neurophysiopathological basis now fairly well-defined which affects particularly vulnerable people. PG is linked to important changes in brain systems such as the prefrontal cortex, the nucleus accumbens, the endogenous opioid system and the extended amygdale. Recent fMRI studies associate PG with blunted mesolimbic activation to non-specific rewards, whereas increased prefrontal cortex, anterior cingulate and ventral striatum activation is observed during gambling-related cue-exposure paradigms. Several neuropsychological studies show higher impulsivity in PG (Odlaug BL. et al., 2013) that, together with specific psychopathological symptoms, such as anxiety and depressed mood, characterize different PG subtypes (Blaszczynski A, Nower L. 2002). Impulsivity transcends multiple psychiatric disorders and is thought to be central to impulse control disorders such as PG. Furthermore, many PGs suffers from depression and decreased mood

Electrostatic and Structural Bases of Fe2+ Translocation through Ferritin Channels

Ferritin molecular cages are marvelous 24-mer supramolecular architectures that enable massive iron storage (>2000 iron atoms) within their inner cavity. This cavity is connected to the outer environment by two channels at C3 and C4 symmetry axes of the assembly. Ferritins can also be exploited as carriers for in vivo imaging and therapeutic applications, owing to their capability to effectively protect synthetic non-endogenous agents within the cage cavity and deliver them to targeted tissue cells without stimulating adverse immune responses. Recently, X-ray crystal structures of Fe(2+)-loaded ferritins provided important information on the pathways followed by iron ions toward the ferritin cavity and the catalytic centers within the protein. However, the specific mechanisms enabling Fe(2+) uptake through wild-type and mutant ferritin channels is largely unknown. To shed light on this question, we report extensive molecular dynamics simulations, site-directed mutagenesis, and kinetic measurements that characterize the transport properties and translocation mechanism of Fe(2+) through the two ferritin channels, using the wild-type bullfrog Rana catesbeiana H' protein and some of its variants as case studies. We describe the structural features that determine Fe(2+) translocation with atomistic detail, and we propose a putative mechanism for Fe(2+) transport through the channel at the C3 symmetry axis, which is the only iron-permeable channel in vertebrate ferritins. Our findings have important implications for understanding how ion permeation occurs, and further how it may be controlled via purposely engineered channels for novel biomedical applications based on ferritin

Ultrasound-induced transformation of fluorescent organic nanoparticles from a molecular rotor into rhomboidal nanocrystals with enhanced emission

Fluorescent organic nanoparticles (FONs) based on aggregation-induced emission (AIE) are receiving increasing attention owing to their simple preparation, enhancedoptical properties, and a wide range of applications. Therefore, finding simple methods to tune the structural and emissive properties of FONs is highly desirable. In this context, we discuss the preparation of highly emissive, amorphous AIE spherical nanoparticles based on a structurally-simple molecular rotor and their sonochemicaltransformation into rhomboidal nanocrystals. Interestingly, the ultrasound-induced modification of the morphology is accompanied by a remarkable enhancement in the stability and emission of the resulting nanocrystals. Detailed characterization of both spherical and rhomboidal nanoparticles was carried out by means of several microscopic, crystallographic, and spectroscopic techniques as well as quantum mechanical calculations. In a nutshell, this work provides a unique example of the ultrasound-induced switching of morphology, stability, and emission in FONsFinancial support from Spanish Ministry of Economy and Competitivity, MICINN (CTQ-2011-24187/BQU), MIUR through FIRB program (contract no. RBFR10DAK6), ERC Advanced Grant 2012 (number 320951

Leveraging fluorescent emission to unitary yield: dimerization of polycyclic aromatic hydrocarbons

We report on the synthesis and characterization of novel substituted 1,1′‐biperylene‐2,2′‐diols in which the dihedral angle between the two polycyclic aromatic hydrocarbon (PAH) units is tailored from ca. 60° to ca. 90° in the solid state by introduction of cyclo‐etheric straps or sterically hindered groups such as the triisopropylsilyl (TIPS) group. Depending on the type of substitution, we lock the dihedral angle between the perylenyl moieties enabling fine‐tuning of the molecular optoelectronic properties, with the molecules displaying the smallest angles acting as exceptionally strong emitters with unitary quantum yields

Chanalyzer : a computational geometry approach for the analysis of protein channel shape and dynamics

Morphological analysis of protein channels is a key step for a thorough understanding of their biological function and mechanism. In this respect, molecular dynamics (MD) is a very powerful tool, enabling the description of relevant biological events at the atomic level, which might elude experimental observations, and pointing to the molecular determinants thereof. In this work, we present a computational geometry-based approach for the characterization of the shape and dynamics of biological ion channels or pores to be used in combination with MD trajectories. This technique relies on the earliest works of Edelsbrunner and on the NanoShaper software, which makes use of the alpha shape theory to build the solvent-excluded surface of a molecular system in an aqueous solution. In this framework, a channel can be simply defined as a cavity with two entrances on the opposite sides of a molecule. Morphological characterization, which includes identification of the main axis, the corresponding local radius, and the detailed description of the global shape of the cavity, is integrated with a physico-chemical description of the surface facing the pore lumen. Remarkably, the possible existence or temporary appearance of fenestrations from the channel interior towards the outer lipid matrix is also accounted for. As a test case, we applied the present approach to the analysis of an engineered protein channel, the mechanosensitive channel of large conductance

Unraveling the peculiar modus operandi of a new class of solvatochromic fluorescent molecular rotors by spectroscopic and quantum mechanical methods

A prototype for a new class of fluorescent molecular rotors (FMRs), namely 4-(diphenylamino)phthalonitrile (DPAP), was synthesized and its sensitivity towards solvent polarity and viscosity probed using photophysical and computational methods. DPAP is characterized by a pronounced fluorosolvatochromism in polarity-dependent absorption, emission and fluorescent lifetime experiments. At the same time, a strong viscosity response is observed, especially in polar and protic solvents. Quantum mechanical calculations assisted in interpreting the unusual solvent sensitivity of DPAP in terms of its high flexibility, giving rise to solvent-independent, barrier-free rotations. As a matter of fact, the modus operandi in DPAP contrasts that of traditional FMRs involving twisted intramolecular charge transfer (TICT) states. The influence of this unusual flexible character on excitation and emission energies was studied using computational methods upon considering twisting of the molecule in solvents of different polarity. Furthermore, a detailed characterization of the excited state profile was attained using time resolved spectroscopy techniques. In particular, a contrasting deactivation pattern of the intramolecular charge transfer (ICT) state was observed in low and high polar media. Moreover, in low and medium polar solvents strong emission is accompanied by triplet excited state formation, while in high polar and protic solvents the ICT state is highly stabilized and decays primarily non-radiatively. Notably, a viscosity increase in the latter solvents hampers rotations leading to a strong emission enhancement. This latter behavior, coupled to a remarkable solvatochromic character, makes DPAP a promising probe for biological and environmental sensing and imaging applications

PATHOLOGICAL GAMBLING: AN ASSOCIATION WITH ALEXITHYMIA, PERSONALITY DISORDERS AND CLINICAL SYNDROMES

Pathological gambling (PG) is a disorder recently conceptualized as a behavioural addiction, because of its neurobiological, neurophysiological and psychological features (American Psychiatric Association. Diagnostic and statistical manual of mental disorders - 5th ed., 2013; Potenza et al., 2012). PG represents both a social and a sanitary cost, in terms of pharmacological and psychological therapies. The aim of this study was to examine the correlation between personality disorders, clinical syndromes and alexithymia levels in a group of pathological gamblers. Furthermore this study aimed at highlighting a relationship between PG and alexithymia, over and above the relationship between personality disorders, clinical syndromes and PG. Sixty treatment- seeking pathological gamblers and 60 healthy controls were included in the study. Psychological assessment included the South Oaks Gambling Screen (SOGS), the Millon Clinical Multiaxial Inventory (MCMI-III) and the Toronto Alexithymia Scale (TAS-20). Pathological gamblers displayed Axis I disorders, such as anxiety, somatoform symptoms, bipolar symptoms, dysthymia, thought disorders and major depression, as well as Axis II disorders such as depressive, antisocial, sadistic, passive-aggressive, self-defeating and paranoid disorders, and greater alexithymia levels. Alexithymia was detected in PG independently from the presence of other psychiatric disorders. Our data show that comorbid psychiatric disorders have been evidentiated in PG. Interestingly alexithymia is related to PG indipendently from other psychopathological disorders, representing a relevant feature, helpful for assessing PG diagnosis and for orienting to the correct therapeutical strategy. REFERENCES American Psychiatric Association. 2013. American Psychiatric Publishing Potenza et al.,2012Psychoph219(2):469-49