Pressure-Induced Excitations in the Out-of-Plane Optical Response of the Nodal-Line Semimetal ZrSiS.

The anisotropic optical response of the layered, nodal-line semimetal ZrSiS at ambient and high pressure is investigated by frequency-dependent reflectivity measurements for the polarization along and perpendicular to the layers. The highly anisotropic optical conductivity is in very good agreement with results from density-functional theory calculations and confirms the anisotropic character of ZrSiS. Whereas the in-plane optical conductivity shows only modest pressure-induced changes, we found strong effects on the out-of-plane optical conductivity spectrum of ZrSiS, with the appearance of two prominent excitations. These pronounced pressure-induced effects can neither be attributed to a structural phase transition according to our single-crystal x-ray diffraction measurements, nor can they be explained by electronic correlation and electron-hole pairing effects, as revealed by theoretical calculations. Our findings are discussed in the context of the recently proposed excitonic insulator phase in ZrSiS.

Polyphenols and obesity prevention: critical insights on molecular regulation, bioavailability and dose in preclinical and clinical settings.

Obesity represents one of the most important public health challenges of the 21st century and is characterized by a multifactorial etiology in which environmental, behavioral, metabolic, and genetic factors work together. Despite the rapid increase in prevalence of obesity in the last decades, especially in children, it remains a preventable disease. To battle obesity a multisector approach promoting healthier lifestyle in terms of physical activity and nutrition is needed. Specifically, biologically active dietary compounds, as polyphenols, are able to modulate the expression of genes involved in the development and progression of obesity and its comorbidities as demonstrated by multiple studies using different obesity models. However, human studies focusing on the transcriptomic modulation by polyphenols in obese patients are still limited and do not often recapitulate the results obtained in preclinical setting likely due to the underestimation of some variables such as bioavailability, dose and form (native vs. metabolized) of polyphenols used. The aim of this review is to summarize the state-of-art of nutrigenomic in vitro, in vivo and ex vivo studies as well as clinical trials based on dietary polyphenols to fight obesity. We also critical discuss the variables to be considered to fill the gap between preclinical and clinical settings.

Probing structural changes upon carbon monoxide coordination to single metal adatoms.

In this work, the adsorption height of Ag adatoms on the Fe3O4(001) surface after exposure to CO was determined using normal incidence x-ray standing waves. The Ag adatoms bound to CO (Ag1 CO) are found to be pulled out of the surface to an adsorption height of 1.15 Å ± 0.08 Å, compared to the previously measured height of 0.96 Å ± 0.03 Å for bare Ag adatoms and clusters. Utilizing DFT+vdW+U calculations with the substrate unit cell dimension fixed to the experimental value, the predicted adsorption height for Ag1 CO was 1.16 Å, in remarkably good agreement with the experimental results.

Direct measurement of Ni incorporation into Fe3O4(001).

The normal incidence X-ray standing wave (NIXSW) technique has been used to follow the evolution of the adsorption geometry of Ni adatoms on the Fe3O4(001)-(√2 × âˆš2)R45° surface as a function of temperature. Two primary surface region sites are identified: a bulk-continuation tetrahedral site and a sub-surface octahedral site, the latter site being preferred at higher annealing temperatures. The ease of incorporation is linked to the presence of subsurface cation vacancies in the (√2 × âˆš2)R45° reconstruction and is consistent with the preference for octahedral coordination observed in the spinel compound NiFe2O4.

Three-Dimensional Electronic Structure of the Type-II Weyl Semimetal WTe_{2}.

By combining bulk sensitive soft-x-ray angular-resolved photoemission spectroscopy and first-principles calculations we explored the bulk electron states of WTe_{2}, a candidate type-II Weyl semimetal featuring a large nonsaturating magnetoresistance. Despite the layered geometry suggesting a two-dimensional electronic structure, we directly observe a three-dimensional electronic dispersion. We report a band dispersion in the reciprocal direction perpendicular to the layers, implying that electrons can also travel coherently when crossing from one layer to the other. The measured Fermi surface is characterized by two well-separated electron and hole pockets at either side of the Γ point, differently from previous more surface sensitive angle-resolved photoemission spectroscopy experiments that additionally found a pronounced quasiparticle weight at the zone center. Moreover, we observe a significant sensitivity of the bulk electronic structure of WTe_{2} around the Fermi level to electronic correlations and renormalizations due to self-energy effects, previously neglected in first-principles descriptions.

The random phase approximation applied to ice.

Standard density functionals without van der Waals interactions yield an unsatisfactory description of ice phases, specifically, high density phases occurring under pressure are too unstable compared to the common low density phase Ih observed at ambient conditions. Although the description is improved by using functionals that include van der Waals interactions, the errors in relative volumes remain sizable. Here we assess the random phase approximation (RPA) for the correlation energy and compare our results to experimental data as well as diffusion Monte Carlo data for ice. The RPA yields a very balanced description for all considered phases, approaching the accuracy of diffusion Monte Carlo in relative energies and volumes. This opens a route towards a concise description of molecular water phases on surfaces and in cavities.

Thickness dependent structural and electronic properties of CuO grown on SrTiO3(100): a hybrid density functional theory study.

We discuss the structural and electronic properties of tetragonal CuO grown on SrTiO3(100) by means of hybrid density functional theory. Our analysis explains the anomalously large Cu-O vertical distance observed in the experiments (≈2.7 Å) in terms of a peculiar frustration between two competing local Cu-O environments characterized by different in-plane and out-of-plane bond lengths and Cu electronic populations. The proper inclusion of substrate effects is crucial to understanding the tetragonal expansion and to reproduce correctly the measured valence band spectrum for a CuO thickness of 3-3.5 unit cells, in agreement with the experimentally estimated thickness.

Interplay between magnetic, electronic, and vibrational effects in monolayer Mn3O4 grown on Pd(100).

The surface stabilized MnO(100)-like monolayer, characterized by a regular c(4 x 2) distribution of Mn vacancies, is studied by hybrid functionals and discussed in the light of available scanning tunneling microscopy and high-resolution electron energy loss spectroscopy data. We show that the use of hybrid functionals is crucial to account for the intermingled nature of magnetic interactions, electron localization, structural distortions, and surface phonons. The proposed Pd(100) supported Mn(3)O(4) structure is excellently compatible with the experiments previously reported in literature.

Two-dimensional manganese oxide nanolayers on Pd(100): the surface phase diagram.

Two-dimensional manganese oxide layers have been grown on Pd(100) and have been characterized by means of scanning tunnelling microscopy, low energy electron diffraction and x-ray photoelectron spectroscopy (XPS). The complex surface phase diagram of MnO(x) on Pd(100) is reported, where nine different novel Mn oxide phases have been detected as a function of the chemical potential of oxygen µ(O). Three regions of the chemical potential of oxygen can be identified, in which structurally related oxide phases are formed, often in coexistence at the surface. The different regions of µ(O) are reflected in the oxidation states of the respective Mn oxide nanolayers as revealed by the Mn 2p and O 1s XPS binding energies. The MnO(x) nanolayers form two-dimensional wetting layers and it is speculated that they mediate the epitaxial growth of MnO on Pd(100) by providing structurally graded interfaces.

Spin fluctuation induced Weyl semimetal state in the paramagnetic phase of EuCd2As2.

Weyl fermions as emergent quasiparticles can arise in Weyl semimetals (WSMs) in which the energy bands are nondegenerate, resulting from inversion or time-reversal symmetry breaking. Nevertheless, experimental evidence for magnetically induced WSMs is scarce. Here, using photoemission spectroscopy, we observe that the degeneracy of Bloch bands is already lifted in the paramagnetic phase of EuCd2As2. We attribute this effect to the itinerant electrons experiencing quasi-static and quasi-long-range ferromagnetic fluctuations. Moreover, the spin-nondegenerate band structure harbors a pair of ideal Weyl nodes near the Fermi level. Hence, we show that long-range magnetic order and the spontaneous breaking of time-reversal symmetry are not essential requirements for WSM states in centrosymmetric systems and that WSM states can emerge in a wider range of condensed matter systems than previously thought.

Evaluation of the pharmacological activity of the major mexiletine metabolites on skeletal muscle sodium currents.

BACKGROUND AND PURPOSE: Mexiletine (Mex), an orally effective antiarrhythmic agent used to treat ventricular arrhythmias, has also been found to be effective for myotonia and neuropathic pain. It is extensively metabolized in humans but little information exists about the pharmacodynamic properties of its metabolites. EXPERIMENTAL APPROACH: To determine their contribution to the clinical activity of Mex, p-hydroxy-mexiletine (PHM), hydroxy-methyl-mexiletine (HMM), N-hydroxy-mexiletine (NHM) (phase I reaction products) and N-carbonyloxy beta-D-glucuronide (NMG) (phase II reaction product) were tested on sodium currents (I(Na)) of frog skeletal muscle fibres. Sodium currents were elicited with depolarizing pulses from different holding potentials (HP=-140, -100, -70 mV) and stimulation frequencies (0.25, 0.5, 1, 2, 5, 10 Hz) using the vaseline-gap voltage-clamp method. KEY RESULTS: All the hydroxylated derivatives blocked the sodium channel in a voltage- and use-dependent manner. The PHM, HMM and NHM metabolites were up to 10-fold less effective than the parent compound. However, HMM showed a greater use-dependent behaviour (10 Hz), compared to Mex and the other metabolites. Similar to Mex, these products behaved as inactivating channel blockers. Conjugation with glucuronic acid (NMG) resulted in almost complete abolition of the pharmacological activity of the parent compound. CONCLUSIONS AND IMPLICATIONS: Thus, although less potent, the phase I metabolites tested demonstrated similar pharmacological behaviour to Mex and might contribute to its clinical profile.

Enhanced solubility and antibacterial activity of lipophilic fluoro-substituted N-benzoyl-2-aminobenzothiazoles by complexation with ß-cyclodextrins.

Some lipophilic fluoro-substituted N-benzoyl-2-aminobenzothiazole antibacterial agents have been evaluated for their activity in the presence of cyclodextrins (CDs) containing aqueous solutions where CDs are adopted as solubilizing excipients for improving the poor water solubility of these compounds. For such purpose both the natural ß-CD and one of FDA/EMA approved CDs for parenteral use (i.e. HP-ß-CD) have been employed. The solubility rank order observed was accounted for by thermal analysis (Differential Scanning Calorimetry) and FT-IR spectroscopy. The most promising compound was subjected to further NMR spectroscopic studies and molecular modelling simulations to verify the interactions between the guest molecule and the CD cavity. The assessment of the antibacterial activity of such compounds against selected Gram positive and Gram negative bacterial strains clearly showed that their antimicrobial effectiveness may, quite in all instances, be positively affected by complexation with ß-CD and HP-ß-CD. These results, which are in some ways in contrast with those already reported in the literature, are herein discussed on the basis of plausible mechanisms. Moreover, this investigation also reveals that the described methodology of complexing both lipophilic and hydrophilic antimicrobial agents with CDs may be an useful approach to enhance their effectiveness as well as a promising strategy to overcome even the microbial resistance problem.

Synthesis of new 2,6-prolylxylidide analogues of tocainide as stereoselective blockers of voltage-gated Na(+) channels with increased potency and improved use-dependent activity.

A series of tocainide chiral analogues were designed, synthesized, and evaluated in vitro, in pure enantiomeric form, as use-dependent blockers of skeletal muscle sodium channels to better understand the structural requirements responsible for the antimyotonic activity. The voltage clamp recordings showed a remarkable increase of both potency and use-dependent behavior with the analogue N-(2, 6-dimethylphenyl)-2-pyrrolidinecarboxamide (1a). In fact (R)-1a was 5-fold more potent than (R)-tocainide in producing the tonic block, i.e., the reduction of peak sodium current in resting conditions after application of the compound, but it was 21-fold more potent in condition of high frequency of stimulation (phasic block). Furthermore, as opposite to tocainide, this compound was also stereoselective, (S)-1a being 2-3-fold less potent than (R)-1a. The introduction in 1a of a methyl group in place of the hydrogen bonded to either the aminic nitrogen atom [N-(2, 6-dimethylphenyl)-1-methyl-2-pyrrolidinecarboxamide (2a)] or the amidic nitrogen atom [N-(2, 6-dimethylphenyl)-N-methyl-2-pyrrolidinecarboxamide (3a)] led unexpectedly to an inversion of stereoselectivity, the (S)-enantiomers being 3-fold more potent than the (R)-ones. The comparison between eutomers showed that (S)-2a and (S)-3a are almost equieffective to (R)-1a in producing a tonic block, the half-maximal concentrations being about 100 microM; however, the use-dependent behavior was remarkably decreased by the presence of the methyl group: i.e., the gain of potency observed at high frequency of stimulation amounted to 3 and 1.6 times for 2a and 3a, respectively. The replacement of both hydrogens bonded to the aminic and amidic nitrogen atoms resulted in N-(2,6-dimethylphenyl)-N, 1-dimethyl-2-pyrrolidinecarboxamide (4a) in which the (S)-isomer was still twice as potent as the (R)-one, but the absolute potency and mostly the use-dependent behavior were strongly reduced, showing therefore no clear advantages with respect to tocainide. The use-dependent behavior, which plays a pivotal role for antimyotonic activity, is strongly reduced by the presence of methyl groups on the nitrogen atoms, likely for modification of pK(a) and/or for constraint of molecular conformation.

Effects of mexiletine on ATP sensitive K+ channel of rat skeletal muscle fibres: a state dependent mechanism of action.

1. The effects of mexiletine were evaluated on the ATP-sensitive K+ channel (K(ATP)) of rat skeletal muscle fibres using patch clamp techniques. The effects of mexiletine were studied on macropatch currents 20 s (maximally activated), 8 min (early stage of rundown) and 15 min (late stage of rundown) after excision in the absence or in the presence of internal ADP (50-100 microM) or UDP (500 microM). In addition, the effects of mexiletine were tested on single channel. 2. In the absence of ADP and UDP, mexiletine inhibited the current through maximally activated channels with an IC50 of -5.58+/-0.3 M. Nucleoside diphosphates shifted the current versus mexiletine concentration relationship to the right on the log concentration axis. UDP (500 microM) was more efficacious than ADP (50-100 microM) in this effect. 3. At the early stage of rundown, the sensitivity of the channel to mexiletine was reduced and nucleoside diphosphates, particularly UDP, antagonized the effect of mexiletine. At the late stage of rundown, mexiletine did not affect the currents. 4. At the single channel level, 1 microM mexiletine reduced the mean burst duration by 63% and prolonged the arithmetic mean closed time intervals between the bursts of openings without altering the open time and closed time distributions. Mexiletine did not affect the single channel conductance. 5. These results show that in skeletal muscle, mexiletine is a state-dependent K(ATP) channel inhibitor which either acts through the nucleotide binding site or a site allosterically coupled to it.

Increased hindrance on the chiral carbon atom of mexiletine enhances the block of rat skeletal muscle Na+ channels in a model of myotonia induced by ATX.

1 The antiarrhythmic drug mexiletine (Mex) is also used against myotonia. Searching for a more efficient drug, a new compound (Me5) was synthesized substituting the methyl group on the chiral carbon atom of Mex by an isopropyl group. Effects of Me5 on Na+ channels were compared to those of Mex in rat skeletal muscle fibres using the cell-attached patch clamp method. 2 Me5 (10 microM) reduced the maximal sodium current (INa) by 29.7+/-4.4 % (n=6) at a frequency of stimulation of 0.3 Hz and 65.7+/-4.4 % (n=6) at 1 Hz. At same concentration (10 microM), Mex was incapable of producing any effect (n=3). Me5 also shifted the steady-state inactivation curves by -7. 9+/-0.9 mV (n=6) at 0.3 Hz and -12.2+/-1.0 mV (n=6) at 1 Hz. 3 In the presence of sea anemone toxin II (ATX; 5 microM), INa decayed more slowly and no longer to zero, providing a model of sodium channel myotonia. The effects of Me5 on peak INa were similar whatever ATX was present or not. Interestingly, Me5 did not modify the INa decay time constant nor the steady-state INa to peak INa ratio. 4 Analysis of ATX-induced late Na+ channel activity shows that Me5 did not affect mean open times and single-channel conductance, thus excluding open channel block property. 5 These results indicate that increasing hindrance on the chiral atom of Mex increases drug potency on wild-type and ATX-induced noninactivating INa and that Me5 might improve the prophylaxis of myotonia.

Increased rigidity of the chiral centre of tocainide favours stereoselectivity and use-dependent block of skeletal muscle Na(+) channels enhancing the antimyotonic activity in vivo.

1. Searching for the structural requirements improving the potency and the stereoselectivity of Na(+) channel blockers as antimyotonic agents, new derivatives of tocainide, in which the chiral carbon atom is constrained in a rigid alpha-proline or pyrrolo-imidazolic cycle, were synthesized as pure enantiomers. 2. Their ability to block Na(+) currents, elicited from -100 to -20 mV at 0.3 Hz (tonic block) and 2-10 Hz (use-dependent block) frequencies, was investigated in vitro on single fibres of frog semitendinosus muscle using the vaseline-gap voltage-clamp method. 3. The alpha-proline derivative, To5, was 5 and 21 fold more potent than tocainide in producing tonic and 10 Hz-use-dependent block, respectively. Compared to To5, the presence of one methyl group on the aminic (To6) or amidic (To7) nitrogen atom decreased use-dependence by 2- and 6-times, respectively. When methylene moieties were present on both nitrogen atoms (To8), both tonic and use-dependent block were reduced. 4. Contrarily to tocainide, all proline derivatives were stereoselective in relation to an increased rigidity. A further increase in the molecular rigidity as in pyrrolo-imidazolic derivatives markedly decreased the drug potency with respect to tocainide. 5. Antimyotonic activity, evaluated as the shortening of the time of righting reflexes of myotonic adr/adr mice upon acute drug in vivo administration was 3 fold more effective for R-To5 than for R-Tocainide. 6. Thus, constraining the chiral centre of tocainide in alpha-proline cycle leads to more potent and stereoselective use-dependent Na(+) channel blockers with improved therapeutic potential.

Rapid sensory remapping in the adult human brain as inferred from phantom breast perception.

We provide evidence for a perceptual marker of neuroplasticity in female mastectomy patients who reported phantom breast perceptions. When tactile stimuli were delivered to dorso-thoracic, shoulder and pinna regions ipsilateral to the mastectomy, these patients (in some cases even 5 days after the operation) referred the stimuli to the amputated breast mainly to the nipple. The somatosensory representation of the stimulated regions is probably adjacent to the former representation of the amputated breast. These results suggest that input from stimulated regions of the skin can drive neurones originally driven by input from the amputated breast. The apparent functional relation between pinna and nipple might give clues to the mechanisms underlying referred sensations and pain.

Stereoselective effects of mexiletine enantiomers on sodium currents and excitability characteristics of adult skeletal muscle fibers.

The effects of the enantiomers of mexiletine were tested on sodium currents of frog skeletal muscle fibers recorded by means of the three vaseline gap voltage clamp method and compared with the effects produced by tocainide enantiomers. The R-(-) mexiletine produced a tonic block of the sodium current, elicited by single depolarizing test pulses from the holding potential of -100 mV to -20 mV, with an IC50 of 43.9 +/- 1 microM, whereas the corresponding S-(+) enantiomer produced the same effects at about twofold higher concentrations. A similar steroselectivity was observed with tocainide enantiomers, but at about 5 fold higher concentrations. Both the R-(-) and S-(+) enantiomers of mexiletine and tocainide produced a further use-dependent block of sodium currents when the test pulse was applied repetitively at a frequency of 2 Hz. The use dependent behavior led to a significant lowering of the IC50 values with respect to the tonic block but the eudismic ratios ([IC50S-(+)]/[IC50R(-)]) and the relative potency between mexiletine and tocainide were maintained. All the tested compounds produced a left shift of the steady state inactivation curves (h infinity), suggesting a high-affinity interaction with the inactivated sodium channels. Again a stronger potency of R-(-) vs. S-(+) enantiomers and of mexiletine vs. tocainide was observed. The excitability characteristics recorded from the semitendinosus muscle by the two microelectrode technique were modified by the tested drugs in agreement with their ability to block sodium current. Thus a concentration-related increase in the threshold current required to elicit an action potential as observed along with a decrease in the amplitude and a shortening of the latency of action potential and a decrease in the firing capability of the membrane. Again the R-(-) isomers were more potent than the S-(+) ones and mexiletine was more effective than tocainide. These data corroborate the presence of a stereospecific site for these drugs on adult skeletal muscle sodium channels. The constant eudismic ratios between the enantiomers during both tonic and use-dependent block suggest that the increase in the apparent affinity of the receptor during state-dependent conformational changes of the channel does not enhance its stereospecificity. The decrease in effective concentration upon high frequency stimulation supports the potential usefulness of low doses of R-(-) mexiletine in the treatment of the abnormal hyperexcitability of the myotonic muscles, with a likely reduction of unwanted side effects.

Inhibition of frog skeletal muscle sodium channels by newly synthesized chiral derivatives of mexiletine and tocainide.

To search for potent use-dependent blockers of skeletal muscle sodium channels as potential antimyotonic agents, the actions of newly synthesized chiral analogs of mexiletine and tocainide were tested in vitro on sodium currents of single fibers of frog semitendinosus muscle by vaseline-gap voltage clamp method. The effect of each drug on the maximal peak Na+ transient (I(Na) max) was evaluated as both tonic and use-dependent block by using infrequent depolarizing stimulation and trains of pulses at 2-10 Hz frequency, respectively. The mexiletine analog 3-(2,6-dimethylphenoxy)-2-methylpropanamine (Me2), having an increased distance between the phenyl and the amino groups, was less potent than mexiletine in producing a tonic block but produced a remarkable use-dependent block. In fact, the half-maximal concentration (IC50) for tonic block of S(-)-Me2 was 108 microM vs. 54.5 microM of R(-)-mexiletine, but the IC50 was 6.2 times lowered by the 10 Hz stimulation with respect to the 2.4 fold decrease observed with mexiletine. The R(-)-mexiletine and the S(-)-Me2 were about twofold more potent than the corresponding enantiomers in producing a tonic block, but the stereoselectivity attenuated during use-dependent blockade. The more lipophilic 2-(4-chloro-2-methylphenoxy)-1-phenylethylamine (Me1), presently available as raceme, produced a potent and irreversible tonic block of the sodium currents with an IC50 of 29 microM, but had a less pronounced use-dependent inhibition, with a 1.9 fold decrease of the IC50 at 10 Hz. The R(-) isomer of 2',6'-valinoxylidide (To1), a tocainide derivative with an increased hindrance on the chiral carbon atom, was twofold (IC50 = 209 microM) and tenfold (IC50 = 27.4 microM) more potent than R(-)-tocainide in tonic and use-dependent block, respectively. Tocainide was almost devoid of stereoselectivity, whereas the eudismic ratio of To1 [(IC50 S(+)-To1/IC50 R(-)-To1] was 1.7. As for mexiletine and Me2, the stereoselectivity of To1 was the weaker the higher the frequency of stimulation. The cyclic pyrrolo-imidazolonic tocainide analog To2 produced a small tonic block at 500 microM, and 1 min stimulation at 10 Hz was needed to show up a 50% block of I(Na) max. All the compounds produced a left-shift of the steady-state inactivation curve correlated positively with the extent of use-dependent inhibition, with the exception of the cyclic To2 that acted as an open-channel blocker. The highly use-dependent blockers Me2 and To1 might be promising drugs to solve high frequency discharges of action potentials typical of myotonic muscles. Concomitantly the high potency of Me1 and the open-channel block exerted by To2 can represent important features to get selective blockers for skeletal muscle sodium channels.

Spectrophotometric and chromatographic detection of Karwinskia humboldtiana (tullidora) toxin in rat serum after tullidora ingestion.

The absorbance spectrum of tullidinol, a tullidora (Karwinskia humboldtiana) toxin, showed peaks at 260 and 410 nm when dissolved in ethanol; the second peak was linearly related to toxin concentration. Silica gel thin layer chromatograms of tullidinol solutions showed a single, yellow spot with an Rf of 0.76. A single dose of tullidora fruit homogenate was orally given to male Wistar rats; the absorbance spectrum of serum from tullidora-treated rats showed peaks at 300 nm and at 410 nm; the second peak was absent in serum from control rats. No spots were detected in chromatograms of normal serum, but a yellow spot with the same Rf as that of tullidinol was found in the serum of tullidora-treated rats. We conclude that tullidinol was detected in the serum of treated animals and that the methods we used for its detection may also help to diagnose accidental tullidora poisoning in cattle and human beings.