The Effect of a DNA Repair Gene on Cellular Invasiveness: Xrcc3 Over-Expression in Breast Cancer Cells

Over-expression of DNA repair genes has been associated with resistance to radiation and DNA-damage induced by chemotherapeutic agents such as cisplatin. More recently, based on the analysis of genome expression profiling, it was proposed that over-expression of DNA repair genes enhances the invasive behaviour of tumour cells. In this study we present experimental evidence utilizing functional assays to test this hypothesis. We assessed the effect of the DNA repair proteins known as X-ray complementing protein 3 (XRCC3) and RAD51, to the invasive behavior of the MCF-7 luminal epithelial-like and BT20 basal-like triple negative human breast cancer cell lines. We report that stable or transient over-expression of XRCC3 but not RAD51 increased invasiveness in both cell lines in vitro. Moreover, XRCC3 over-expressing MCF-7 cells also showed a higher tumorigenesis in vivo and this phenotype was associated with increased activity of the metalloproteinase MMP-9 and the expression of known modulators of cell-cell adhesion and metastasis such as CD44, ID-1, DDR1 and TFF1. Our results suggest that in addition to its' role in facilitating repair of DNA damage, XRCC3 affects invasiveness of breast cancer cell lines and the expression of genes associated with cell adhesion and invasion

Upregulation of mGlu2 receptors via NF-kB p65 acetylation is involved in the proneurogenic and antidepressant effects of acetyl-L-carnitine

Acetyl-L-carnitine (ALC) is a naturally occurring molecule with an important role in cellular bioenergetics and as donor of acetyl groups to proteins, including NF-kappa B p65. In humans, exogenously administered ALC has been shown to be effective in mood disturbances, with a good tolerability profile. No current information is available on the antidepressant effect of ALC in animal models of depression and on the putative mechanism involved in such effect. Here we report that ALC is a proneurogenic molecule, whose effect on neuronal differentiation of adult hippocampal neural progenitors is independent of its neuroprotective activity. The in vitro proneurogenic effects of ALC appear to be mediated by activation of the NF-kappa B pathway, and in particular by p65 acetylation, and subsequent NF-kappa B-mediated upregulation of metabotropic glutamate receptor 2 (mGlu2) expression. When tested in vivo, chronic ALC treatment could revert depressive-like behavior caused by unpredictable chronic mild stress, a rodent model of depression with high face validity and predictivity, and its behavioral effect correlated with upregulated expression of mGlu2 receptor in hippocampi of stressed mice. Moreover, chronic, but not acute or subchronic, drug treatment significantly increased adult born neurons in hippocampi of stressed and unstressed mice. We now propose that this mechanism could be potentially involved in the antidepressant effect of ALC in humans. These results are potentially relevant from a clinical perspective, as for its high tolerability profile ALC may be ideally employed in patient subpopulations who are sensitive to the side effects associated with classical antidepressant

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Thickness measurements using photonic modes in monochromated electron energy-loss spectroscopy

Characteristic energies of photonic modes are a sensitive function of a nanostructures' geometrical parameters. In the case of translationally invariant planar waveguides, the eigen-energies reside in the infrared to ultraviolet parts of the optical spectrum and they sensitively depend on the thickness of the waveguide. Using swift electrons and the inherent Cherenkov radiation in dielectrics, the energies of such photonic states can be effectively probed via monochromated electron energy-loss spectroscopy (EELS). Here, by exploiting the strong photonic signals in EELS with 200 keV electrons, we correlate the energies of waveguide peaks in the 0.5-3.5 eV range with planar thicknesses of the samples. This procedure enables us to measure the thicknesses of cross-sectional transmission electron microscopy samples over a 1-500 nm range and with best-case accuracies below \ub12%. The measurements are absolute with the only requirement being the optical dielectric function of the material. Furthermore, we provide empirical formulation for rapid and direct thickness estimations for a 50-500 nm range. We demonstrate the methodology for two semiconducting materials, silicon and gallium arsenide, and discuss how it can be applied to other dielectrics that produce strong optical fingerprints in EELS. The asymptotic form of the loss function for two-dimensional materials is also discussed.Peer reviewed: YesNRC publication: Ye

In situ controlled modification of the helium density in single helium-filled nanobubbles

We demonstrate that the helium density and corresponding pressure can be modified in single nano-scale bubbles embedded in semiconductors by using the electron beam of a scanning transmission electron microscope as a multifunctional probe: the measurement probe for imaging and chemical analysis and the irradiation source to modify concomitantly the pressure in a controllable way by fine tuning of the electron beam parameters. The control of the detrapping rate is achieved by varying the experimental conditions. The underlying physical mechanisms are discussed; our experimental observations suggest that the helium detrapping from bubbles could be interpreted in terms of direct ballistic collisions, leading to the ejection of the helium atoms from the bubble.Peer reviewed: YesNRC publication: Ye

Structure and Mineralogy of Hydrophilic and Biwettable Sub-2 µm Clay Aggregates in Oil Sands Bitumen Froth

A primary concern of commercial mined oil sands operations is the extent to which one can minimize the content of water and solids contaminants in the solvent-diluted bitumen products resulting from the bitumen production processes. During bitumen production, particles of about 2 µm or less may be responsible for the stabilization of water-in-bitumen emulsions that form during aqueous extraction of bitumen and purification of bitumen froth subsequently during the froth treatment processes, thus leading to the presence of those contaminants in solvent-diluted bitumen products. In this study, we separate and analyze sub-2 µm clay solids isolated from typical bitumen froth fed to a froth treatment plant at a commercial mined oil sands operation. Analytical transmission electron microscopy (TEM) with spatially-resolved energy-dispersive X-ray spectroscopy (EDX) and electron energy-loss spectroscopy (EELS) demonstrate key differences in morphology and composition between sub-2 µm clay aggregates with two distinct wettability characteristics: hydrophilic vs. biwettable particle surfaces. In particular, clay platelets with <200 nm lateral dimensions and thicknesses of a few atomic layers, which are intermixed within coarser sub-2 µm clay aggregates, are found to confer clear differences in morphological characteristics and wettability behaviors to the sub-2 µm clay aggregates. The <200 nm clay platelets found within sub-2 µm biwettable clays tend to arrange themselves with random orientations, whereas <200 nm clay platelets within sub-2 µm hydrophilic clays typically form well-ordered face-to-face stacks. Moreover, in biwettable sub-2 µm clay aggregates, <200 nm clay platelets often cover the surfaces of ~1–2 µm sized mineral particles, whereas similarly sized mineral particles in hydrophilic sub-2 µm clay aggregates, in contrast, generally have exposed surfaces without clay platelet coverage. These biwettable vs. hydrophilic behaviors are attributed to a difference in the surface characteristics of the <200 nm clay platelets caused by toluene-unextractable organic carbon coatings. Nanometer-scale carbon mapping reveals an inhomogeneous toluene-unextractable organic carbon coating on the surfaces of <200 nm platelets in biwettable clays. In contrast, hydrophilic clays have a significantly lower amount of toluene-unextractable organic carbon, which tends to be concentrated at steps or near metal oxide nanoparticles on clay particle surfaces. Mixing surface-active organic species, such as asphaltene, resin, or carboxylic organic acids of various types with inorganic solids can lead to a dramatically enhanced emulsion stability. Consequently, understanding the origin and characteristics of sub-2 µm clay solids in bitumen froth is important to (i) clarify their potential role in the formation of stable water-in-oil emulsions during bitumen production and (ii) improve froth treatment process performance to further reduce contaminant solids in solvent-diluted bitumen products. We discuss the implications of our results from these two perspectives