Search

Yayun Liang,1 Cynthia Besch-Williford,2 Matthew T Cook,3 Anthony Belenchia,4 Rolf A Brekken,5 Salman M Hyder11Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA; 2IDEXX BioAnalytics, Columbia, MO, USA; 3Department of Biology, Washburn University, Topeka, KS, USA; 4Department of Nutrition and Exercise Physiology and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA; 5Hamon Center for Therapeutic Oncology Research and Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USABackground: Approximately 15–20% of all human breast cancers are classified as triple-negative because they lack estrogen and progesterone receptors and Her-2-neu, which are commonly targeted by chemotherapeutic drugs. New treatment strategies are therefore urgently needed to combat triple-negative breast cancers (TNBCs). Almost 80% of the triple-negative tumors express mutant p53 (mtp5), a functionally defective tumor suppressor protein. Whereas wild-type p53 (wtp53) promotes cell-cycle arrest and apoptosis and inhibits vascular endothelial growth factor-dependent angiogenesis, mtp53 fails to regulate these functions, resulting in tumor vascularization, growth, resistance to chemotherapy, and metastasis. Restoration of p53 function is therefore a promising drug-targeted strategy for suppressing TNBC metastasis.Methods: APR-246 is a small-molecule drug that reactivates mtp53, thereby restoring p53 function. In this study, we sought to determine whether administration of APR-246, either alone or in combination with 2aG4, an antibody that targets phosphatidylserine residues on tumor blood vessels and disrupts tumor vasculature, effectively inhibits stem cell-like characteristics of tumor cells and migration in vitro, and metastasis of human mtp53-expressing TNBC cells to the lungs in mouse models.Results: APR-246 reduced both the stem cell-like properties and migration of TNBC cells in vitro. In mouse models, administration of either APR-246 or 2aG4 reduced metastasis of TNBC cells to the lungs; a combination of the two diminished lung metastasis to the same extent as either agent alone. Combination treatment significantly reduced the incidence of lung metastasis compared either single agent alone.Conclusion: Metastasis of human mtp53-expressing TNBC cells to the lungs of nude mice is inhibited by the treatment that combines activation of mtp53 with targeting of phosphatidylserine residues on tumor blood vessels. We contend therefore that our findings strongly support the use of combination treatment involving mtp53 activation and immunotherapy in patients with TNBC.Keywords: breast cancer, metastasis, blood-vessel targeting agent, p53, APR-246

Abstract We report on the experimental quantification of the contribution to non-equilibrium entropy production stemming from the quantum coherence content in the initial state of a qubit exposed to both coherent driving and dissipation. Our experimental demonstration builds on the exquisite experimental control of the spin state of a nitrogen-vacancy defect in diamond and is underpinned, theoretically, by the formulation of a generalized fluctuation theorem designed to track the effects of quantum coherence. Our results provide significant evidence of the possibility to pinpoint the genuinely quantum mechanical contributions to the thermodynamics of non-equilibrium quantum processes in an open quantum systems scenario.

The formalism of linear response theory can be extended to encompass physical situations where an open quantum system evolves toward a nonequilibrium steady state. Here, we use the framework put forward by Konopik and Lutz [Phys. Rev. Res. 1, 033156 (2019)2643-156410.1103/PhysRevResearch.1.033156] to go beyond unitary perturbations of the dynamics. Considering an open system comprised of two coupled quantum harmonic oscillators, we study the system's response to unitary perturbations, affecting the Hamiltonian dynamics, as well as nonunitary perturbations, affecting the properties of the environment, e.g., its temperature and squeezing. We show that linear response, combined with a quantum probing approach, can effectively provide valuable quantitative information about the perturbation and characteristics of the environment, even in cases of nonunitary dynamics.

That light propagating in a gravitational field gets frequency-shifted is one of the basic consequences of any metric theory of gravity rooted in the equivalence principle. At the same time, also a time dependent material’s refractive index can frequency-shift light propagating in it. The mathematical analogy between the two effects is such that the latter has been used to study the optical analogue of a black-hole spacetime. Here, we combine these two effects by showing that light propagation in non-linear media in the presence of a moving refractive index perturbation can lead to a gravity-dependent blueshift. We find that the predicted blueshift surpasses the gravitational redshift even if the medium is considered to be perfectly stiff. In realistic scenarios, by far the strongest frequency shift arises due to the deformation of the dielectric medium and the corresponding photoelastic change of refractive index. This has the potential to facilitate optical sensing of small gravity gradients.

Matter wave interferometry with increasingly larger masses could pave the way to understanding the nature of wavefunction collapse, the quantum to classical transition, or even how an object in a spatial superposition interacts with its gravitational field. In order to improve upon the current mass record, it is necessary to move into the nanoparticle regime. In this paper, we provide a design for a nanoparticle Talbot–Lau matter wave interferometer that circumvents the practical challenges of previously proposed designs. We present numerical estimates of the expected fringe patterns that such an interferometer would produce, considering all major sources of decoherence. We discuss the practical challenges involved in building such an experiment, as well as some preliminary experimental results to illustrate the proposed measurement scheme. We show that such a design is suitable for seeing interference fringes with 106 amu SiO2 particles and that this design can be extended to even 108 amu particles by using flight times below the typical Talbot time of the system.

Several approaches to quantum gravity lead to nonlocal modifications of fields' dynamics. This, in turn, can give rise to nonlocal modifications of quantum mechanics at non-relativistic energies. Here, we analyze the nonlocal Schrödinger evolution of a quantum harmonic oscillator in one such scenario, where the problem can be addressed without the use of perturbation theory. We demonstrate that although deviations from standard quantum predictions occur at low occupation numbers, where they could potentially be detected or constrained by high-precision experiments, the classical limits of quantum probability densities and free energy remain unaffected up to energies comparable with the nonlocality scale. These results provide an example of nonlocal quantum dynamics compatible with classical predictions, suggesting massive quantum objects as a promising avenue for testing some phenomenological aspects of quantum gravity. [ABSTRACT FROM AUTHOR]

Recent work has revealed the central role played by the Kirkwood-Dirac quasiprobability (KDQ) as a tool to properly account for non-classical features in the context of condensed matter physics (scrambling, dynamical phase transitions) metrology (standard and post-selected), thermodynamics (power output and fluctuation theorems), foundations (contextuality, anomalous weak values) and more. Given the growing relevance of the KDQ across the quantum sciences, our aim is two-fold: First, we highlight the role played by quasiprobabilities in characterizing the statistics of quantum observables and processes in the presence of measurement incompatibility. In this way, we show how the KDQ naturally underpins and unifies quantum correlators, quantum currents, Loschmidt echoes, and weak values. Second, we provide novel theoretical and experimental perspectives by discussing a wide variety of schemes to access the KDQ and its non-classicality features.

Background: Obese and pre-diabetic women have a higher risk for cardiovascular death than age-matched men with the same symptoms, and there are no effective treatments. We reported that obese and pre-diabetic female Zucker Diabetic Fatty (ZDF-F) rats recapitulate metabolic and cardiac pathology of young obese and pre-diabetic women and exhibit suppression of cardio-reparative AT2R. Here, we investigated whether NP-6A4, a new AT2R agonist with the FDA designation for pediatric cardiomyopathy, mitigate heart disease in ZDF-F rats by restoring AT2R expression. Methods: ZDF-F rats on a high-fat diet (to induce hyperglycemia) were treated with saline, NP-6A4 (10 mg/kg/day), or NP-6A4 + PD123319 (AT2R-specific antagonist, 5 mg/kg/day) for 4 weeks (n = 21). Cardiac functions, structure, and signaling were assessed by echocardiography, histology, immunohistochemistry, immunoblotting, and cardiac proteome analysis. Results: NP-6A4 treatment attenuated cardiac dysfunction, microvascular damage (−625%) and cardiomyocyte hypertrophy (−263%), and increased capillary density (200%) and AT2R expression (240%) (p < 0.05). NP-6A4 activated a new 8-protein autophagy network and increased autophagy marker LC3-II but suppressed autophagy receptor p62 and autophagy inhibitor Rubicon. Co-treatment with AT2R antagonist PD123319 suppressed NP-6A4’s protective effects, confirming that NP-6A4 acts through AT2R. NP-6A4-AT2R-induced cardioprotection was independent of changes in body weight, hyperglycemia, hyperinsulinemia, or blood pressure. Conclusions: Cardiac autophagy impairment underlies heart disease induced by obesity and pre-diabetes, and there are no drugs to re-activate autophagy. We propose that NP-6A4 can be an effective drug to reactivate cardiac autophagy and treat obesity- and pre-diabetes-induced heart disease, particularly for young and obese women.

We make use of the powerful formalism of quantum parameter estimation to assess the characteristic rates of a continuous spontaneous localization (CSL) model affecting the motion of a massive mechanical system. We show that a study performed in non-equilibrium conditions unveils the advantages provided by the use of genuinely quantum resources—such as quantum correlations—in estimating the CSL-induced diffusion rate. In stationary conditions, instead, the gap between quantum performance and a classical scheme disappears. Our investigation contributes to the ongoing effort aimed at identifying suitable conditions for the experimental assessment of collapse models.

We consider a finite one-dimensional chain of quantum rotors interacting with a set of thermal baths at different temperatures. When the interaction between the rotors is made chiral, such a system behaves as an autonomous thermal motor, converting heat currents into nonvanishing rotational ones. Such a dynamical response is strongly pronounced in the range of the Hamiltonian parameters for which the ground state of the system in the thermodynamic limit exhibits a quantum phase transition. Such working points are associated with large quantum coherence and multipartite quantum correlations within the state of the system. This suggests that the optimal operating regime of such a quantum autonomous motor is one of maximal quantumness.

Obesity affects over 42% of the United States population and exacerbates heart disease, the leading cause of death in men and women. Obesity also increases pro-inflammatory cytokines that cause chronic tissue damage to vital organs. The standard-of-care does not sufficiently attenuate these inflammatory sequelae. Angiotensin II receptor AT2R is an anti-inflammatory and cardiovascular protective molecule; however, AT2R agonists are not used in the clinic to treat heart disease. NP-6A4 is a new AT2R peptide agonist with an FDA orphan drug designation for pediatric cardiomyopathy. NP-6A4 increases AT2R expression (mRNA and protein) and nitric oxide generation in human cardiovascular cells. AT2R-antagonist PD123319 and AT2RSiRNA suppress NP-6A4-effects indicating that NP-6A4 acts through AT2R. To determine whether NP-6A4 would mitigate cardiac damage from chronic inflammation induced by untreated obesity, we investigated the effects of 2-weeks NP-6A4 treatment (1.8 mg/kg delivered subcutaneously) on cardiac pathology of male Zucker obese (ZO) rats that display obesity, pre-diabetes and cardiac dysfunction. NP-6A4 attenuated cardiac diastolic and systolic dysfunction, cardiac fibrosis and cardiomyocyte hypertrophy, but increased myocardial capillary density. NP-6A4 treatment suppressed tubulointerstitial injury marker urinary β-NAG, and liver injury marker alkaline phosphatase in serum. These protective effects of NP-6A4 occurred in the presence of obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia, and without modulating blood pressure. NP-6A4 increased expression of AT2R (consistent with human cells) and cardioprotective erythropoietin (EPO) and Notch1 in ZO rat heart, but suppressed nineteen inflammatory cytokines. Cardiac miRNA profiling and in silico analysis showed that NP-6A4 activated a unique miRNA network that may regulate expression of AT2R, EPO, Notch1 and inflammatory cytokines, and mitigate cardiac pathology. Seventeen pro-inflammatory and pro-fibrotic cytokines that increase during lethal cytokine storms caused by infections such as COVID-19 were among the cytokines suppressed by NP-6A4 treatment in ZO rat heart. Thus, NP-6A4 activates a novel anti-inflammatory network comprised of 21 proteins in the heart that was not reported previously. Since NP-6A4’s unique mode of action suppresses pro-inflammatory cytokine network and attenuates myocardial damage, it can be an ideal adjuvant drug with other anti-glycemic, anti-hypertensive, standard-of-care drugs to protect the heart tissues from pro-inflammatory and pro-fibrotic cytokine attack induced by obesity.

A recent study on the immunotherapy treatment of renal cell carcinoma reveals better outcomes in obese patients compared to lean subjects. This enigmatic contradiction has been explained, in the context of the debated obesity paradox, as the effect produced by the cell-cell interaction network on the tumor microenvironment during the immune response. To better understand this hypothesis, we provide a computational framework for the in silico study of the tumor behavior. The starting model of the tumor, based on the cell-cell interaction network, has been described as a multiagent system, whose simulation generates the hypothesized effects on the tumor microenvironment. The medical needs in the immunotherapy design meet the capabilities of a multiagent simulator to reproduce the dynamics of the cell-cell interaction network, meaning a reaction to environmental changes introduced through the experimental data.

Matter wave interferometry with increasingly larger masses could pave the way to understanding the nature of wavefunction collapse, the quantum to classical transition, or even how an object in a spatial superposition interacts with its gravitational field. In order to improve upon the current mass record, it is necessary to move into the nanoparticle regime. In this paper, we provide a design for a nanoparticle Talbot–Lau matter wave interferometer that circumvents the practical challenges of previously proposed designs. We present numerical estimates of the expected fringe patterns that such an interferometer would produce, considering all major sources of decoherence. We discuss the practical challenges involved in building such an experiment, as well as some preliminary experimental results to illustrate the proposed measurement scheme. We show that such a design is suitable for seeing interference fringes with 10 6 amu SiO2 particles and that this design can be extended to even 10 8 amu particles by using flight times below the typical Talbot time of the system. [ABSTRACT FROM AUTHOR]

Quantum hypothesis testing has shown the advantages that quantum resources can offer in the discrimination of competing hypothesis. Here, we apply this framework to optomechanical systems and fundamental physics questions. In particular, we focus on an optomechanical system composed of two cavities employed to perform quantum channel discrimination. We show that input squeezed optical noise, and feasible measurement schemes on the output cavity modes, allow to obtain an advantage with respect to any comparable classical schemes. We apply these results to the discrimination of models of spontaneous collapse of the wavefunction, highlighting the possibilities offered by this scheme for fundamental physics searches.

Background: Obese and pre-diabetic women have a higher risk for cardiovascular death than age-matched men with the same symptoms, and there are no effective treatments. We reported that obese and pre-diabetic female Zucker Diabetic Fatty (ZDF-F) rats recapitulate metabolic and cardiac pathology of young obese and pre-diabetic women and exhibit suppression of cardio-reparative AT2R. Here, we investigated whether NP-6A4, a new AT2R agonist with the FDA designation for pediatric cardiomyopathy, mitigate heart disease in ZDF-F rats by restoring AT2R expression. Methods: ZDF-F rats on a high-fat diet (to induce hyperglycemia) were treated with saline, NP-6A4 (10 mg/kg/day), or NP-6A4 + PD123319 (AT2R-specific antagonist, 5 mg/kg/day) for 4 weeks (n = 21). Cardiac functions, structure, and signaling were assessed by echocardiography, histology, immunohistochemistry, immunoblotting, and cardiac proteome analysis. Results: NP-6A4 treatment attenuated cardiac dysfunction, microvascular damage (−625%) and cardiomyocyte hypertrophy (−263%), and increased capillary density (200%) and AT2R expression (240%) (p < 0.05). NP-6A4 activated a new 8-protein autophagy network and increased autophagy marker LC3-II but suppressed autophagy receptor p62 and autophagy inhibitor Rubicon. Co-treatment with AT2R antagonist PD123319 suppressed NP-6A4's protective effects, confirming that NP-6A4 acts through AT2R. NP-6A4-AT2R-induced cardioprotection was independent of changes in body weight, hyperglycemia, hyperinsulinemia, or blood pressure. Conclusions: Cardiac autophagy impairment underlies heart disease induced by obesity and pre-diabetes, and there are no drugs to re-activate autophagy. We propose that NP-6A4 can be an effective drug to reactivate cardiac autophagy and treat obesity- and pre-diabetes-induced heart disease, particularly for young and obese women. [ABSTRACT FROM AUTHOR]

We make use of the powerful formalism of quantum parameter estimation to assess the characteristic rates of a continuous spontaneous localization (CSL) model affecting the motion of a massive mechanical system. We show that a study performed in non-equilibrium conditions unveils the advantages provided by the use of genuinely quantum resources—such as quantum correlations—in estimating the CSL-induced diffusion rate. In stationary conditions, instead, the gap between quantum performance and a classical scheme disappears. Our investigation contributes to the ongoing effort aimed at identifying suitable conditions for the experimental assessment of collapse models. [ABSTRACT FROM AUTHOR]

Graph neural networks have proven their effectiveness across a wide spectrum of graph-based tasks. Despite their successes, they share the same limitations as other deep learning architectures and pose additional challenges for their formal verification. To overcome these problems, we proposed a specification language, μ G , that can be used to program graph neural networks. This language has been implemented in a Python library called libmg that handles the definition, compilation, visualization, and explanation of μ G graph neural network models. We illustrate its usage by showing how it was used to implement a Computation Tree Logic model checker in our previous work, and evaluate its performance on the benchmarks of the Model Checking Contest. In the future, we plan to use μ G to further investigate the issues of explainability and verification of graph neural networks. [ABSTRACT FROM AUTHOR]

Whether the cosmological expansion can influence the local dynamics, below the galaxy clusters scale, has been the subject of intense investigations in the past three decades. In this work, we consider McVittie and Kottler spacetimes, embedding a spherical object in a FLRW spacetime. We calculate the influence of the cosmological expansion on the frequency shift of a resonator and estimate its effect on the exchange of light signals between local observers. In passing, we also clarify some of the statements made in the literature. [ABSTRACT FROM AUTHOR]

Obesity affects over 42% of the United States population and exacerbates heart disease, the leading cause of death in men and women. Obesity also increases pro-inflammatory cytokines that cause chronic tissue damage to vital organs. The standard-of-care does not sufficiently attenuate these inflammatory sequelae. Angiotensin II receptor AT2R is an anti-inflammatory and cardiovascular protective molecule; however, AT2R agonists are not used in the clinic to treat heart disease. NP-6A4 is a new AT2R peptide agonist with an FDA orphan drug designation for pediatric cardiomyopathy. NP-6A4 increases AT2R expression (mRNA and protein) and nitric oxide generation in human cardiovascular cells. AT2R-antagonist PD123319 and AT2RSiRNA suppress NP-6A4-effects indicating that NP-6A4 acts through AT2R. To determine whether NP-6A4 would mitigate cardiac damage from chronic inflammation induced by untreated obesity, we investigated the effects of 2-weeks NP-6A4 treatment (1.8 mg/kg delivered subcutaneously) on cardiac pathology of male Zucker obese (ZO) rats that display obesity, pre-diabetes and cardiac dysfunction. NP-6A4 attenuated cardiac diastolic and systolic dysfunction, cardiac fibrosis and cardiomyocyte hypertrophy, but increased myocardial capillary density. NP-6A4 treatment suppressed tubulointerstitial injury marker urinary β-NAG, and liver injury marker alkaline phosphatase in serum. These protective effects of NP-6A4 occurred in the presence of obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia, and without modulating blood pressure. NP-6A4 increased expression of AT2R (consistent with human cells) and cardioprotective erythropoietin (EPO) and Notch1 in ZO rat heart, but suppressed nineteen inflammatory cytokines. Cardiac miRNA profiling and in silico analysis showed that NP-6A4 activated a unique miRNA network that may regulate expression of AT2R, EPO, Notch1 and inflammatory cytokines, and mitigate cardiac pathology. Seventeen pro-inflammatory and pro-fibrotic cytokines that increase during lethal cytokine storms caused by infections such as COVID-19 were among the cytokines suppressed by NP-6A4 treatment in ZO rat heart. Thus, NP-6A4 activates a novel anti-inflammatory network comprised of 21 proteins in the heart that was not reported previously. Since NP-6A4's unique mode of action suppresses pro-inflammatory cytokine network and attenuates myocardial damage, it can be an ideal adjuvant drug with other anti-glycemic, anti-hypertensive, standard-of-care drugs to protect the heart tissues from pro-inflammatory and pro-fibrotic cytokine attack induced by obesity. [ABSTRACT FROM AUTHOR]

Quantum hypothesis testing has shown the advantages that quantum resources can offer in the discrimination of competing hypothesis. Here, we apply this framework to optomechanical systems and fundamental physics questions. In particular, we focus on an optomechanical system composed of two cavities employed to perform quantum channel discrimination. We show that input squeezed optical noise, and feasible measurement schemes on the output cavity modes, allow to obtain an advantage with respect to any comparable classical schemes. We apply these results to the discrimination of models of spontaneous collapse of the wavefunction, highlighting the possibilities offered by this scheme for fundamental physics searches. [ABSTRACT FROM AUTHOR]

Clinical and experimental studies show that angiotensin II (AngII) promotes vascular pathology via activation of AngII type 1 receptors (AT1Rs). We recently reported that NP‐6A4, a selective peptide agonist for AngII type 2 receptor (AT2R), exerts protective effects on human vascular cells subjected to serum starvation or doxorubicin exposure. In this study, we investigated whether NP‐6A4–induced AT2R activation could mitigate AngII‐induced abdominal aortic aneurism (AAA) using AngII‐treated Apoe−/− mice. Male Apoe−/− mice were infused with AngII (1 µg/kg/min) by implanting osmotic pumps subcutaneously for 28 days. A subset of mice was pre‐treated subcutaneously with NP‐6A4 (2.5 mg/kg/day) or vehicle for 14 days prior to AngII, and treatments were continued for 28 days. NP‐6A4 significantly reduced aortic stiffness of the abdominal aorta induced by AngII as determined by ultrasound functional analyses and histochemical analyses. NP‐6A4 also increased nitric oxide bioavailability in aortic tissues and suppressed AngII‐induced increases in monocyte chemotactic protein‐1, osteopontin and proteolytic activity of the aorta. However, NP‐6A4 did not affect maximal intraluminal aortic diameter or AAA incidences significantly. These data suggest that the effects of AT2R agonist on vascular pathologies are selective, affecting the aortic stiffness and proteolytic activity without affecting the size of AAA. [ABSTRACT FROM AUTHOR]

Speech and hearing screening conducted with 136 penitentiary inmates revealed normal prevalence figures for articulation and fluency disorders but appreciably higher prevalence for voice and hearing disorders. Possible correlations with age levels 21-25 years and educational levels 0-6 years were noted. (Author/CL)

When a massive quantum body is put into a spatial superposition, it is of interest to consider the quantum aspects of the gravitational field sourced by the body. We argue that in order to understand how the body may become entangled with other massive bodies via gravitational interactions, it must be thought of as being entangled with its own Newtonian-like gravitational field. Thus, a Newtonian-like gravitational field must be capable of carrying quantum information. Our analysis supports the view that table-top experiments testing entanglement of systems interacting via gravity do probe the quantum nature of gravity, even if no "gravitons" are emitted during the experiment. [ABSTRACT FROM AUTHOR]

Vitamin D is an essential nutrient that is metabolized in the body to generate an active metabolite (1,25(OH)2D) with hormone-like activity and highly diverse roles in cellular function. Vitamin D deficiency (VDD) is a prevalent but easily p reventable nutritional disturbance. Emerging evidence demonstrates the importance of s ufficient vitamin D concentrations during fetal life with deficiencies leading to long-term effects into adulthood. Here, we provide a detailed review and perspective of evidence for the role of maternal VDD in offspring long-term health, particularly as i t relates to developmental origins of health and disease (DOHaD). We focus on the roles in neurobehavioral and cardiometabolic disorders in humans and highlight recent finding s from zebrafish and rodent models that probe potential mechanisms linking early life VDD to later life health outcomes. Moreover, we explore evidence implicating epigenetic mechanisms as a mediator of this link. Gaps in our current understanding of how maternal VDD might result in deleterious offspring outcomes later in life are also addressed. [ABSTRACT FROM AUTHOR]