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Dexpramipexole (DEX) has been described as the first-in-class F1Fo ATP synthase activator able to boost mitochondrial bioenergetics and provide neuroprotection in experimental models of ischemic brain injury. Although DEX failed in a phase III trial in patients with amyotrophic lateral sclerosis, it showed favorable safety and tolerability profiles. Recently, DEX emerged as a Nav1.8 Na+ channel and transient outward K+ (IA) conductance blocker, revealing therefore an unexpected, pleiotypic pharmacodynamic profile. In this study, we performed electrophysiological experiments in vitro aimed to better characterize the impact of DEX on voltage-dependent currents and synaptic transmission in the hippocampus. By means of patch-clamp recordings on isolated hippocampal neurons, we found that DEX increases outward K+ currents evoked by a voltage ramp protocol. This effect is prevented by the non-selective voltage-dependent K+ channel (Kv) blocker TEA and by the selective small-conductance Ca2+-activated K+ (SK) channel blocker apamin. In keeping with this, extracellular field recordings from rat hippocampal slices also demonstrated that the compound inhibits synaptic transmission and CA1 neuron excitability. Overall, these data further our understanding on the pharmacodynamics of DEX and disclose an additional mechanism that could underlie its neuroprotective properties. Also, they identify DEX as a lead to develop new modulators of K+ conductances.

NOD mice represent a unique strain that recapitulates some aspects of progressive MS when subjected to experimental autoimmune encephalomyelitis (EAE). It is unknown, however, whether a proneness to demyelination and/or defect in remyelination contribute to disease progression in NOD mice. Answering to this question might help deciphering the molecular and cellular events underpinning disease evolution in progressive MS. Here, we compared the cuprizone-dependent demyelination and remyelination responses, as well as their functional correlates, in NOD, C57BL/6, and SJL mice typically adopted to model progressive, chronic or relapsing EAE. We report that demyelination occurred to a similar extent in the three mice strains, and that in none of them there was evidence of axonal degeneration during prolonged demyelination. Moreover, immunostaining for GFAP+ astrocytes, Iba1+ microglia, and NG2+ oligodendrocyte precursor cells similarly increased in the 3 mouse strains after cuprizone exposure. The mice underwent concomitant and complete remyelination 2 weeks after cuprizone withdrawal. On a functional level, NOD mice showed the earliest reduction of spontaneous motility and full recovery, but no impairment of motor skill. Conversely, C57BL/6 animals showed phasic reduction of both spontaneous motility and motor skill. Lastly, SJL mice presented the most severe neurological impairment with long-lasting reduction of spontaneous motility and motor skill. Overall, data suggest that the unique feature of EAE progression in NOD mice is not due to proneness to demyelination or intrinsic defects in myelin formation. Findings also unravel important functional differences in the response of the three mouse stains to cuprizone that can be harnessed to design and interpret future experiments.

Background and purpose Drugs able to counteract progressive multiple sclerosis (MS) represent a largely unmet therapeutic need. Even though the pathogenesis of disease evolution is still obscure, accumulating evidence indicates that mitochondrial dysfunction plays a causative role in neurodegeneration and axonopathy in progressive MS patients. Here, we investigated the effects of dexpramipexole, a compound with a good safety profile in humans and able to sustain mitochondria functioning and energy production, in a mouse model of progressive MS. Experimental approach Female non-obese diabetic mice were immunized with MOG35-55 . Functional, immune and neuropathological parameters were analysed during disease evolution in animals treated or not with dexpramipexole. The compound's effects on bioenergetics and neuroprotection were also evaluated in vitro. Key results We found that oral treatment with dexpramipexole at a dose consistent with that well tolerated in humans delayed disability progression, extended survival, counteracted reduction of spinal cord mitochondrial DNA content and reduced spinal cord axonal loss of mice. Accordingly, the drug sustained in vitro bioenergetics of mouse optic nerve and dorsal root ganglia and counteracted neurodegeneration of organotypic mouse cortical cultures exposed to the adenosine triphosphate-depleting agents oligomycin or veratridine. Dexpramipexole, however, was unable to affect the adaptive and innate immune responses both in vivo and in vitro. Conclusion and implication The present findings corroborate the hypothesis that neuroprotective agents may be of relevance to counteract MS progression and disclose the translational potential of dexpramipexole to treatment of progressive MS patients as a stand-alone or adjunctive therapy.

Earlier studies have shown a major involvement of Ventral Tegmental Area (VTA) dopamine (DA) neurons in mediating the rewarding effects of ethanol (EtOH). Much less is known on the role of this system in mediating the transition from moderate to excessive drinking and abuse. Here we sought to explore the hypothesis that early stage drinking in rodents, resembling recreational EtOH use in humans, is sufficient to dysregulate VTA DA transmission thus increasing the propensity to use over time. To this purpose, midbrain slice recordings in mice previously exposed to an escalating (3, 6 and 12%) 18-day voluntary EtOH drinking paradigm was used. By recording from DA and γ-aminobutyric acid (GABA) VTA neurons in midbrain slices, we found that moderate EtOH drinking leads to a significant suppression of the spontaneous activity of VTA DA neurons, while increasing their response to acute EtOH application. We also found that chronic EtOH leads to the enhancement of GABA input frequency onto a subset of DA neurons. Structurally, chronic EtOH induced a significant increase in the number of GABA axonal boutons contacting DA neurons, suggesting deep rewiring of the GABA network. This scenario is consistent with a downmodulation of the reward DA system induced by moderate EtOH drinking, a neurochemical state defined as "hypodopaminergic" and previously associated with advanced stages of drug use in humans. In this context, increased sensitivity of DA neurons towards acute EtOH may represent the neurophysiological correlate of increased unitary rewarding value, possibly driving progression to addiction.

Even though pharmacological approaches able to counteract age-dependent cognitive impairment have been highly investigated, drugs improving cognition and memory are still an unmet need. It has been hypothesized that sustaining energy dynamics within the aged hippocampus can boost memory storage by sustaining synaptic functioning and long term potentiation (LTP). Dexpramipexole (DEX) is the first-in-class compound able to sustain neuronal bioenergetics by interacting with mitochondrial F1Fo-ATP synthase. In the present study, for the first time we evaluated the effects of DEX on synaptic fatigue, LTP induction, learning and memory retention. We report that DEX improved LTP maintenance in CA1 neurons of acute hippocampal slices from aged but not young rats. However, we found no evidence that DEX counteracted two classic parameters of synaptic fatigue such as fEPSP reduction or the train area during the high frequency stimulation adopted to induce LTP. Interestingly, patch-clamp recordings in rat hippocampal neurons revealed that DEX dose-dependently inhibited (IC50 814 nM) the IA current, a rapidly-inactivating K+ current that negatively regulates neuronal excitability as well as cognition and memory processes. In keeping with this, DEX counteracted both scopolamine-induced spatial memory loss in rats challenged in Morris Water Maze test and memory retention in rats undergoing Novel Object Recognition. Overall, the present study discloses the ability of DEX to boost hippocampal synaptic plasticity, learning and memory. In light of the good safety profile of DEX in humans, our findings may have a realistic translational potential to treatment of cognitive disorders.

Drugs able to efficiently counteract progression of multiple sclerosis (MS) are still an unmet need. Several lines of evidence indicate that histone deacetylase inhibitors (HDACi) are clinically-available epigenetic drugs that might be repurposed for immunosuppression in MS therapy. Here, we studied the effects of HDACi on disease evolution in myelin oligodendrocyte glycoprotein (MOG)-immunized NOD mice, an experimental model of progressive experimental autoimmune encephalomyelitis (PEAE). To obtain data of potential clinical relevance, the HDACi panobinostat, givinostat and entinostat were administered orally adopting a daily treatment protocol after disease onset. We report that the 3 drugs efficiently reduced in vitro lymphocyte proliferation in a dose-dependent manner. Notably, however, none of the drugs delayed evolution of PEAE or reduced lethality in NOD mice. In striking contrast with this, however, the lymphocyte proliferation response to MOG as well as Th1 and Th17 spinal cord infiltrates were significantly lower in animals exposed to the HDACi compared to those receiving vehicle. When put into a clinical context, for the first time data cast doubt on the relevance of HDACi to treatment of progressive MS (PMS). Also, our findings further indicate that, akin to PMS, neuropathogensis of PEAE in NOD mice becomes independent from autoimmunity, thereby corroborating the relevance of this model to experimental PMS research.

The stones used for the construction of road surfaces have a complex mineralogical and hence chemical composition. They are made up of several types of minerals put together. This generates a significant difference in adhesion with the bituminous binder. The aim of this study is to create a mathematical model able to predict the adhesion between bitumen and stone on the basis of contact angle measurements made on different pure minerals. The mathematical model used was developed keeping in mind the exponential bond that the minerals have with the corresponding bond angle. This model also confirmed the established fact that the lower the value of Δ, the better the adhesion between the bitumen and the aggregate.

BackgroundIn spite of the substantial therapeutic efficacy of triptans, their site of action is still debated. Subcutaneous sumatriptan is the most efficacious symptomatic treatment for cluster headache (CH) patients, showing therapeutic onset within a few minutes after injection even in migraine patients. However, whether subcutaneous sumatriptan is able to reach the CNS within this short time frame is currently unknown.MethodsHere, by means of liquid chromatography/mass spectrometry, we investigated peripheral and brain distribution of subcutaneous sumatriptan soon after injection in rats at a dose equivalent to that used in patients. Tissue sumatriptan contents were compared to those of oxazepam, a prototypical lipophilic, neuroactive drug.ResultsWe report that sumatriptan accumulated within brain regions of relevance to migraine and CH pathogenesis such as the hypothalamus and the brainstem as soon as 1 and 5 minutes after injection. Notably, sumatriptan brain distribution was faster than that of oxazepam, reaching concentrations exceeding its reported binding affinity for 5HT1B/Dreceptors, and in the range of those able to inhibit neurotransmitter release in vivo.ConclusionOur findings indicate that sumatriptan distributes within the CNS soon after injection, and are in line with prompt pain relief by parenteral sumatriptan in CH patients.

Selective targeting of sodium channel subtypes Nav1.7, Nav1.8, and Nav1.9, preferentially expressed by peripheral nociceptors, represents a unique opportunity to develop analgesics devoid of central side effects. Several compounds that target Nav1.7 and Nav1.8 with different degrees of selectivity have been developed and are currently being tested in clinical trials for multiple pain indications. Among these chemicals, benzothiazole-like compounds emerged as potent sodium channel blockers. We evaluated the effects of dexpramipexole, a benzothiazole-bearing drug with pleiotypic neuroactive properties and a good safety profile in humans, on sodium conductances of dorsal root ganglia neurons, as well as in multiple nociceptive and neuropathic pain models. Dexpramipexole blocks TTX-resistant sodium conductances in cultured rat dorsal root ganglion neurons with an IC50 of 294.4 nM, suggesting selectivity towards Nav1.8. In keeping with this, dexpramipexole does not affect sodium currents in dorsal root ganglion neurons from Nav1.8 null mice and acquires binding pose predicted to overlap that of the Nav1.8 channel-selective blocker A-8034637. The drug provides analgesia when parenterally, orally, or topically applied in inflammatory and visceral mouse pain models, as well as in mice affected by neuropathic pain induced by oxaliplatin, nerve constriction, or diabetes. Pain reduction in mice occurs at doses consistent with those adopted in clinical trials. The present findings confirm the relevance of selective targeting of peripheral Nav1.8 channels to pain therapy. In light of the excellent tolerability of dexpramipexole in humans, our results support its translational potential for treatment of pain.

We attempted to gather information on the pathogenesis of medication-overuse headache, as well as on the neurochemical mechanisms through which symptomatic medication overuse concurs to headache chronification. Transcriptional profiles were therefore evaluated as an index of the homeostasis of the trigeminovascular system in the trigeminal ganglion of female rats exposed for 1 month to daily oral doses of eletriptan or indomethacin. We report that both drug treatments change trigeminal ganglion gene expression to a similar extend. Of note, qualitative transcriptomic analysis shows that eletriptan and indomethacin prompt nearly identical, increased expression of genes coding for proteins involved in migraine pathogenesis and central pain sensitization such as neuropeptides, their cognate receptors, prostanoid, and nitric oxide-synthesizing enzymes, as well as TRP channels. These genes, however, were not affected in thoracic dorsal root ganglia. Of note, lowering of orofacial nociceptive thresholds, as well as forepaw hyperalgesia occurred in both indomethacin- and eletriptan-treated rats. Our study reveals that chronic rat exposure to 2 acute headache medications with completely different mechanisms of action prompts pain sensitization with highly similar induction of pronociceptive genes selectively within the trigeminal ganglion. Data further our understanding of medication-overuse headache pathogenesis and provide hints for specific mechanism-based treatment options.

In the last several years, NAD+ supplementation has emerged as an innovative and safe therapeutic strategy for a wide spectrum of disorders, including diabetes and neuropathy. However, critical questions remain as to how NAD+ and its precursors are taken up by cells, as well as the effects of long-lasting intracellular NAD+ (iNAD+) increases. Here, we investigated the kinetics of iNAD+ levels in different cell types challenged with prolonged exposure to extracellular NAD+ (eNAD+). Surprisingly, we found that after the initial increase, iNAD+ contents decreased back to control levels (iNAD+ resetting). Focusing our attention on HeLa cells, we found that oxygen and ATP consumption occurred with similar temporal kinetics after eNAD+ exposure. Using [3H]NAD+ and [14C]NAD+, we determined that NAD+ resetting was not due to increased dinucleotide extrusion but rather due to reduced uptake of cleaved NAD+ products. Indeed, eNAD+ exposure reduced the expression of the ecto-5′-nucleotidase CD73, the nicotinamide adenine mononucleotide transporter solute carrier family 12 member 8, and the nicotinamide riboside kinase. Interestingly, silencing the NAD+-sensor enzyme sirtuin 1 prevented eNAD+-dependent transcriptional repression of ecto-5′-nucleotidase, solute carrier family 12 member 8, and nicotinamide riboside kinase, as well as iNAD+ resetting. Our findings provide the first evidence for a sirtuin 1–mediated homeostatic response aimed at maintaining physiological iNAD+ levels in conditions of excess eNAD+ availability. These data may be of relevance for therapies designed to support the NAD+ metabolome via extracellular supplementation of the dinucleotide or its precursors.

Progressive multiple sclerosis (PMS) is a devastating disorder sustained by neuroimmune interactions still wait to be identified. Recently, immune-independent, neural bioenergetic derangements have been hypothesized as causative of neurodegeneration in PMS patients. To gather information on the immune and neurodegenerative components during PMS, in the present study we investigated the molecular and cellular events occurring in a Non-obese diabetic (NOD) mouse model of experimental autoimmune encephalomyelitis (EAE). In these mice, we also evaluated the effects of clinically-relevant immunosuppressive (dexamethasone) or bioenergetic drugs (bezafibrate and biotin) on functional, immune and neuropathological parameters. We found that immunized NOD mice progressively accumulated disability and severe neurodegeneration in the spinal cord. Unexpectedly, although CD4 and CD8 lymphocytes but not B or NK cells infiltrate the spinal cord linearly with time, their suppression by different dexamethasone treatment schedules did not affect disease progression. Also, the spreading of the autoimmune response towards additional immunogenic myelin antigen occurred neither in the periphery nor in the CNS of EAE mice. Conversely, we found that altered mitochondrial morphology, reduced contents of mtDNA and decreased transcript levels for respiratory complex subunits occurred at early disease stages and preceded axonal degeneration within spinal cord columns. However, the mitochondria boosting drugs, bezafibrate and biotin, were unable to reduce disability progression. Data suggest that EAE NOD mice recapitulate some features of PMS. Also, by showing that bezafibrate or biotin do not affect progression in NOD mice, our study suggests that this model can be harnessed to anticipate experimental information of relevance to innovative treatments of PMS.

To compare the immunosuppressive and cytotoxic effects of three anti-inflammatory eye drops formulations containing betamethasone plus chloramphenicol (B+C), dexamethasone plus netilmicin (D+N) or dexamethasone plus tobramycin (D+T).

Road pavement is principally made of mineral aggregates and a bitumen binder. Aggregates, due to their mineralogical nature, have complex chemical compositions and physical properties, which are strongly dependent on the minerals that constitute the stones. In pavement technology, bitumen/aggregate affinity is of paramount importance. Moisture damage in hot mix asphalt (HMA) is one of the major concerns in durability of flexible pavements, to improve the adhesion between the bitumen and the stones and increase the life of the road pavements often it is necessary using additives as the antistripping agents. Currently, there are several techniques such as the Boiling Test, the Rolling Bottle Test (RBT), etc., which evaluate the adhesion between the bitumen and the stones, however, most of them are based on a subjective evaluation. In the present paper, several types of mineral aggregates are characterized in detail by optical microscopy (OM) and X-ray powder diffraction (XRPD) in order to correlate the Boiling Test and the contact angle method to investigate the level of bitumen/aggregate affinity. For this reason, a single type of modified bitumen and two adhesion promoters were studied. The obtained results show the reliability of the technique used. However, there are still some limitations regarding the use of a contact angle test in assessing bitumen/aggregate affinity.

Emerging evidence indicates that transcriptome alterations due to epigenetic deregulation concur to ALS pathogenesis. Accordingly, pan-histone deacetylase (HDAC) inhibitors delay ALS development in mice, but these compounds failed when tested in ALS patients. Possibly, lack of selectivity toward specific classes of HDACs weakens the therapeutic effects of pan-HDAC inhibitors. Here, we tested the effects of the HDAC Class II selective inhibitor MC1568 on disease evolution, motor neuron survival as well as skeletal muscle function in SOD1G93A mice. We report that HDACs did not undergo expression changes during disease evolution in isolated motor neurons of adult mice. Conversely, increase in specific Class II HDACs (-4, -5 and -6) occurs in skeletal muscle of mice with severe neuromuscular impairment. Importantly, treatment with MC1568 causes early improvement of motor performances that vanishes at later stages of disease. Notably, motor improvement is not paralleled by reduced motor neuron degeneration but by increased skeletal muscle electrical potentials, reduced activation of mir206/FGFBP1-dependent muscle reinnervation signaling, and increased muscle expression of myogenic genes.

Ferrogels (or magnetic hydrogels) are cross-linked polymer networks containing magnetic nanoparticles: they are mechanically soft and highly elastic and at the same time they exhibit a strong magnetic response. Our work focuses on an combinatorial strategy to improve the efficacy of 5-Fluorouracil (5-FU) assisted chemotherapy, by developing novel multifunctional pH-sensitive ferrogels. We designed gels based on N,N′-dimethylacrylamide monomers polymerized in presence of methacrylic acid or 2-aminoethyl methacrylate hydrochloride, containing ferro-nanoparticles. The influence of polymeric matrix composition and exposition to magnetic field (MF) on swelling behavior and drugs release were investigated at pH 7.4 and 5. In particular, the magnetic field was obtained by using permanent magnetic bar (0.25 T) or electromagnet (0.5 and 1.2 T), with the aim to analyze quantitatively the magnetic effects. A strong influence of the magnetic field on ferrogels properties have been observed. Swelling analysis indicated a dependence on both pH and network composition, reaching a maximum at pH 7.4, for formulations containing methacrylic acid, while the application of MF appeared to decrease the swelling percentages. Release profiles of 5-FU showed effective modulation in release by application of MF: drug release is always higher in the presence of a magnetic field and generally increases with its intensity. The combining effect of pH sensitive properties and application of MF improved the performance of the systems. Results showed that our ferrogels may be technologically applicable as devices for delivery of 5-FU in a controllable manner.

The dynamic phase diagram of triethylene glycol dodecyl ether (C12E3) in D2O was determined for 40, 50, and 60 wt % of surfactant. The shear flow effect on the nonionic lamellar phase was investigated as a function of temperature and concentration. The transition from planar lamellae (Lα)-to-multilamellar vesicles (MLVs) was characterized by means of rheology, rheo-small-angle neutron and light scattering. New insight into the nature of the transition region between Lα and the MLVs state is provided. A disorder-order transition was also observed by SANS. This is attributed to a transition from disordered MLVs to a close-packed array of MLV's with slightly higher order than before. Moreover flow instability was observed in the shear-thickening regime at 40 °C.

The mechanical properties of bitumen are the result of the chemical composition and arrangement of the molecular structures (phases present). The loss of elasticity of the bitumen with aging is mai...

The aim of the present work is to illustrate and discuss an application of rheo-NMR techniques in the investigation of the flow micro-morphology of a rheo-thinning fluid. The viscoelastic material is composed by weakly hydrated nonionic Wormlike Micelles (WM), stabilized by the biocompatible phospholipid in an organic solvent (lecithin organogel). By applying rheo-NMR techniques, such as micro-imaging and flow velocimetry in Couette flow, to lecithin organogels in the concentrated isotropic phase, a new phase nucleating inhomogeneously at the inner rotating cylinder showing periodic fluctuations in space in some cases, has been identified for applied shear rates within the isotropic-nematic stress plateau. On the other hand, evident slippage phenomena have been found in flow regimes consistent with a full shear-induced nematic state. Bulk rheometric investigations executed in oscillatory, steady state and transient mode have been finally carried out to bridge different flow micro-heterogeneities detected by rheo-NMR with a variety of mechanical responses manifested by lecithin WM.

Bitumens are currently modelled as a colloidal system and are the most used materials for road paving. Despite this large application, asphalts are still affected by some inconveniences that bring to road deterioration. This is prevalently due to temperature cycling which is related to the given local climate conditions and to the incident traffic load. In the last decades bitumen performances have been improved by means of different types of additives in order to match various expectations. This improvement is often the result of the indications given by traditional empirical standardized tests like penetration grade, temperature ductility and Fraas breaking point. The comprehension of the chemical mechanism that regulates the action of the used additives can greatly help in designing new and better performance materials. By means of a Stress Controlled Rheometer we present a laboratory evaluation of the rheological properties of a 70/100 bitumen which has been doped by different percentage of Polyphosph...

The role of nonionic vesicles on the rheological behavior of Pluronic F127 is investigated above the dilute regime and below the cloud point of the nonionic surfactant. F127 is a copolymer possessing sol-gel transition by heating attributed to a phase transition from micellar to cubic. The presence of surfactant vesicles is expected to enhance the compartmentalization of a variety of drugs, independently of their affinity to the solvent. Such entrapment would be suitable for controlled release of the drugs in different applications. We address here a mixed Pluronic-nonionic surfactant system with particular emphasis to the effects of the surfactant on the rheological properties of the Pluronics, and the correlation between these properties and drug release control. The results show that the rheological properties of the mixed system are mainly governed by the behavior of the polymer alone and that the mixed system can be useful to control the percutaneous permeation of a small drug, such as Diclofenac Sodium salt.

The temperature dependent rheological and structural behavior of a long-chain C(16)E(4) (tetraethylene glycol monohexadecyl ether) surfactant in D(2)O has been studied within the regime of low shear range. In the absence of shear flow, the system forms a lamellar liquid crystalline phase at relatively high temperatures. The present paper reports on the shear-induced multi-lamellar vesicle (MLV) formation in C(16)E(4)/D(2)O at 40 wt.% of surfactant in the temperature range of 40-55 °C. The transition from planar lamellar structure to multi-lamellar vesicles has been investigated by time-resolved experiments combining rheology and nuclear magnetic resonance (rheo-NMR), rheo small-angle neutron scattering (rheo-SANS) and rheometry. The typical transient viscosity behavior of MLV formation has been discovered at low shear rate value of 0.5s(-1).

At high temperatures, pentaethylene glycol monododecyl ether (C12E5) in D2O forms a swollen lamellar phase. This letter reports the shear-induced multilamellar vesicle (MLV) formation in a sample that contains 40 wt % C12E5 dissolved in D2O at 55 °C. This transition has been investigated by time-resolved rheo-nuclear magnetic resonance, rheo small-angle neutron scattering, and rheometry. The typical transient viscosity behavior of MLV formation has been discovered at 1 s(-1). For the first time, it has been found that MLVs are not stable over time when subjected to high shear rates. Our results show that the MLV stability is confined in a narrow region in the range 1-10 s(-1) shear rates. This is not observed for other CnEm surfactants.

Rheology and rheo-(2)H NMR measurements are presented for 30 wt % ammonium perfluorononanoate (APFN)/(2)H(2)O mixture in the temperature range 20-70 °C. A first-order lamellar-to-nematic transition occurs at 42 °C, and a first-order nematic-to-isotropic transition occurs at 49 °C. Different rheological behaviors of the lamellar phase were observed with increasing the temperature. The lamellar structure at low temperature (Lα(-)) has a clear gel-like viscoelasticity, while at high temperature the lamellar structure (Lα(+)) has a liquid-like response. In this study we have observed for the first time, along with the lamellar phase of a surfactant containing fluorinated fatty acid, the formation of multilamellar vesicles (MLVs) ("onions") induced by shear. With the aid of nonlinear rheology and rheo-NMR techniques, onion formation was found to occur in both temperature regimes of the lamellar phase, but at different strain units. It is suggested that the lamellar phase consists of smectic structures in both Lα(-) and Lα(+), but with different percentages of defect density.

Interest in the modulation of nicotinamide adenine dinucleotide (NAD) metabolome is gaining great momentum because of its therapeutic potential in different human disorders. Suppression of nicotinamide salvage by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, however, gave inconclusive results in neoplastic patients because several metabolic routes circumvent the enzymatic block converging directly on nicotinamide mononucleotide adenylyl transferases (NMNATs) for NAD synthesis. Unfortunately, NMNAT inhibitors have not been identified. Here, we report the identification of Vacor as a substrate metabolized by the consecutive action of NAMPT and NMNAT2 into the NAD analog Vacor adenine dinucleotide (VAD). This leads to inhibition of both enzymes, as well as NAD-dependent dehydrogenases, thereby causing unprecedented rapid NAD depletion, glycolytic block, energy failure, and necrotic death of NMNAT2-proficient cancer cells. Conversely, lack of NMNAT2 expression confers complete resistance to Vacor. Remarkably, Vacor prompts VAD formation and growth suppression in NMNAT2-positive neuroblastoma and melanoma xenografts. Our data show the first evidence of harnessing the entire nicotinamide salvage pathway for antimetabolic strategies. Synthesis and consumption of the pyridine nucleotide NAD are increased in cancer cells and contribute to cell proliferation and neoplastic transformation. Buonvicino et al. identified Vacor as a new structure interfering with NAD metabolome which may lead to the development of new antineoplastic molecules.

In this paper we studied the spectro-mechanical properties of polymer gel electrolytes and blends by means of shear rheology. These electrolytes were obtained by immobilizing EC/PC/LiClO4 solutions in a polymeric matrix of PEO, PAN and PMMA, respectively. Two structural and thermoreversible transitions, a strong-to-weak gel and a gel-to-sol, were revealed and discussed. Moreover, PMMA-PVdF blends have been studied as a function of the different polymeric ratios in order to obtain the best compromise between ionic conduction and mechanical properties. Interesting mechanical properties were observed at some intermediate blend compositions.

Metastability and phase coexistence are important concepts in colloidal science. Typically, the phase diagram of colloidal systems is considered at the equilibrium without the presence of an external field. However, several studies have reported phase transition under mechanical deformation. The reason behind phase coexistence under shear flow is not fully understood. Here, multilamellar vesicle (MLV)-to-sponge (L3 ) and MLV-to-Lα transitions upon increasing temperature are detected using flow small-angle neutron scattering techniques. Coexistence of Lα and MLV phases at 40 °C under shear flow is detected by using flow NMR spectroscopy. The unusual rheological behavior observed by studying the lamellar phase of a non-ionic surfactant is explained using (2) H NMR and diffusion flow NMR spectroscopy with the coexistence of planar lamellar-multilamellar vesicles. Moreover, a dynamic phase diagram over a wide range of temperatures is proposed. (Less)

In the present study, blend ionic conducting membranes formed by poly(methyl- methacrylate (PMMA) / poly(vinilydenefluoride) (PVDF) (blend ratio PMMA/PVdF = 80/20), lithium perchlorate (LiC104) as a salt and a mixture of ethylene carbonate (EC)-propylene carbonate (PC) as plasticizer are prepared and characterized by impedance spectroscopy and dynamic rheological experiments. We compared the results obtained on the blends with those on PMMA gel-based polymer electrolytes incorporating the same EC/PC mixture of plasticizer and the same quantities of salt. The main focus of this study is to illustrate the rheological data of the gels and blends electrolytes to point up their mechanical stability with the temperature in sight of the technological application. The conductivity values are reported in the 20-100 ~ temperature range for different lithium salt contents, while the rheological behaviour has been recorded up to 140 ~

In this study the material behaviour of both a liquid and lamellar lyomesophase were investigated by rheometrical means in steady and oscillatory shear flow. Three different aqueous mixtures were analyzed in order to probe the structural changes occurring at low (32 wt.%), intermediate (52 wt.%) and high (74 wt.%) polymer concentration for the commercial Pluronic copolymer PE 6200 (BASF-Germany). The liquid phase at low and intermediate compositions appeared as a direct micellar solution whose aggregates grew progressively with increasing temperature. These mixtures showed a micellar to lamellar phase transition at ca. 45 °C. The mixture at 74 wt.% polymer showed a larger liquid phase in the temperature interval 20–60 °C. This solution structure was not well defined since an expected reverse micellar organisation did not fit with experimental data. The lamellar phase of the PE 6200/water system appeared stable within the temperature range 45–60 °C and was studied for the mixtures at low and intermediate compositions. The 32 wt.% mixture showed a defected lamellar phase that aligns macroscopically under shear and then gives rise to a planar lamellae to MLVs (vesicles) transition at a shearing higher than 1 s −1 . Mechanical spectra showed a sensitive frequency dependence of material moduli. Against, the 52 wt.% polymer mixture presented an ideal lamellar organisation showing a simple steady flow response under the overall shearing interval 0.1–100 s −1 . Its mechanical spectrum was typical of a weak-gel fluid ( G ′ ≈ G ″ ≈ ν n and G ′ > G ″) in agreement with the viscoelastic behaviour of typical lamellar phases of low molecular weight surfactants.

Polymer electrolytes with ionic conductivities on the order of mS cm-1 at room temperature were prepared from the gelification of LiClO4 /ethylene carbonate–propylene carbonate (EC–PC) solutions into a poly(acrylonitrile) (PAN) matrix. Oscillating rheological experiments were performed on gels prepared at different solvent/salt molar ratios in order to investigate their mechanical properties. Temperature sweep tests (25–120°C) showed changes in the rheological behaviour that was related to structural transitions. A strong–weak gel transition takes place at about 80°C, independent of salt concentration hence assignable only to the polymeric matrix. This transition is completely reversible during cooling ramps and represents a necessary mechanical property from a processing standpoint. A gel–sol transition was observed at ca. 110°C where both viscoelastic moduli reduce themselves by a factor 100, reporting the formation of a fluid system with G''>G'.

The mechanical and electrochemical properties of gel electrolytes, formed by immobilizing ethylene carbonate (EC)–propylene carbonate (PC)/lithium perchlorate (LiClO 4 ) solutions in a polyacrylonitrile (PAN) matrix, were investigated by oscillating rheological experiments, conductivity measurements and 1 H-NMR spectroscopy. The gel's rheological behaviour showed two thermoreversible structural transitions in the temperature range 25–120 °C independent from the salt content in the membranes but can be attributed to the only polymeric matrix. In this paper, we also report a study of the EC–PC/LiClO 4 solutions in a wide concentration range performed by pulsed gradient spin–echo NMR (PGSE–NMR) technique. The solvent self-diffusion coefficient measurements have allowed elaborating a model to describe the solvation mechanism of the lithium ions in these solutions.

We report on the first rheological study of the structural relaxations in a nematic liquid crystalline phase. Linear dynamic and transient shear experiments were applied to a polydomain nematic phase of the CTAB/water system: a liquid crystalline mixture composed of 28 wt% CTAB at 35 °C. The decay of the shear modulus, G(t), was analyzed using the CONTIN inverse Laplace transform to obtain a distribution of relaxation times which were compared with ones from the usual fitting procedure based on a generalized Maxwell model. The behavior of the nematic lyotropic structure of the CTAB/water system is characterized by the presence of both slow and fast relaxation times. These were interpreted as being due to a progressive loss of the lyotropic domain orientation and to the breaking/reforming process of the cylindrical aggregates, respectively.

The solvation mechanism of lithium ions in pure ethylene carbonate (EC) solutions has been studied in a wide concentration range by different techniques and for temperatures up to 100 °C. For low concentrations (R=[Li+]/[EC]⩽0.1) the solvation number of Li+ cations in the solution has been found to be ∼7, by using nuclear magnetic resonance techniques. This number decreases at higher concentration, and complexes Li+-EC with ∼3 solvent molecules per cation are formed when R=0.33. The temperature dependence of the solvation has been investigated for the more concentrated solutions by Raman spectroscopy. When the temperature increases, the relative intensity of the Raman bands upshifted by the lithium interaction also increases remarkably, indicating that Li+ ions form complexes with a higher solvation number. On the other hand, a higher degree of reassociation of Li+ cations with perchlorate anions is observed.

Thermoreversible polymer gel electrolytes with ionic conductivities of about 10−3 S cm−1 at room temperature, were prepared from poly(acrylonitrile) (PAN)-ethylene carbonate (EC)-LiClO4 at different solvent/salt ratios. A temperature dependence was investigated for the electrical and mechanical properties, as well as for spectroscopic changes associate to the solvation mechanism of lithium ions in these gel. The measurements performed on this system concern ionic conductivity, study of self-diffusion coefficient by 1H–NMR, Raman spectroscopy and, finally, an accurate analysis of its mechanical proprieties by rheological tests. The gels present a strong-weak gel transition at about 70 °C, independent from salt concentration hence assignable only to the polymeric matrix. However, this transition is completely reversible on cooling, being this a necessary mechanical property for industrial applications. The Raman study has pointed out an increase, on heating, of the Li+ coordination number by EC molecules, a...

The phase diagram of the water-Gemini 16-4-16 system has been investigated and the phase boundaries were determined. DSC and optical microscopy were used to define the region of existence of the different phases. No liquid crystalline phases have been observed, however, a two-phase region and a wide gel phase follow the solution region. The solution region can be highly viscous, depending on composition and temperature. Surface tension and electrical conductance experiments have been performed, to define micelle formation and counter-ion binding to micelles. Interactions and motions over short distances were studied by 1H-NMR relaxation experiments. The drastic decrease of spin–spin relaxation time, T2, with Gemini composition ( ≈2 wt.%) was explained in terms of particle growth. Pulsed field gradient spin-echo (PGSE) NMR experiments were used to determine water and surfactant self-diffusion. Some modifications in the micellar structure were inferred on increasing the Gemini content in the mixture. Dynamic rheological experiments were performed for probing the solution microstructure. The observed high solution viscosity and the shear relaxation processes were rationalized in terms of the presence of entangled threadlike aggregates at a moderate concentration (≈ 4 wt.%). According to the Bohlin theory of flow as a cooperative phenomenon, the number of the micellar aggregates correlated to each other, and the interaction strength between the micellar units was obtained as a function of Gemini concentration.

We present a theoretical study of the potentialities of the Inverse Laplace Transform when applied to Pulsed Gradient Spin Echo NMR data from water in lyotropic liquid crystalline mesophases. This mathematical application should be able to produce structural information about the studied systems by the determination of the self-diffusion coefficient distribution, giving in this way a significant fingerprint of the molecular organisation in lamellar and reverse hexagonal phases. The critical point of finding the best algorithm to treat the data has been faced: several numerical methods have been tested comparing the performances of the different algorithms with results predictable by theory.

The solution behavior of the fluorinated surfactant tetraethylammonium perfluorooctane-sulfonate, PFOS, in water−trifluoroethanol, TFE, mixtures has been investigated by surface tension, electrical conductance, and PGSE (pulsed gradient spin−echo) NMR self-diffusion methods. Addition of progressive amounts of TFE in the solvent has little influence on the critical micellar concentration, cmc. Conversely, self-diffusion, counterion binding, and the surface pressure at the cmc are significantly affected by added fluoroalkanol. The above effects have been explained in terms of the solvent viscosity, dielectric permittivity, and surface activity, respectively. The complete phase behavior of the above system has been drawn, and the phase boundaries were determined. According to the above findings, added surfactant promotes the separation of the homogeneous solvent mixture into two coexisting fluid phases. The observed behavior was rationalized on thermodynamic grounds.

Water-soluble poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (PEO–PPO–PPO) triblock copolymers are high-molecular-weight nonionic copolymers and form micellar solutions and liquid-crystalline mesophases in water. We studied the temperature dependence of polymer and water self-diffusion in solutions and lyotropic mesophases of the PEO13 PPO30 PEO13/water and PEO21 PPO47 PEO21/water binary systems. The self-diffusion measurements were performed by means of the pulsed field gradient spin-echo NMR method. The analysis of the water mobility was realised using “the obstruction factor” and “the two-site model”, which consider the reduction of the water self-diffusion due to the microstructure of the lyotropic aggregates and to the presence of one part of the solvent bound to the polymer aggregate surfaces. We calculated the water obstruction factors and the hydration numbers as a function both of the polymer composition and of the temperature. The results are compared with the data obtained in mesophases formed by classical surfactants.

Pulsed field gradient spin−echo (PGSE) FT-NMR experiments have been performed in order to characterize the structure of a reverse hexagonal lyomesophase of a nonionic surfactant−water−oil system, weakly charged. The nonionic surfactant system contains pentaethylene glycol dodecyl ether (C12E5), water, decane, and small amounts of an ionic surfactant, sodium dodecyl sulfate (SDS). The observed spin−echo attenuation due to water self-diffusion at different temperatures and compositions has been interpreted with a one-dimensional diffusion model, i.e., a self-diffusion in randomly oriented array of capillaries with both transverse dimensions

The self-diffusion of some organic molecules in silicone rubber and of water and water-ethanol mixtures in sodium alginate membranes was investigated to obtain information on the transport behavior in these systems. The temperature dependence of self-diffusion was examined by the pulsed field gradient NMR technique. The experimental data confirm the homogeneous amorphous nature of PDMS and the affinity of silicone rubber to apolar solvents. The interrelations between solvent and polymer structures of the sodium alginate membrane varying the temperature have been obtained using differential scanning calorimetric. The results have been compared with the trend of self-diffusion coefficients, and structure modifications of the membranes have been evidenced. The overall results confirm the potentialities of the technique used in measuring transport parameter in polymeric membranes.

Carbon nanotubes were dispersed in a sodium dodecylsulfate/decanol/water nematic fluid. The long-term stability of the dispersions is ensured by the small density gradients existing between nanotubes and the nematic fluid, and by its viscosity, as well. Presumably, surfactant or nematic micelles adsorb onto nanotubes and concur to stabilize them. A Rheo 2H NMR characterization was performed. It was supported by classical 2H quadrupole splitting and pulsed field gradient spin–echo NMR, allowing to ascertain the diffusive trends therein. The nematic fluid shows uniaxial spectral profiles and marked diffusion anisotropy. No such effects were observed in nanotube-containing nematic dispersions. In addition, the measured water self-diffusion values are substantially lower than the pure nematic fluid. In the absence of shear, dispersed nanotubes do not modify the quadrupole splitting amplitude, but affect the spectral profiles. The reasons for the observed behavior are briefly outlined. In the presence of shear...

In this paper, the performance of a diagrammatic method based on geometric and algebraic considerations is illustrated. This method, based on the particular symmetry of a thermodynamic diagram, allows to obtain the most important thermodynamic expressions of a simple system. In fact, these thermodynamic expressions can be developed with the application of various geometric patterns to the proposed diagram. The particular symmetry of the thermodynamic diagram allows to develop a matrix formulation of the different geometric patterns. This matrix formalism requires that the thermodynamic parameters of the diagram be recast in a vectorial form.

Solution properties of perfluorononanoic acid and of its alkali metal salts, as well as of lithium, sodium and potassium perfluorooctanoates have been studied by surface tension, volumetric, colligative, emf and electrical conductance experiments and were supported by studies on phase equilibria, performed in close proximity to the CMC. Thermodynamics of micelle formation has been analysed both in terms of a charged-phase model and according to an isodesmic multiple equilibrium aproach so as to account for counterion effect on micellization and for the cooperativity of micellar association, respectively.

The phase diagram of the system composed by Water, Sodium Dodecylsulfate and Aerosol OT, at 25°C, has been investigated. Some physico-chemical properties of the system were determined by optical microscopy, electrical conductance and NMR investigation on 2 H and 23 Na nuclei. Information on binding and counterion dynamics, as well as on the mesophases structure, were inferred by comparing quadrupole splittings and electrical conductance findings

In PEMFC, the polymer electrolyte membrane (PEM) is one of the crucial components which strongly determine the cell performance. Nafion is the electrolyte that been most extensively studied. Despite to its high thermal and chemical stability, it manifests a strong dependence of proton conductivity on hydration level, indeed conductivity dramatically declines as temperature rises above 80 °C and relative humidity/hydration decreases. It is thus highly important to enhance the proton conductivity of the Nafion electrolyte membrane under low RH in order to accomplish higher PEMFCs performance. Additionally, in polymer nanocomposite research, the basic aim is to enhance several properties of polymeric components by using molecular or nanoscale reinforcements in order to increase tensile strength, modulus, heat resistance and impact resistance. One area of research has focused on using carbon nanotubes (CNTs) which, under the electronic percolation level, offer many opportunities for new composites thanks to their superior properties. However, CNTs are generally insoluble in common solvents and polymers, and they agglomerate easily, forming entangled bundles which lead to many defect sites in the composites. In this study, a new class of hybrid materials based on carbon nanotubes (CTNs) rooted on aluminosilicate smectite clays, was synthesized by catalytic chemical vapor deposition (CCVD) method and proposed as nanoadditives in a perfluorosulfonic acid (Nafion®) membrane. The clay platelets were used as alternative substrate for immobilizing the catalytic metal centres necessary for the growth of carbon nanotubes, owing to their unique swelling, ion-exchange and intercalation properties. Side-wall chemical oxidation and organo-functionalization of the CNTs was performed using organic ester molecules containing hydrophilic groups (-RSO3H). SWy−fCNTs nanoadditives were incorporated in the polymer by solution-precipitation method, producing highly homogeneous nanocomposite membranes with outstanding mechanical properties and functionalities obtained by combining both the clays and nanotubes features. The intent is to favour a "branched" structure among the hydrophilic pores inside the membrane, in order to facilitate the proton transport by a more efficient Grotthuss-type mechanism, from one acid site to another, in the dehydration state. Additionally, the presence of hydrophilic 2D platelike layers in the polymeric matrix is of great interest due to the significant gains in thermal stability, mechanical and barrier properties of the resulting nanocomposites. This last property may be exploited in the Direct Methanol Fuel Cells (DMFCs) to reduce the methanol crossover through obstruction effect and increased tortuosity of the fuel diffusion path. Synthesized materials are characterized by a combination of techniques (TGA, Raman, FT-IR, SEM, TEM and DMA), while a deep investigation on the water and methanol transport properties are performed by NMR spectroscopy (PFG and relaxation times). The results demonstrated that membranes containing the organo-functionalized hybrid nanoadditives are able to guarantee a very high proton diffusion in “quasi-anhydrous” conditions, i.e. in the region of high temperatures (above 100 °C) under very low RH, and unveiling a reduction of the methanol diffusion. In accordance, proton conductivity has gained one order of magnitude respect to recast polymer when the cell operating conditions become more drastic. Concerning the mechanical investigation, the adding of such hybrid nanoadditives to Nafion polymer produce membranes more structured and with higher stiffness with higher solidity and extending their thermal stability, which are highly advantageous characteristics for use in fuel cell applications.

Pulsed Field Gradient NMR experiments, in their original time domain, have been carried out to separate both water and surfactant self-diffusion coefficients in the micellar solution of the system cetyltrimethylammonium bromide/water. These results have been supported by those obtained by NMR experiments performed with a Fourier Transform spectrometer. The water self-diffusion coefficients were used to calculate the obstruction effect of the micellar aggregates in accordance with a stoichiometric model already used for lyotropic mesophases. It was found that the micellar aggregates change shape with the concentration and are characterized by an average hydration number of approximately 9 +/- 3.

The effects of salinity on the lateral headgroup interactions of dipalmitoylphosphatidylcholine (DPPC) molecules in fully hydrated multilayers have been investigated by spin label electron spin resonance (ESR) spectroscopy and differential scanning calorimetry (DSC).

X-ray absorption fine structure has been used to elucidate the local environment of ions in polymer electrolytes formed from short-chain oligomers of polyethylene oxide. The gel sectioning technique has been used to measure the radiotracer diffusion coefficients of Na+ and H2O in oligomeric polymer electrolytes. The diffusion coefficient has been studied with respect to a wide concentration and temperature range. Activation energies for diffusion were obtained for Na+ and H2O. Activation energies for diffusion and diffusion coefficients have been obtained for the oligomer chains by means of pfg-NMR.

The phase diagram of the system composed by water, glycerol and Triton TX 100, an industrial arylalkyl surfactant with polyoxyethylene glycol chain as polar head group, has been determined in a wide temperature range, to get information on the links between solvent effect and the formation of organized surfactant assemblies. The occurrence of solution and anisotropic phases is quite sensitive to the amount of glycerol, as well as to temperature. Experimental investigation on transport properties was made to get information on aggregate structure, as well as on micelle size and shape and on obstruction to solvent free diffusion.