Ultrasound-enhanced mass transfer during single-bubble diffusive growth

Ultrasound is known to enhance surface bubble growth and removal in catalytic and microfluidic applications, yet the contributions of rectified diffusion and microstreaming phenomena towards mass transfer remain unclear. We quantify the effect of ultrasound on the diffusive growth of a single spherical CO$_2$ bubble growing on a substrate in supersaturated water. The time dependent bubble size, shape, oscillation amplitude and microstreaming flow field are resolved. We show and explain how ultrasound can enhance the diffusive growth of surface bubbles by up to two orders of magnitude during volumetric resonance. The proximity of the wall forces the bubble to oscillate non-spherically, thereby generating vigorous streaming during resonance that results in convection-dominated growth.Comment: Accepted in Phys. Rev. Fluid

Diffusive growth of successive bubbles in confinement

We analyse how a succession of single bubbles extracts dissolved gas from a liquid solution while they grow and detach in a confinement induced by the presence of lateral walls. Like bubbles growing on a liquid-immersed unconfined surface, these bubbles absorb the dissolved gas in the liquid around them and hence deplete their surroundings. The supersaturation level, ζ , stands out as the main parameter which determines the diffusive bubble dynamics, both in the confined and unconfined scenarios. For slightly supersaturated solutions, the bubble evolution is rather similar for the two cases. We observe nonetheless mildly higher concentration gradients within confinement due to the lack of gas renewal. This causes a slightly enhancement of density-driven convection as compared to the unconfined case, which results in a higher mass transfer rate towards the bubble and a somewhat faster long-term gas depletion. For larger supersaturations, the onset of natural convection is inhibited by the presence of the confinement. Confinement promotes the gas mixing within the cavity as well. These two effects combined result in a slower depletion in the confined case as compared to the unconfined one. The two opposite behaviours for small and large supersaturation suggest that there must be a transition in between the two scenarios. The cross-over has been estimated to occur at ζ≈0.17 . We propose a modified depletion model which accounts for the confined configuration and its effect on the effective area through which gas diffuses into the bubble. The model can accurately describe the experimental results and sheds more light on the origin of the depletion effect due to the successive bubble growth

Gas depletion through single gas bubble diffusive growth and its effect on subsequent bubbles

When a gas bubble grows by diffusion in a gas–liquid solution, it affects the distribution of gas in its surroundings. If the density of the solution is sensitive to the local amount of dissolved gas, there is the potential for the onset of natural convection, which will affect the bubble growth rate. The experimental study of the successive quasi-static growth of many bubbles from the same nucleation site described in this paper illustrates some consequences of this effect. The enhanced growth due to convection causes a local depletion of dissolved gas in the neighbourhood of each bubble beyond that due to pure diffusion. The quantitative data of sequential bubble growth provided in the paper show that the radius-versus-time curves of subsequent bubbles differ from each other due to this phenomenon. A simplified model accounting for the local depletion is able to collapse the experimental curves and to predict the progressively increasing bubble detachment times

E-cadherin expression is associated with somatostatin analogue response in acromegaly

Acromegaly is a rare disease resulting from hypersecretion of growth hormone (GH) and insulin‐like growth factor 1 (IGF1) typically caused by pituitary adenomas, which is associated with increased mortality and morbidity. Somatostatin analogues (SSAs) represent the primary medical therapy for acromegaly and are currently used as first‐line treatment or as second‐line therapy after unsuccessful pituitary surgery. However, a considerable proportion of patients do not adequately respond to SSAs treatment, and therefore, there is an urgent need to identify biomarkers predictors of response to SSAs. The aim of this study was to examine E‐cadherin expression by immunohistochemistry in fifty‐five GH‐producing pituitary tumours and determine the potential association with response to SSAs as well as other clinical and histopathological features. Acromegaly patients with tumours expressing low E‐cadherin levels exhibit a worse response to SSAs. E‐cadherin levels are associated with GH‐producing tumour histological subtypes. Our results indicate that the immunohistochemical detection of E‐cadherin might be useful in categorizing acromegaly patients based on the response to SSAs.ISCIII‐Subdirección General de Evaluación y Fomento de la Investigación PI13/02043 PI16/00175FEDER PI13/02043 PI16/00175Junta de Andalucía A‐0023‐2015 A‐0003‐2016 CTS‐1406 BIO‐0139Andalusian Ministry of Health C‐0015‐2014CIBERobn PI13/ 02043 PI16/0017

Transition to convection in single bubble diffusive growth

We investigate the growth of gas bubbles in a water solution at rest with a supersaturation level that is generally associated with diffusive mass transfer. For CO2 bubbles, it has been previously observed that, after some time of growing in a diffusive regime, a density-driven convective flow enhances the mass transfer rate into the bubble. This is due to the lower density of the gas-depleted liquid which surrounds the bubble. In this work, we report on experiments with different supersaturation values, measuring the time t(conv) it takes for convection to dominate over the diffusion-driven growth. We demonstrate that by considering buoyancy and drag forces on the depleted liquid around the bubble, we can satisfactorily predict the transition time. In fact, our analysis shows that this onset does not only depend on the supersaturation, but also on the absolute pressure, which we corroborate in experiments. Subsequently, we study how the depletion caused by the growth of successive single bubbles influences the onset of convection. Finally, we study the convection onset around diffusively growing nitrogen N-2 bubbles. As N-2 is much less soluble in water, the growth takes much longer. However, after waiting long enough and consistent with our theory, convection still occurs as for any gas-liquid combination, provided that the density of the solution sufficiently changes with the gas concentration

The nucleation rate of single O2 nanobubble at Pt nanoelectrodes

Nanobubble nucleation is a problem that affects efficiency in electrocatalytic reactions since those bubbles can block the surface of the catalytic sites. In this article, we focus on the nucleation rate of O2 nanobubbles resulting from the electrooxidation of H2O2 at Pt disk nanoelectrodes. Bubbles form almost instantaneously when a critical peak current, inbp, is applied, but for lower currents, bubble nucleation is a stochastic process in which the nucleation (induction) time, tind, dramatically decreases as the applied current approaches inbp, a consequence of the local supersaturation level, ζ, increasing at high currents. Here, by applying different currents below inbp, nanobubbles take some time to nucleate and block the surface of the Pt electrode at which the reaction occurs, providing a means to measure the stochastic tind. We study in detail the different conditions in which nanobubbles appear, concluding that the electrode surface needs to be preconditioned to achieve reproducible results. We also measure the activation energy for bubble nucleation, Ea, which varies in the range from (6 to 30)kT, and assuming a spherically cap-shaped nanobubble nucleus, we determine the footprint diameter L = 8–15 nm, the contact angle to the electrode surface θ = 135–155°, and the number of O2 molecules contained in the nucleus (50 to 900 molecules)

Gas bubble evolution on microstructured silicon substrates

The formation, growth and detachment of gas bubbles on electrodes are omnipresent in electrolysis and other gas-producing chemical processes. To better understand their role in the mass transfer efficiency, we perform experiments involving successive bubble nucleations from a predefined nucleation site which consists of a superhydrophobic pit on top of a micromachined pillar. The experiments on bubble nucleation at these spots permit the comparison of mass transfer phenomena connected to electrolytically generated H$_2$ bubbles with the better-understood evolution of CO$_2$ bubbles in pressure-controlled supersaturated solutions. In both cases, bubbles grow in a diffusion-dominated regime. For CO$_2$ bubbles, it is found that the growth rate coefficient of subsequent bubbles always decreases due to the effect of gas depletion. In contrast, during constant current electrolysis, the bubble growth rates are affected by the evolution of a boundary layer of dissolved H$_2$ gas near the flat electrode which competes with gas depletion. This competition results in three distinct regimes. Initially, the bubble growth slows down with each new bubble in the succession due to the dominant depletion of the newly-formed concentration boundary layer. In later stages, the growth rate increases due to a local increase of gas supersaturation caused by the continuous gas production and finally levels off to an approximate steady growth rate. The gas transport efficiency associated with the electrolytic bubble succession follows a similar trend in time. Finally, for both H$_2$ and CO$_2$ bubbles, detachment mostly occurs at smaller radii than theory predicts and at a surprisingly wide spread of sizes. A number of explanations are proposed, but the ultimate origin of the spreading of the results remains elusive

Molecular analysis of prolactinoma formation in Pten-deficient mice.

Pituitary tumors are abnormal masses developed in the pituitary gland. Although they are generally benign, between 40-50% of pituitary adenomas cannot be removed by surgery alone due to local invasion. Moreover, they are associated with hormonal dysregulation. Prolactinoma is the most common type (50-60%), followed by somatotropic cell adenoma (10-15%), corticotropic cell adenoma (5-10%) and finally thyrotropinoma (less than 1%) (Cano González et al., 2015).Previous descriptive studies have suggested a possible role for the PI3K/AKT/mTOR signaling pathway in the formation of pituitary adenomas. In this study, we used genetic mouse models to assess the oncogenic capacity of this signaling pathway in the pituitary. For this purpose, conditional knockout mice have been generated in which the Pten gene is inactivated specially in the pituitary, indirectly causing the AKT overexpression. To accomplish this, a HesX1-Cre mouse line, whose expression is controlled by a pituitary-specific promoter and which is present in very early stages of embryonic development (Rizzoti, 2015) were crossed with mouse lines in which the Pten gene is floxed by two LoxP sequences.We have analyzed the pituitary in Pten-deficient mice at three different ages: 12, 6 and 1 month of age, comparing genotype and sex. At young ages, Pten-deficient mice show pituitary hyperplasia. After 12 months of age, Pten-deficient mice develop pituitary tumors. However, this is only observed in mutant female mice, whereas male mice simply display pituitary hyperplasia. Data from immunohistochesmistry, immunofluorescence, and blood hormones show that Pten-deficient mice developed prolactinomas. These tumors show high rates of cell proliferation as well as alterations in the expression levels of several cell cycle inhibitors

A Somatostatin Receptor Subtype-3 (SST3) Peptide Agonist Shows Antitumor Effects in Experimental Models of Nonfunctioning Pituitary Tumors

[Purpose] Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST2 and SST5. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST2. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST3-agonists and characterize their effects on experimental NFPT models.[Experimental Design] Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST3-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST3-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST3-agonist. [Results] We successfully identified the first SST3-agonist peptides. SST3-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro, and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST3-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST3-agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs. [Conclusions] This study demonstrates that SST3-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST3, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.This work has been funded by the following grants: Junta de Andalucía [CTS-1406 (R.M. Luque), BIO-0139 (J.P. Castaño)]; Ministerio de Ciencia, Innovación y Universidades [BFU2016-80360-R (J.P. Castaño)] and Instituto de Salud Carlos III, co-funded by European Union [ERDF/ESF, “Investing in your future”: PI16/00264 (R.M. Luque), CP15/00156 (M.D. Gahete) and CIBERobn]. CIBER is an initiative of Instituto de Salud Carlos III

Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors

Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defective (HRD) cancers rely on oxidative metabolism to supply NAD+ and ATP for poly(ADP-ribose) polymerase (PARP)-dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD+ concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient-derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors