CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC.

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated CTLs. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC.

Infrared Signatures for Phase Identification in Hafnium Oxide Thin Films.

Phase identification in HfO2-based thin films is a prerequisite to understanding the mechanisms stabilizing the ferroelectric phase in these materials, which hold great promise in next-generation nonvolatile memory and computing technology. While grazing-incidence X-ray diffraction is commonly employed for this purpose, it has difficulty unambiguously differentiating between the ferroelectric phase and other metastable phases that may exist due to similarities in the d-spacings, their low intensities, and the overlapping of reflections. Infrared signatures provide an alternative route. However, their use in phase identification remains limited because phase control has overwhelmingly been accomplished via substituents, thereby convoluting infrared signatures between the substituents and the phase changes that they induce. Herein, we report the infrared optical responses of three undoped hafnium oxide films where annealing conditions have been used to create films consisting primarily of the ferroelectric polar orthorhombic Pca21, antipolar orthorhombic Pbca, and monoclinic P21/c phases, as was confirmed via transmission electron microscopy (TEM), UV-visible optical properties, and electrical property measurements. Vibrational signatures acquired from synchrotron nano-Fourier transform infrared spectroscopy (nano-FTIR) are shown to be capable of differentiating between the phases in a nondestructive, rapid, and nanoscale manner. The utility of nano-FTIR is illustrated for a film exhibiting an antiferroelectric polarization response. In this sample, it is proven that this behavior results from the Pbca phase rather than the often-cited tetragonal phase. By demonstrating that IR spectroscopy can unambiguously distinguish phases in this material, this work establishes a tool needed to isolate the factors dictating the ferroelectric phase stability in HfO2-based materials.

Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer.

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A with zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages toward an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon (IFN) response uniformly across models. The induction of an IFN response is partially due to the inhibition of Sox4 translation by zotatifin. A similar induction of IFN-stimulated genes was observed in breast cancer patient biopsies following zotatifin treatment. Surprisingly, zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened IFN response, resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for zotatifin, and provide a rationale for new combination regimens consisting of zotatifin and chemotherapy or immunotherapy as treatments for TNBC.

Targeting EIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer.

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A by Zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages towards an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that Zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon response uniformly across models. The induction of an interferon response is partially due to the inhibition of Sox4 translation by Zotatifin. A similar induction of interferon-stimulated genes was observed in breast cancer patient biopsies following Zotatifin treatment. Surprisingly, Zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened interferon response resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for Zotatifin, and provide a rationale for new combination regimens comprising Zotatifin and chemotherapy or immunotherapy as treatments for TNBC.

Ferroelectricity in hafnia controlled via surface electrochemical state.

Ferroelectricity in binary oxides including hafnia and zirconia has riveted the attention of the scientific community due to the highly unconventional physical mechanisms and the potential for the integration of these materials into semiconductor workflows. Over the last decade, it has been argued that behaviours such as wake-up phenomena and an extreme sensitivity to electrode and processing conditions suggest that ferroelectricity in these materials is strongly influenced by other factors, including electrochemical boundary conditions and strain. Here we argue that the properties of these materials emerge due to the interplay between the bulk competition between ferroelectric and structural instabilities, similar to that in classical antiferroelectrics, coupled with non-local screening mediated by the finite density of states at surfaces and internal interfaces. Via the decoupling of electrochemical and electrostatic controls, realized via environmental and ultra-high vacuum piezoresponse force microscopy, we show that these materials demonstrate a rich spectrum of ferroic behaviours including partial-pressure-induced and temperature-induced transitions between ferroelectric and antiferroelectric behaviours. These behaviours are consistent with an antiferroionic model and suggest strategies for hafnia-based device optimization.

Atomic-scale polarization switching in wurtzite ferroelectrics.

Ferroelectric wurtzites have the potential to revolutionize modern microelectronics because they are easily integrated with multiple mainstream semiconductor platforms. However, the electric fields required to reverse their polarization direction and unlock electronic and optical functions need substantial reduction for operational compatibility with complementary metal-oxide semiconductor (CMOS) electronics. To understand this process, we observed and quantified real-time polarization switching of a representative ferroelectric wurtzite (Al0.94B0.06N) at the atomic scale with scanning transmission electron microscopy. The analysis revealed a polarization reversal model in which puckered aluminum/boron nitride rings in the wurtzite basal planes gradually flatten and adopt a transient nonpolar geometry. Independent first-principles simulations reveal the details and energetics of the reversal process through an antipolar phase. This model and local mechanistic understanding are a critical initial step for property engineering efforts in this emerging material class.

Oxygen Adsorption on Polar and Non-Polar Zn:ZnO Heterostructures from First Principles.

Zn:ZnO nanostructures have been studied extensively due to their potential use in many applications, such as oxygen scavengers for food packaging applications. Under atmospheric conditions, ZnO grows on the surface of Zn via an oxidation process. The mechanisms governing Zn oxidation are still not fully understood, with classical oxidation models, such as the Cabrera Mott, underestimating the oxide thickness of Zn:ZnO core-shell structures. In this work, Ab initio DFT calculations were performed to assess the adsorption properties of oxygen molecules on Zn:ZnO heterostructures to help elucidate the mechanisms involved in the growth of a ZnO film on a Zn substrate. Results suggest that the charge transfer mechanism from the Zn:ZnO heterostructures to the adsorbed oxygen layer can be promoted by two different processes: the electronic doping of ZnO due to the formation of the Zn:ZnO interface and the excess surface charge due to the presence of dangling bonds on the as cleaved ZnO.

Accuracy of Local Polarization Measurements by Scanning Transmission Electron Microscopy.

Accurately determining local polarization at atomic resolution can unveil the mechanisms by which static and dynamical behaviors of the polarization occur, including domain wall motion, defect interaction, and switching mechanisms, advancing us toward the better control of polarized states in materials. In this work, we explore the potential of atomic-resolution scanning transmission electron microscopy to measure the projected local polarization at the unit cell length scale. ZnO and PbMg1/3Nb2/3O3 are selected as case studies, to identify microscope parameters that can significantly affect the accuracy of the measured projected polarization vector. Different STEM imaging modalities are used to determine the location of the atomic columns, which, when combined with the Born effective charges, allows for the calculation of local polarization. Our results indicate that differentiated differential phase contrast (dDPC) imaging enhances the accuracy of measuring local polarization relative to other imaging modalities, such as annular bright-field or integrated-DPC imaging. For instance, under certain experimental conditions, the projected spontaneous polarization for ZnO can be calculated with 1.4% error from the theoretical value. Furthermore, we quantify the influence of sample thickness, probe defocus, and crystal mis-tilt on the relative errors of the calculated polarization.

Zn and Zn-Fe Nanostructures with Multifunctional Properties as Components for Food Packaging Materials.

Metallic and bimetallic nanostructures have shown interesting chromatic and antibacterial properties, and they can be used in various applications. In this work, zinc (Zn) and iron (Fe) nanostructures were produced with different morphologies: (i) pure Zn; (ii) Zn-Fe nanoalloys; (iii) Zn-Fe nanolayers (Zn-Fe NLs); and (iv) Zn nanolayers combined with Fe nanoparticles (Zn NLs + Fe NPs). The aim was to produce components for food packaging materials with active and intelligent properties, including oxygen absorption capacity, chromatic properties, and antibacterial properties. Thus, the morphology, structure, and chemical composition of the samples were characterized and correlated with their oxidation, chromatic, and antibacterial properties. The results revealed a relevant reduction in the coating's opacity after oxidation varying from 100 to 10% depending on the morphology of the system. All coatings exhibited significant antibacterial activity against S. aureus, revealing a direct correlation with Zn content. The incorporation of Fe for all atomic arrangements showed a negative impact on the antibacterial effect against E. coli, decreasing to less than half the zone of inhibition for Zn-Fe NLs and Zn NLs + Fe NPs and suppressing the antibacterial effect for Zn-Fe alloy when compared with the pure Zn system.

Behavior of Partially Grouted Concrete Masonry Walls under Quasi-Static Cyclic Lateral Loading.

Eight partially grouted (PG-RM) concrete masonry walls were tested to study the influence of the strength and width of blocks, the wall aspect ratio, the horizontal and vertical reinforcement ratio, and the presence of edge elements (flanges). The results were analyzed in terms of the failure mode, damage progression, shear strength, lateral stiffness degradation, equivalent viscous damping ratio, and displacement ductility. Additionally, the performances of some existing shear expressions were analyzed by comparing the measured and predicted lateral load capacity of the tested walls. Based on the results, a slight increment in the lateral stiffness was achieved when employing stronger blocks, while the shear strength remained constant. Besides, increasing the width of concrete blocks did not have a significant effect on the shear strength nor in the initial tangential stiffness, but it generated a softer post-peak strength degradation. Increasing the wall aspect ratio reduced the brittleness of the response and the shear strength. Reducing the amount of vertical reinforcement lowered the resulting shear strength, although it also slowed down the post-peak resistance degradation. Transversal edge elements provided integrity to the wall response, generated softer resistance degradation, and improved the symmetry of the response, but they did not raise the lateral resistance.

Effects of Multi-Point Contacts during Object Contour Scanning Using a Biologically-Inspired Tactile Sensor.

Vibrissae are an important tactile sense organ of many mammals, in particular rodents like rats and mice. For instance, these animals use them in order to detect different object features, e.g., object-distances and -shapes. In engineering, vibrissae have long been established as a natural paragon for developing tactile sensors. So far, having object shape scanning and reconstruction in mind, almost all mechanical vibrissa models are restricted to contact scenarios with a single discrete contact force. Here, we deal with the effect of multi-point contacts in a specific scanning scenario, where an artificial vibrissa is swept along partly concave object contours. The vibrissa is modeled as a cylindrical, one-sided clamped Euler-Bernoulli bending rod undergoing large deflections. The elasticae and the support reactions during scanning are theoretically calculated and measured in experiments, using a spring steel wire, attached to a force/torque-sensor. The experiments validate the simulation results and show that the assumption of a quasi-static scanning displacement is a satisfying approach. Beyond single- and two-point contacts, a distinction is made between tip and tangential contacts. It is shown that, in theory, these contact phases can be identified solely based on the support reactions, what is new in literature. In this way, multipoint contacts are reliably detected and filtered in order to discard incorrectly reconstructed contact points.

Silica nanocarriers with user-defined precise diameters by controlled template self-assembly.

Mesoporous silica nanoparticles (MSNs) feature ideal structural properties and surface chemistry for use as nanocarriers of molecules, polymers and biomolecules in cutting-edge applications. One important challenge remaining in their preparation is the ability to tune their diameter in the range of a few tens of nanometers, with narrow size dispersity, preferably using a simple, sustainable and scalable synthetic process. This work presents a fully controllable low-temperature and purely aqueous sol-gel method to prepare MSNs with user-defined diameters from 15 nm to 80 nm and narrow size dispersity. The method also allows modification of the pore structure and offers the possibility of incorporating a luminescent species in the silica network for optical traceability. Control was achieved by tuning the colloidal stability of the assembly of cylindrical micelles that template the MSN synthesis. Using CTAB cylindrical micelles as template and sodium hydroxide (NaOH) as catalyst, precise diameter control was achieved either by changing the pH (that controls micelle surface charge) or by adding salt at constant pH (to tune the ionic strength and charge screening). This new sustainable MSN synthesis method provides full control over the nanoparticle diameters and can be used as a platform for the application of MSNs with user-defined sizes in different fields.

Effect of Congruence Between Sound and Video on Heart Rate and Self-Reported Measures of Emotion.

Most studies of emotional responses have used unimodal stimuli (e.g., pictures or sounds) or congruent bimodal stimuli (e.g., video clips with sound), but little is known about the emotional response to incongruent bimodal stimuli. The aim of the present study was to evaluate the effect of congruence between auditory and visual bimodal stimuli on heart rate and self-reported measures of emotional dimension, valence and arousal. Subjects listened to pleasant, neutral, and unpleasant sounds, accompanied by videos with and without content congruence, and heart rate was recorded. Dimensions of valence and arousal of each bimodal stimulus were then self-reported. The results showed that heart rate depends of the valence of the sounds but not of the congruence of the bimodal stimuli. The valence and arousal scores changed depending on the congruence of the bimodal stimuli. These results suggest that the congruence of bimodal stimuli affects the subjective perception of emotion.