Capillary condensation under atomic-scale confinement.

Capillary condensation of water is ubiquitous in nature and technology. It routinely occurs in granular and porous media, can strongly alter such properties as adhesion, lubrication, friction and corrosion, and is important in many processes used by microelectronics, pharmaceutical, food and other industries1-4. The century-old Kelvin equation5 is frequently used to describe condensation phenomena and has been shown to hold well for liquid menisci with diameters as small as several nanometres1-4,6-14. For even smaller capillaries that are involved in condensation under ambient humidity and so of particular practical interest, the Kelvin equation is expected to break down because the required confinement becomes comparable to the size of water molecules1-22. Here we use van der Waals assembly of two-dimensional crystals to create atomic-scale capillaries and study condensation within them. Our smallest capillaries are less than four ångströms in height and can accommodate just a monolayer of water. Surprisingly, even at this scale, we find that the macroscopic Kelvin equation using the characteristics of bulk water describes the condensation transition accurately in strongly hydrophilic (mica) capillaries and remains qualitatively valid for weakly hydrophilic (graphite) ones. We show that this agreement is fortuitous and can be attributed to elastic deformation of capillary walls23-25, which suppresses the giant oscillatory behaviour expected from the commensurability between the atomic-scale capillaries and water molecules20,21. Our work provides a basis for an improved understanding of capillary effects at the smallest scale possible, which is important in many realistic situations.

Molecular transport through capillaries made with atomic-scale precision.

Nanometre-scale pores and capillaries have long been studied because of their importance in many natural phenomena and their use in numerous applications. A more recent development is the ability to fabricate artificial capillaries with nanometre dimensions, which has enabled new research on molecular transport and led to the emergence of nanofluidics. But surface roughness in particular makes it challenging to produce capillaries with precisely controlled dimensions at this spatial scale. Here we report the fabrication of narrow and smooth capillaries through van der Waals assembly, with atomically flat sheets at the top and bottom separated by spacers made of two-dimensional crystals with a precisely controlled number of layers. We use graphene and its multilayers as archetypal two-dimensional materials to demonstrate this technology, which produces structures that can be viewed as if individual atomic planes had been removed from a bulk crystal to leave behind flat voids of a height chosen with atomic-scale precision. Water transport through the channels, ranging in height from one to several dozen atomic planes, is characterized by unexpectedly fast flow (up to 1 metre per second) that we attribute to high capillary pressures (about 1,000 bar) and large slip lengths. For channels that accommodate only a few layers of water, the flow exhibits a marked enhancement that we associate with an increased structural order in nanoconfined water. Our work opens up an avenue to making capillaries and cavities with sizes tunable to ångström precision, and with permeation properties further controlled through a wide choice of atomically flat materials available for channel walls.

Rilpivirine plus cobicistat-boosted darunavir as a two-drug switch regimen in HIV-infected, virologically suppressed subjects on steady standard three-drug therapy: a randomized, controlled, non-inferiority trial (PROBE 2).

BACKGROUND: We explored the combination of rilpivirine plus cobicistat-boosted darunavir [a two-drug regimen (2DR)] when switching from standard triple combined ART. METHODS: In this randomized, open-label, non-inferiority trial, participants had an HIV-RNA <50 copies/mL on a stable (>6 months) three-drug regimen. The primary endpoint was proportion with HIV-RNA <50 copies/mL at Week 24 (snapshot algorithm), with a -12% non-inferiority margin. ClinicalTrials.gov: NCT04064632. RESULTS: One hundred and sixty patients were allocated (1:1) to 2DR or to continue current ART (CAR). At Week 24, 72 (90.0%) of participants with 2DR and 75 (93.8%) with CAR maintained HIV-RNA <50 copies/mL [difference -3.75% (95% CI = -11.63 to 5.63)], confirming non-inferiority. Non-inferiority was confirmed considering an HIV-RNA >50 copies/mL (0% for 2DR; 3.7% for CAR; 95% CI = -0.4 to 7.9). Four patients reported adverse events not leading to treatment discontinuation (one patient in the 2DR group and three patients in the CAR group); eight subjects discontinued therapy in the 2DR group and three in the CAR group. With 2DR, lipid serum concentrations increased, but differences were statistically significant only for tenofovir disoproxil fumarate-containing CAR and in 2DR patients receiving a pre-switch regimen including tenofovir disoproxil fumarate. Median bone stiffness decreased in the CAR group from 86.1 g/cm2 (IQR = 74-98) to 83.2 g/cm2 (IQR = 74-97) and increased in the 2DR group from 84.9 g/cm2 (IQR = 74-103) to 85.5 g/cm2 (IQR = 74-101). The reduction within the CAR group was significant (P = 0.043). CONCLUSIONS: Once-daily rilpivirine plus cobicistat-boosted darunavir is an effective 2DR that combines a high virological efficacy with a potential to avoid major NRTI toxicities.

Anatomical variations of the median nerve and of the vascular-nervous structures at the wrist.

Three cases of anatomical variation of the median nerve at the wrist found during our surgical activity led us to take the opportunity to expose anatomical variations by reviewing already published reviews. Consequently, on the basis of anatomical studies, clinical reports and imaging, as a result of careful examination of the published literature, it has been observed that the interventions in such anatomical area must take into account these variations. In particular, the most performed procedure is the lysis of the transverse carpal ligament (TCL), which is not free from complications. In our opinion it is therefore necessary, in order to avoid the complications of the nervous, vascular and tendinous sections, to use some specific technical procedures.

Nanoscale dielectric microscopy of non-planar samples by lift-mode electrostatic force microscopy.

Lift-mode electrostatic force microscopy (EFM) is one of the most convenient imaging modes to study the local dielectric properties of non-planar samples. Here we present the quantitative analysis of this imaging mode. We introduce a method to quantify and subtract the topographic crosstalk from the lift-mode EFM images, and a 3D numerical approach that allows for extracting the local dielectric constant with nanoscale spatial resolution free from topographic artifacts. We demonstrate this procedure by measuring the dielectric properties of micropatterned SiO2 pillars and of single bacteria cells, thus illustrating the wide applicability of our approach from materials science to biology.

Age-related ultrastructural and monoamine oxidase changes in the rat optic nerve.

The aim of this paper is to study the morphology and the distribution of the monoamine oxidase enzymatic system in the optic nerve of 4 month-old Wistar (young) and 28 month-old Wistar (old) rats. The optic nerve was harvested from 20 young and old rats. The segment of optic nerve was divided longitudinally into two pieces, each 0.1 mm in length. The first piece was used for transmission electron microscopy. The second piece was stained with histochemical reaction for monoamine oxidase. The agerelated changes in the optic nerve of rats include micro-anatomical details, ultrastructure and monoamine oxidase histochemical staining. A strong decrease of the thin nerve fibers and a swelling of the thick ones can be observed in optic nerve fibers of old rats. Increased monoamine oxidase histochemical staining of the optic nerve of aged rats is well demonstrated. The increase of meningeal shealth and the decrease of thin nerve fibers of the optic nerve in old rats are well documented. Morphological, ultrastructural and histochemical changes observed in optic nerve fibers of the old rats show a close relation with aging.

Finite-size effects and analytical modeling of electrostatic force microscopy applied to dielectric films.

A numerical analysis of the polarization force between a sharp conducting probe and a dielectric film of finite lateral dimensions on a metallic substrate is presented with the double objective of (i) determining the conditions under which the film can be approximated by a laterally infinite film and (ii) proposing an analytical model valid in this limit. We show that, for a given dielectric film, the critical diameter above which the film can be modeled as laterally infinite depends not only on the probe geometry, as expected, but mainly on the film thickness. In particular, for films with intermediate to large thicknesses (>100 nm), the critical diameter is nearly independent from the probe geometry and essentially depends on the film thickness and dielectric constant following a relatively simple phenomenological expression. For films that can be considered as laterally infinite, we propose a generalized analytical model valid in the thin-ultrathin limit (<20-50 nm) that reproduces the numerical calculations and the experimental data. Present results provide a general framework under which accurate quantification of electrostatic force microscopy measurements on dielectric films on metallic substrates can be achieved.

Quantitative electrostatic force microscopy with sharp silicon tips.

Electrostatic force microscopy (EFM) probes are typically coated in either metal (radius ∼ 30 nm) or highly-doped diamond (radius ∼ 100 nm). Highly-doped silicon probes, which offer a sharpened and stable tip apex (radius ∼ 1-10 nm) and are usually used only in standard atomic force microscopy, have been recently shown to allow enhanced lateral resolution in quantitative EFM and its application for dielectric constant measurement. Here we present the theoretical modelling required to quantitatively interpret the electrostatic force between these sharpened tips and samples. In contrast to a sphere-capped cone geometry used to describe metal/diamond-coated tips, modelling a sharpened silicon tip requires a geometry comprised of a cone with two different angles. Theoretical results are supported by experimental measurements of metallic substrates and ∼10 nm radius dielectric nanoparticles. This work is equally applicable to EFM and other electrical scanned probe techniques, where it allows quantifying electrical properties of nanomaterials and 3D nano-objects with higher resolution.

Calibrated complex impedance and permittivity measurements with scanning microwave microscopy.

We present a procedure for calibrated complex impedance measurements and dielectric quantification with scanning microwave microscopy. The calibration procedure works in situ directly on the substrate with the specimen of interest and does not require any specific calibration sample. In the workflow tip-sample approach curves are used to extract calibrated complex impedance values and to convert measured S11 reflection signals into sample capacitance and resistance images. The dielectric constant of thin dielectric SiO2 films were determined from the capacitance images and approach curves using appropriate electrical tip-sample models and the εr value extracted at f = 19.81 GHz is in good agreement with the nominal value of εr ∼ 4. The capacitive and resistive material properties of a doped Si semiconductor sample were studied at different doping densities and tip-sample bias voltages. Following a simple serial model the capacitance-voltage spectroscopy curves are clearly related to the semiconductor depletion zone while the resistivity is rising with falling dopant density from 20 Ω to 20 kΩ. The proposed procedure of calibrated complex impedance measurements is simple and fast and the accuracy of the results is not affected by varying stray capacitances. It works for nanoscale samples on either fully dielectric or highly conductive substrates at frequencies between 1 and 20 GHz.

Origin of dielectric polarization suppression in confined water from first principles.

It has long been known that the dielectric constant of confined water should be different from that in bulk. Recent experiments have shown that it is vanishingly small, however the origin of the phenomenon remains unclear. Here we used ab initio molecular dynamics simulations (AIMD) and AIMD-trained machine-learning potentials to understand water's structure and electronic properties underpinning this effect. For the graphene and hexagonal boron-nitride substrates considered, we find that it originates in the spontaneous anti-parallel alignment of the water dipoles in the first two water layers near the solid interface. The interfacial layers exhibit net ferroelectric ordering, resulting in an overall anti-ferroelectric arrangement of confined water. Together with constrained hydrogen-bonding orientations, this leads to much reduced out-of-plane polarization. Furthermore, we directly contrast AIMD and simple classical force-field simulations, revealing important differences. This work offers insight into a property of water that is critical in modulating surface forces, the electric-double-layer formation and molecular solvation, and shows a way to compute it.

Unraveling the parahormetic mechanism underlying the health-protecting effects of grapeseed procyanidins.

Proanthocyanidins (PACs), the predominant constituents within Grape Seed Extract (GSE), are intricate compounds composed of interconnected flavan-3-ol units. Renowned for their health-affirming properties, PACs offer a shield against a spectrum of inflammation associated diseases, such as diabetes, obesity, degenerations and possibly cancer. While monomeric and dimeric PACs undergo some absorption within the gastrointestinal tract, their larger oligomeric and polymeric counterparts are not bioavailable. However, higher molecular weight PACs engage with the colonic microbiota, fostering the production of bioavailable metabolites that undergo metabolic processes, culminating in the emergence of bioactive agents capable of modulating physiological processes. Within this investigation, a GSE enriched with polymeric PACs was employed to explore in detail their impact. Through comprehensive analysis, the present study unequivocally verified the gastrointestinal-mediated transformation of medium to high molecular weight polymeric PACs, thereby establishing the bioaccessibility of a principal catabolite termed 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (VL). Notably, our findings, encompassing cell biology, chemistry and proteomics, converge to the proposal of the notion of the capacity of VL to activate, upon oxidation to the corresponding quinone, the nuclear factor E2-related factor 2 (Nrf2) pathway-an intricate process that incites cellular defenses and mitigates stress-induced responses, such as a challenge brought by TNFα. This mechanistic paradigm seamlessly aligns with the concept of para-hormesis, ultimately orchestrating the resilience to stress and the preservation of cellular redox equilibrium and homeostasis as benchmarks of health.

Nanoscale measurement of the dielectric constant of supported lipid bilayers in aqueous solutions with electrostatic force microscopy.

We present what is, to our knowledge, the first experimental demonstration of dielectric constant measurement and quantification of supported lipid bilayers in electrolyte solutions with nanoscale spatial resolution. The dielectric constant was quantitatively reconstructed with finite element calculations by combining thickness information and local polarization forces which were measured using an electrostatic force microscope adapted to work in a liquid environment. Measurements of submicrometric dipalmitoylphosphatidylcholine lipid bilayer patches gave dielectric constants of ε(r) ~ 3, which are higher than the values typically reported for the hydrophobic part of lipid membranes (ε(r) ~ 2) and suggest a large contribution of the polar headgroup region to the dielectric response of the lipid bilayer. This work opens apparently new possibilities in the study of biomembrane electrostatics and other bioelectric phenomena.

Theory of amplitude modulated electrostatic force microscopy for dielectric measurements in liquids at MHz frequencies.

A theoretical analysis of amplitude modulated electrostatic force microscopy (AM-EFM) in liquid media at MHz frequencies, based on a simple tip-sample parallel plate model, is presented. The model qualitatively explains the main features of AM-EFM in liquid media and provides a simple explanation of how the measured electric forces are affected by: the frequency of the applied voltage, the tip-sample distance, the ionic concentration, the relative dielectric constant of the solution, and the relative dielectric constant and thickness of the sample. These results provide a simple framework for the design of AM-EFM measurements for localized dielectric characterization in liquid media.

Quantification of the dielectric constant of single non-spherical nanoparticles from polarization forces: eccentricity effects.

We analyze by means of finite-element numerical calculations the polarization force between a sharp conducting tip and a non-spherical uncharged dielectric nanoparticle with the objective of quantifying its dielectric constant from electrostatic force microscopy (EFM) measurements. We show that for an oblate spheroid nanoparticle of given height the strength of the polarization force acting on the tip depends linearly on the eccentricity, e, of the nanoparticle in the small eccentricity and low dielectric constant regimes (1 < e < 2 and 1 < ε(r) < 10), while for higher eccentricities (e > 2) the dependence is sub-linear and finally becomes independent of e for very large eccentricities (e > 30). These results imply that a precise account of the nanoparticle shape is required to quantify EFM data and obtain the dielectric constants of non-spherical dielectric nanoparticles. Experimental results obtained on polystyrene, silicon dioxide and aluminum oxide nanoparticles and on single viruses are used to illustrate the main findings.

Infections occurring in adult patients receiving mechanical circulatory support: the two-year experience of an Italian National Referral Tertiary Care Center.

OBJECTIVE: Infection during mechanical circulatory support is a frequent adverse complication. We analyzed infections occurring in this population in a national tertiary care center, and assessed the differences existing between the setting of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs). DESIGN, SETTING, AND PARTICIPANTS: An observational study was made of patients treated with ECMO or VAD in the San Raffaele Scientific Institute (Italy) between 2009 and 2011. INTERVENTIONS: None. RESULTS: Thirty-nine percent of the 46 patients with ECMO and 69% of the 15 patients with VAD developed infection. We observed a mortality rate of 36.1% during mechanical circulatory support and of 55.7% during the global hospitalization period. Although Gram-negative infections were predominant overall, patients with ECMO were more prone to develop Candida infection (29%), and patients with VAD tended to suffer Staphylococcus infection (18%). Patients with infection had longer ECMO support (p=0.03), VAD support (p=0.01), stay in the intensive care unit (p=0.002), and hospital admission (p=0.03) than patients without infection. Infection (regression coefficient=3.99, 95% CI 0.93-7.05, p=0.02), body mass index (regression coefficient=0.46, 95% CI 0.09-0.83, p=0.02), fungal infection (regression coefficient=4.96, 95% CI 1.42-8.44, p=0.009) and obesity (regression coefficient=10.47, 95% CI 1.77-19.17, p=0.02) were predictors of the duration of ECMO support. Stepwise logistic regression analysis showed the SOFA score at the time of implant (OR=12.33, 95% CI 1.15-132.36, p=0.04) and VAD (OR=1.27, 95% CI 1.04-1.56, p=0.02) to be associated with infection. CONCLUSIONS: Infection is a major challenge during ECMO and VAD support. Each mechanical circulatory support configuration is associated with specific pathogens; fungal infections play a major role.

Cytotoxic drugs for patients with breast cancer in the era of targeted treatment: back to the future?

BACKGROUND: Despite current trend of targeted therapy development, cytotoxic agents are a mainstay of treatment of patients with breast cancer. We reviewed recent advances in cytotoxic therapy for patients with metastatic breast cancer (MBC). MATERIALS AND METHODS: Medline searches were conducted for English language studies using the term 'MBC' and 'cytotoxic drugs'. The data search was restricted to the period 2000-2011. RESULTS: Several novel cytotoxic compounds, all microtubule inhibitors, have been approved for clinical use in MBC: (i) nab-paclitaxel, reported to improve tumour response and decrease hypersensitivity reactions in comparison with other taxanes; (ii) ixabepilone, shown to have clinical benefit in taxane- and anthracycline-resistant disease and (iii) eribulin, shown to improve overall survival in heavily pre-treated patients, when compared with best available standard treatment. Agents, such as larotaxel, vinflunine, trabectidin and formulations, including cationic liposomal paclitaxel or paclitaxel poliglumex, are currently under evaluation in phase II/III trials. CONCLUSION: Toxicity and chemotherapy resistance are still major limitations in the treatment of patients with MBC. Further research into new cytotoxic compounds is needed in order to maximise benefit, whilst minimising toxicity.

Sex-specific estimates of dispersal show female philopatry and male dispersal in a promiscuous amphibian, the alpine salamander (Salamandra atra).

Amphibians display wide variations in life-history traits and life cycles that should prove useful to explore the evolution of sex-biased dispersal, but quantitative data on sex-specific dispersal patterns are scarce. Here, we focused on Salamandra atra, an endemic alpine species showing peculiar life-history traits. Strictly terrestrial and viviparous, the species has a promiscuous mating system, and females reproduce only every 3 to 4 years. In the present study, we provide quantitative estimates of asymmetries in male vs. female dispersal using both field-based (mark-recapture) and genetic approaches (detection of sex-biased dispersal and estimates of migration rates based on the contrast in genetic structure across sexes and age classes). Our results revealed a high level of gene flow among populations, which stems exclusively from male dispersal. We hypothesize that philopatric females benefit from being familiar with their natal area for the acquisition and defence of an appropriate shelter, while male dispersal has been secondarily favoured by inbreeding avoidance. Together with other studies on amphibians, our results indicate that a species' mating system alone is a poor predictor of sex-linked differences in dispersal, in particular for promiscuous species. Further studies should focus more directly on the proximate forces that favour or limit dispersal to refine our understanding of the evolution of sex-biased dispersal in animals.

Local adaptation and matching habitat choice in female barn owls with respect to melanic coloration.

Local adaptation is a major mechanism underlying the maintenance of phenotypic variation in spatially heterogeneous environments. In the barn owl (Tyto alba), dark and pale reddish-pheomelanic individuals are adapted to conditions prevailing in northern and southern Europe, respectively. Using a long-term dataset from Central Europe, we report results consistent with the hypothesis that the different pheomelanic phenotypes are adapted to specific local conditions in females, but not in males. Compared to whitish females, reddish females bred in sites surrounded by more arable fields and less forests. Colour-dependent habitat choice was apparently beneficial. First, whitish females produced more fledglings when breeding in wooded areas, whereas reddish females when breeding in sites with more arable fields. Second, cross-fostering experiments showed that female nestlings grew wings more rapidly when both their foster and biological mothers were of similar colour. The latter result suggests that mothers should particularly produce daughters in environments that best match their own coloration. Accordingly, whiter females produced fewer daughters in territories with more arable fields. In conclusion, females displaying alternative melanic phenotypes bred in habitats providing them with the highest fitness benefits. Although small in magnitude, matching habitat selection and local adaptation may help maintain variation in pheomelanin coloration in the barn owl.

Role of autophagy inhibitors and inducers in modulating the toxicity of trimethyltin in neuronal cell cultures.

Trimethyltin (TMT) is a triorganotin compound which determines neurodegeneration of specific brain areas particularly damaging the limbic system. Earlier ultrastructural studies indicated the formation of autophagic vacuoles in neurons after TMT intoxication. However, no evaluation has been attempted to determine the role of the autophagic pathway in TMT neurotoxicity. To assess the contribution of autophagy to TMT-induced neuronal cell death, we checked the vulnerability of neuronal cultures to TMT after activation or inhibition of autophagy. Our results show that autophagy inhibitors (3-methyladenine and L-asparagine) greatly enhanced TMT neurotoxicity. Conversely, known activators of autophagy, such as lithium and rapamycin, displayed neuroprotection against this toxic compound. Due to its diverse targets, the action of lithium was complex. When lithium was administered according to a chronic treatment protocol (6 days pretreatment) it was able to rescue both hippocampal and cortical neurons from TMT (or from glutamate toxicity used as reference). This effect was accompanied by an increased phosphorylation of glycogen synthase kinase 3 which is a known target for lithium neuroprotection. If the pre-incubation time was reduced to 2 h (acute treatment protocol), lithium was still able to counteract TMT toxicity in hippocampal but not in cortical neurons. The neuroprotective effect of lithium acutely administered against TMT in hippocampal neurons can be completely reverted by an excess of inositol and is possibly related to the inactivation of inositol monophosphatase, a key regulator of autophagy. These data indicate that TMT neurotoxicity can be dramatically modified, at least in vitro, by lithium addition which seems to act through different mechanisms if acutely or chronically administered.

Quantifying the dielectric constant of thick insulators by electrostatic force microscopy: effects of the microscopic parts of the probe.

We present a systematic analysis of the effects that the microscopic parts of electrostatic force microscopy probes (the cone and cantilever) have on the electrostatic interaction between the tip apex and thick insulating substrates (thickness > 100 µm). We discuss how these effects can influence the measurement and quantification of the local dielectric constant of the substrates. We propose and experimentally validate a general methodology that takes into account the influence of the cone and the cantilever, thus enabling us to obtain very accurate values of the dielectric constants of thick insulators.