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9 pages, 9 figures, 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 non-vanishing 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 quantum autonomous motor is one of maximal quantumness., A.I. gratefully acknowledges the financial support of The Faculty of Science and Technology at Aarhus University through a Sabbatical scholarship and the hospitality of the Quantum Technology group, the Centre for Theoretical Atomic, Molecular and Optical Physics and the School of Mathematics and Physics, during his stay at Queen’s University Belfast. A.B. acknowledges the hospitality of the Institute for Theoretical Physics and the “Nonequilibrium quantum dynamics” group at Universität Stuttgart, where part of this work was carried out. R.P. and M.P. acknowledge the support by the SFI-DfE Investigator Programme (Grant No. 15/IA/2864) the Eropean Union’s Horizon 2020 FET-Open project SuperQuLAN (899354) and TEQ (766900). M.P. acknowledges support by the Leverhulme Trust Research Project Grant UltraQuTe (Grant No. RGP-2018-266), the Royal Society Wolfson Fellowship (RSWF/R3/183013), the UK EPSRC (Grant No. EP/T028424/1) and the Department for the Economy Northern Ireland under the US-Ireland R&D Partnership Programme. A.B. also acknowledges support from H2020 through the MSCA IF pERFEcTO (Grant Agreement No. nr. 795782) and from the DeutscheForschungsgemeinschaft (DFG, German Research Foundation) Project No. BR5221/4-1.

Light propagation in curved spacetime is at the basis of some of the most stringent tests of Einstein's general relativity. At the same time, light propagation in media is at the basis of several communication systems. Given the ubiquity of the gravitational field, and the exquisite level of sensitivity of optical measurements, the time is ripe for investigations combining these two aspects and studying light propagation in media located in curved spacetime. In this work, we focus on the effect of a weak gravitational field on the propagation of optical solitons in non-linear optical media. We derive a non-linear Schr\"{o}dinger equation describing the propagation of an optical pulse in an effective, gradient-index medium in flat spacetime, encoding both the material properties and curved spacetime effects. In analyzing the special case of propagation in a 1D optical fiber, we also include the effect of mechanical deformations and show it to be the dominant effect for a fiber oriented in the radial direction in Schwarzschild spacetime., Comment: 7+19 pages, 11 figures. Comments are welcome!

The objective of the proposed macroscopic quantum resonators (MAQRO) mission is to harness space for achieving long free-fall times, extreme vacuum, nano-gravity, and cryogenic temperatures to test the foundations of physics in macroscopic quantum experiments at the interface with gravity. Developing the necessary technologies, achieving the required sensitivities and providing the necessary isolation of macroscopic quantum systems from their environment will lay the path for developing novel quantum sensors. Earlier studies showed that the proposal is feasible but that several critical challenges remain, and key technologies need to be developed. Recent scientific and technological developments since the original proposal of MAQRO promise the potential for achieving additional science objectives. The proposed research campaign aims to advance the state of the art and to perform the first macroscopic quantum experiments in space. Experiments on the ground, in micro-gravity, and in space will drive the proposed research campaign during the current decade to enable the implementation of MAQRO within the subsequent decade., Quantum Science and Technology, 8 (1), ISSN:2058-9565

Shooting glass beads across the inside of a satellite could probe the limits of quantum wave behaviour. Here’s how. Shooting glass beads across the inside of a satellite could probe the limits of quantum wave behaviour. Here’s how.

Abstract FigureThe primary objective of this study was to identify a universal wastewater biomarker for population normalization for SARS-CoV-2 wastewater-based epidemiology (WBE). A total of 2,624 wastewater samples (41 weeks) were collected weekly during May 2021-April 2022 from 64 wastewater facilities across Missouri, U.S. Three wastewater biomarkers, caffeine and its metabolite, paraxanthine, and pepper mild mottle virus (PMMoV), were compared for the population normalization effectiveness for wastewater SARS-CoV-2 surveillance. Paraxanthine had the lowest temporal variation and strongest relationship between population compared to caffeine and PMMoV. This result was confirmed by data from ten different Wisconsin’s WWTPs with gradients in population sizes, indicating paraxanthine is a promising biomarker of the real-time population across a large geographical region. The estimated real-time population was directly compared against the population patterns with human movement mobility data. Of the three biomarkers, population normalization by paraxanthine significantly strengthened the relationship between wastewater SARS-CoV-2 viral load and COVID-19 incidence rate the most (40 out of 61 sewersheds). Caffeine could be a promising population biomarker for regions where no significant exogenous caffeine sources (e.g., discharges from food industries) exist. In contrast, PMMoV showed the highest variability over time, and therefore reduced the strength of the relationship between sewage SARS-CoV-2 viral load and the COVID-19 incidence rate, as compared to wastewater data without population normalization and the population normalized by either recent Census population or the population estimated based on the number of residential connections and average household size for that municipality from the Census. Overall, the findings of this long-term surveillance study concluded that the paraxanthine has the best performance as a biomarker for population normalization for SARS-CoV-2 wastewater-based epidemiology.

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.

Quantum technologies are opening novel avenues for applied and fundamental science at an impressive pace. In this perspective article, we focus on the promises coming from the combination of quantum technologies and space science to test the very foundations of quantum physics and, possibly, new physics. In particular, we survey the field of mesoscopic superpositions of nanoparticles and the potential of interferometric and non-interferometric experiments in space for the investigation of the superposition principle of quantum mechanics and the quantum-to-classical transition. We delve into the possibilities offered by the state-of-the-art of nanoparticle physics projected in the space environment and discuss the numerous challenges, and the corresponding potential advancements, that the space environment presents. In doing this, we also offer an ab-initio estimate of the potential of space-based interferometry with some of the largest systems ever considered and show that there is room for tests of quantum mechanics at an unprecedented level of detail. This perspective presents current and future possibilities offered by space technology for testing quantum mechanics, with a focus on mesoscopic superposition of nanoparticles and the potential of interferometric and non-interferometric experiments in space.

We make use of the powerful formalism of quantum parameter estimation to assess the characteristic rates of a Continuous Spontaneous Localisation (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., Comment: 7 pages, 3 figures

We put forth a unifying formalism for the description of the thermodynamics of continuously monitored systems, where measurements are only performed on the environment connected to a system. We show, in particular, that the conditional and unconditional entropy production, which quantify the degree of irreversibility of the open system's dynamics, are related to each other by the Holevo quantity. This, in turn, can be further split into an information gain rate and loss rate, which provide conditions for the existence of informational steady states, i.e., stationary states of a conditional dynamics that are maintained owing to the unbroken acquisition of information. We illustrate the applicability of our framework through several examples.

The objective of the proposed MAQRO mission is to harness space for achieving long free-fall times, extreme vacuum, nano-gravity, and cryogenic temperatures to test the foundations of physics in macroscopic quantum experiments. This will result in the development of novel quantum sensors and a means to probe the foundations of quantum physics at the interface with gravity. Earlier studies showed that the proposal is feasible but that several critical challenges remain, and key technologies need to be developed. These new technologies will open up the potential for achieving additional science objectives. The proposed research campaign aims to advance the state of the art and to perform the first macroscopic quantum experiments in space. Experiments on the ground, in micro-gravity, and in space will drive the proposed research campaign during the current decade to enable the implementation of MAQRO within the subsequent decade., Comment: 9 pages, 2 figures, submitted as a Research Campaign Whitepaper for the BPS2023 Decadal Survey

SARS-CoV-2 genetic material has been detected in raw wastewater around the world throughout the COVID-19 pandemic and has served as a useful tool for monitoring community levels of SARS-CoV-2 infections. SARS-CoV-2 genetic material is highly detectable in a patient’s feces and the household wastewater for several days before and after a positive COVID-19 qPCR test from throat or sputum samples. Here, we characterize genetic material collected from raw wastewater samples and determine recovery efficiency during a concentration process. We find that pasteurization of raw wastewater samples did not reduce SARS-CoV-2 signal if RNA is extracted immediately after pasteurization. On the contrary, we find that signal decreased by approximately half when RNA was extracted 24-36 hours post-pasteurization and ∼90% when freeze-thawed prior to concentration. As a matrix control, we use an engineered enveloped RNA virus. Surprisingly, after concentration, the recovery of SARS-CoV-2 signal is consistently higher than the recovery of the control virus leading us to question the nature of the SARS-CoV-2 genetic material detected in wastewater. We see no significant difference in signal after different 24-hour temperature changes; however, treatment with detergent decreases signal ∼100-fold. Furthermore, the density of the samples is comparable to enveloped retrovirus particles, yet, interestingly, when raw wastewater samples were used to inoculate cells, no cytopathic effects were seen indicating that wastewater samples do not contain infectious SARS-CoV-2. Together, this suggests that wastewater contains fully intact enveloped particles.

Wastewater-based epidemiology (WBE) has been one of the most cost-effective approaches to track the SARS-CoV-2 levels in the communities since the COVID-19 outbreak in 2020. Normalizing SARS-CoV-2 concentrations by the population biomarkers in wastewater can be critical for interpreting the viral loads, comparing the epidemiological trends among the sewersheds, and identifying the vulnerable communities. In this study, five population biomarkers, pepper mild mottle virus (pMMoV), creatinine (CRE), 5-hydroxyindoleacetic acid (5-HIAA), caffeine (CAF) and its metabolite paraxanthine (PARA) were investigated for their utility in normalizing the SARS-CoV-2 loads through developed direct and indirect approaches. Their utility in assessing the real-time population contributing to the wastewater was also evaluated. The best performed candidate was further tested for its capacity for improving correlation between normalized SARS-CoV-2 loads and the clinical cases reported in the City of Columbia, Missouri, a university town with a constantly fluctuated population. Our results showed that, except CRE, the direct and indirect normalization approaches using biomarkers allow accounting for the changes in wastewater dilution and differences in relative human waste input over time regardless flow volume and population at any given WWTP. Among selected biomarkers, PARA is the most reliable population biomarker in determining the SARS-CoV-2 load per capita due to its high accuracy, low variability, and high temporal consistency to reflect the change in population dynamics and dilution in wastewater. It also demonstrated its excellent utility for real-time assessment of the population contributing to the wastewater. In addition, the viral loads normalized by the PARA-estimated population significantly improved the correlation (rho=0.5878, pHIGHLIGHT (bullet points)The paraxanthine (PARA), the metabolite of the caffeine, is a more reliable population biomarker in SARS-CoV-2 wastewater-based epidemiology studies than the currently recommended pMMoV genetic marker.SARS-CoV-2 load per capita could be directly normalized using the regression functions derived from correlation between paraxanthine and population without flowrate and population data.Normalizing SARS-CoV-2 levels with the chemical marker PARA significantly improved the correlation between viral loads per capita and case numbers per capita.The chemical marker PARA demonstrated its excellent utility for real-time assessment of the population contributing to the wastewater.

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.

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 preventable nutritional disturbance. Emerging evidence demonstrates the importance of sufficient 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 it relates to developmental origins of health and disease (DOHaD). We focus on the roles in neurobehavioral and cardiometabolic disorders in humans and highlight recent findings 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.

Objective— Abdominal aortic aneurysm is caused by the accumulation of inflammatory cells in the aortic wall. Our recent studies demonstrated that inhibition of Notch signaling attenuates abdominal aortic aneurysm formation by shifting the macrophage balance towards anti-inflammatory (M2) phenotype. Using IL12p40 −/− (interleukin 12 p40) mice, we investigated the effects of M2-predominant macrophages on the development of abdominal aortic aneurysm. Approach and Results— Male (8–10 week-old) wild-type and IL12p40 −/− mice (n=15) on C57BL/6 background were infused with Ang II (angiotensin II, 1000 ng/kg per minute) by implanting osmotic pumps subcutaneously for 28 days. In the IL12p40 −/− mice, Ang II significantly increased the maximal intraluminal diameter (9/15) as determined by transabdominal ultrasound imaging. In addition, IL12p40-deletion significantly increased aortic stiffness in response to Ang II as measured by pulse wave velocity and atomic force microscopy. Histologically, IL12p40 −/− mice exhibited increased maximal external diameter of aorta and aortic lesions associated with collagen deposition and increased elastin fragmentation compared with wild-type mice infused with Ang II. Mechanistically, IL12p40 deficiency by siRNA (small interfering RNA) augmented the Tgfβ2 -mediated Mmp2 expression in wild-type bone marrow–derived macrophages without affecting the expression of Mmp9 . No such effects of IL12p40 deficiency on MMP2/MMP9 was observed in human aortic smooth muscle cells or fibroblasts. Depletion of macrophages in IL12p40 −/− mice by clodronate liposomes significantly decreased the maximal external diameter of aorta and aortic stiffness in response to Ang II as determined by imaging and atomic force microscopy. Conclusions— IL12p40 depletion promotes the development of abdominal aortic aneurysm, in part, by facilitating recruitment of M2-like macrophages and potentiating aortic stiffness and fibrosis mediated by Tgfβ2 .

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., Comment: 10 pages, 10 figures, 1 table

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20105-3

SARS-CoV-2 genetic material has been detected in raw wastewater around the world throughout the COVID-19 pandemic and has served as a useful tool for monitoring community levels of SARS-CoV-2 infections. SARS-CoV-2 genetic material is highly detectable in a patient's feces and the household wastewater for several days before and after a positive COVID-19 qPCR test from throat or sputum samples. Here, we characterize genetic material collected from raw wastewater samples and determine recovery efficiency during a concentration process. We find that pasteurization of raw wastewater samples did not reduce SARS-CoV-2 signal if RNA is extracted immediately after pasteurization. On the contrary, we find that signal decreased by approximately half when RNA was extracted 24–36 h post-pasteurization and ~90% when freeze-thawed prior to concentration. As a matrix control, we use an engineered enveloped RNA virus. Surprisingly, after concentration, the recovery of SARS-CoV-2 signal is consistently higher than the recovery of the control virus leading us to question the nature of the SARS-CoV-2 genetic material detected in wastewater. We see no significant difference in signal after different 24-hour temperature changes; however, treatment with detergent decreases signal ~100-fold. Furthermore, the density of the samples is comparable to enveloped retrovirus particles, yet, interestingly, when raw wastewater samples were used to inoculate cells, no cytopathic effects were seen indicating that wastewater samples do not contain infectious SARS-CoV-2. Together, this suggests that wastewater contains fully intact enveloped particles., Graphical abstract Unlabelled Image

Quantum field theory is completely characterized by the field correlations between spacetime points. In turn, some of these can be accessed by locally coupling to the field simple quantum systems, also known as particle detectors. In this letter we consider what happens when a quantum-controlled superposition of detectors at different space-time points is used to probe the correlations of the field. We show that, due to quantum interference effects, two detectors can gain information on field correlations that would not be accessible, otherwise. This has relevant consequences for information theoretic quantities, like entanglement and mutual information harvested from the field. In particular, the quantum control allows for extraction of entanglement in scenarios where this is, otherwise, provably impossible.

Mutations in the tumor suppressor p53 gene are frequently associated with various cancers, including human breast cancer. Unlike wild-type p53 (wtp53), mutant p53 protein (mtp53) fails to promote apoptosis, resulting in tumor cell survival and resistance to chemotherapeutic drugs. Consequently, restoration of p53 function is a promising strategy for targeted cancer therapy. The aim of this study was to determine whether administration of APR-246, a small molecule that restores p53 function, either alone or in combination with 2aG4, an antibody that disrupts tumor blood vessels by targeting phosphatidylserine (high levels of which are present in tumor blood vessels) effectively suppresses breast cancer growth and metastasis. We previously reported that the proposed therapy is effective against hormone-dependent breast cancers which express mtp53, though not against breast cancer cells expressing wtp53. Furthermore, APR-246 alone and in combination with 2aG4 dramatically reduced xenograft blood vessel density, an important observation since blood vessels provide a major route for tumor metastasis. Most patients who succumb to breast cancer, and in particular, those with triple-negative breast cancer (TNBC) do so following metastasis to distant organs. TNBCs are devoid of chemotherapeutic targets; consequently, patients are administered toxic, non-specific drugs. However, since more than 80% of TNBCs express mtp53 it was our goal to determine whether APR-246/2aG4 might offer a new targeted approach through which to suppress metastatic TNBC. Female nude mice (n = 10-11/ group) were injected with MDA-MB-435 cells that metastasize efficiently to the lungs. Five days later APR-246 administration began; mice were injected i.v. with 100 mg/kg APR-246 every other day (11 treatments), followed by twice a week for a further 8 treatments. 2aG4 or C44 control antibody was administered i.p (100 μg/mouse) at the same time as APR-246. Compared with vehicle-treated mice, the number of metastatic colonies/lung were significantly reduced (P < 0.05, ANOVA) in animals given APR-246 or 2aG4 alone, or a combination of the two. This might be explained by induction of tumor cell apoptosis in the lungs. While treatment with APR-246 or 2aG4 alone reduced the number of MDA-MB-435-induced metastatic colonies, it took a combination of the two to significantly lower the incidence of metastasis (combination therapy brought about a 50% reduction in incidence of metastasis compared with controls; p

The entropy production rate is a key quantity in non-equilibrium thermodynamics of both classical and quantum processes. No universal theory of entropy production is available to date, which hinders progress towards its full grasping. By using a phase space-based approach, here we take the current framework for the assessment of thermodynamic irreversibility all the way to quantum regimes by characterizing entropy production -- and its rate -- resulting from the continuous monitoring of a Gaussian system. This allows us to formulate a sharpened second law of thermodynamics that accounts for the measurement back-action and information gain from a continuously monitored system. We illustrate our framework in a series of physically relevant examples., Comment: 15+6 pages, 2 figures. This version matches the one accepted for publication in npj Quantum Inf

Cardiovascular disease incidence continues to rise and new treatment paradigms are warranted. We reported previously that activation of Angiotensin II receptor (encoded by the X-linked Agtr2 gene) by a new peptide agonist, NP-6A4, was more effective in protecting mouse cardiomyocyte HL-1 cells and human coronary artery vascular smooth muscle cells (hCAVSMCs) from acute nutrient deficiency than other drugs tested. To elucidate further the protective effects of NP-6A4 in human cells, we studied the effects of NP-6A4 treatment on functions of human coronary artery endothelial cells (hCAECs), and hCAVSMCs. In hCAVSMCs, NP-6A4 (1 μM) increased Agtr2 mRNA (sixfold, p < 0.05) after 12-h exposure, whereas in hCAECs, significant increase in Agtr2 mRNA (hCAECs: eightfold) was observed after prolonged exposure. Interestingly, NP-6A4 treatment (1 μM, 12 h) increased AT2R protein levels in all human cells tested. Pre-treatment with AT2R-antagonist PD123319 (20 μM) and anti-AT2R siRNA (1 μM) suppressed this effect. Thus, NP-6A4 activates a positive feedback loop for AT2R expression and signaling in hCAVSMCs and hCAECs. NP-6A4 (1–20 μM) increased cell index (CI) of hCAVSMCs as determined by real time cell analyzer (RTCA), indicating that high concentrations of NP-6A4 were not cytotoxic for hCAVSMCs, rather promoting better cell attachment and growth. Seahorse Extracellular Flux Assay revealed that NP-6A4 (1 μM) treatment for 7 days increased whole cell-based mitochondrial parameters of hCAVSMCs, specifically maximal respiration (p < 0.05), spare respiratory capacity (p < 0.05) and ATP production (p < 0.05). NP-6A4 (1 μM; 7 days) also suppressed Reactive Oxygen Species (ROS) in hCAVSMCs. Exposure to Doxorubicin (DOXO) (1 μM) increased ROS in hCAVSMCs and this effect was suppressed by NP-6A4 (1 μM). In hCAECs grown in complete medium, NP-6A4 (1 μM) and Ang II (1 μM) exerted similar changes in CI. Additionally, NP-6A4 (5 μM: 12 h) increased expression of eNOS (sixfold, p < 0.05) and generation of nitric oxide (1.3-fold, p < 0.05) in hCAECs and pre-treatment with PD123319 (20 μM) suppressed this effect partially (65%). Finally, NP-6A4 decreased phosphorylation of Jun-N-terminal kinase, implicated in apoptosis of ECs in atherosclerotic sites. Taken together, NP-6A4, through its ability to increase AT2R expression and signaling, exerts different cell-specific protective effects in human VSMCs and ECs.

Introduction: Abdominal aortic aneurysm (AAA) is caused by the immune and inflammatory cell accumulation of the aortic wall, leading to enhanced inflammation and aneurysm formation. Our recent studies demonstrate that inhibition of Notch signaling attenuates AAA formation by shifting the macrophage balance towards anti-inflammatory (M2) phenotype. Using IL12p40 knockout (KO) mice, we investigated the direct effects of M2-like macrophages in the development of AAA. Methods and Results: Male (8-10 week-old) wild-type (WT) and IL12p40-KO mice (n=10) on C57BL/6 background were infused with angiotensin-II (AngII, 1,000 ng/kg/min) by implanting osmotic pumps subcutaneously for 28 days. Comparable increase in mean, systolic and diastolic arterial blood pressure was observed between WT and IL12p40-KO mice in response to AngII. Unexpectedly, AngII significantly increased the AAA-associated mortality (2/10) and luminal expansion (7/10) in IL12p40-KO mice as determined by transabdominal ultrasound. In addition, IL12p40-deficiency significantly increased aortic stiffness in the abdominal aortas in response to AngII than WT as measured by pulse wave velocity (PWV) and atomic force microscopy (AFM). Macroscopic and histological examination also showed that IL12p40-KO mice exhibited severe abdominal aortic lesion formation and increased maximal aortic width compared to WT mice. Increased elastin fragmentation and collagen deposition was detected in aorta of AngII-infused IL12p40-KO mice compared to AngII-infused WT mice. Further, there was no significant change in the total cholesterol, triglycerides and HDL-cholesterol levels in the serum of WT and IL12p40-KO mice treated with AngII. Importantly, bone marrow derived macrophages (BMDM) from IL12p40-KO mice showed increased mRNA expression of M2-markers (TGF-β1 and IL10) and decreased expression of M1-markers (iNOS and TNF-α) at basal level compared to WT BMDM. Conclusions: IL12p40 deficiency may promote the development of AAA, in part, by facilitating recruitment of M2-like macrophages and potentiating aortic-stiffness and fibrosis mediated by TGF-β1 and IL10. In summary, optimal M1/M2 balance rather than predominance of M2-phenotype may be prerequisite to prevent AAA formation.

We analyse a gedankenexperiment previously considered by Mari et al. that involves quantum superpositions of charged and/or massive bodies ("particles") under the control of the observers, Alice and Bob. In the electromagnetic case, we show that the quantization of electromagnetic radiation (which causes decoherence of Alice's particle) and vacuum fluctuations of the electromagnetic field (which limits Bob's ability to localize his particle to better than a charge-radius) both are essential for avoiding apparent paradoxes with causality and complementarity. We then analyze the gravitational version of this gedankenexperiment. We correct an error in the analysis of Mari et al. and of Baym and Ozawa, who did not properly account for the conservation of center of mass of an isolated system. We show that the analysis of the gravitational case is in complete parallel with the electromagnetic case provided that gravitational radiation is quantized and that vacuum fluctuations limit the localization of a particle to no better than a Planck length. This provides support for the view that (linearized) gravity should have a quantum field description., Comment: 9 pages, 1 figure. Version accepted for publication in Phys.Rev.D

The use of animal models in vitamin D deficiency (VDD) research, particularly in regard to maternal deficits, has increased dramatically, yet these studies may be confounded due to ill-conceived experimental timelines. We conducted 2 experiments to (1) characterize the time course of VDD induction and repletion and (2) explore the long-term consequences of VDD on calcium homeostasis and body composition in reproductive-age female mice. Eight-week-old female C57BL/6 mice were randomized to receive either a vitamin D sufficient (VDS) or VDD diet; serum was collected weekly. At week 4, VDD mice were switched to VDS diet, and serum was collected weekly until week 8. Another group of same-age female mice was maintained on VDD diet for 40 wk. Body weights and serum were collected every 2 wk until week 40, when body composition was measured by using echoMRI. Mice did not become VDD until week 3 of the VDD diet and, after decreasing slightly at 4 wk, serum 25-hydroxyvitamin D remained unchanged through 40 wk. Vitamin D repletion to 25-hydroxyvitamin D concentrations considered adequate by the Institute of Medicine took 2 to 3 wk. Prolonged VDD in mice was marked by hypocalcemia and hyperparathyroidism and led to proportional decreases in both lean and fat mass. These data provide guidance in the design of studies using mice as a maternal VDD model, especially those exploring its effects on the developmental origins of health and disease and highlight the importance of monitoring and controlling the calciotropic effects of diet-induced VDD. This study also shows that prolonged VDD in reproductive-age female C57BL/6 mice induces metabolically meaningful changes in absolute, but not relative, body composition.

The signaling between two observers in 3+1 dimensional flat spacetime coupled locally to a non-local field is considered. We show that in the case where two observers are purely timelike related -- so that an exchange of on-shell massless quanta cannot occur -- signaling is still possible because of a violation of Huygens' principle. In particular, we show that the signaling is exponentially suppressed by the non-locality scale. Furthermore, we consider the case in which the two observers are light-like related and show that the non-local modification to the local result is polynomially suppressed in the non-locality scale. This may have implications for phenomenological tests of non-local theories., Comment: 9 pages, 3 Figures. RevTeX 4.1

Obese adolescents represent a particularly vulnerable group for vitamin D deficiency which appears to have negative consequences on insulin resistance and glucose homeostasis. Poor vitamin D status is also associated with future risk of type 2 diabetes and metabolic syndrome in the obese. The biological mechanisms by which vitamin D influences glycemic control in obesity are not well understood, but are thought to involve enhancement of peripheral/hepatic uptake of glucose, attenuation of inflammation and/or regulation of insulin synthesis/secretion by pancreatic β cells. Related to the latter, recent data suggest that the active form of vitamin, 1,25-dihydroxyvitamin D, does not impact insulin release in healthy pancreatic islets; instead they require an environmental stressor such as inflammation or vitamin D deficiency to see an effect. To date, a number of observational studies exploring the relationship between the vitamin D status of obese adolescents and markers of glucose homeostasis have been published. Most, although not all, show significant associations between circulating 25-hydroxyvitamn D concentrations and insulin sensitivity/resistance indices. In interpreting the collective findings of these reports, significant considerations surface including the effects of pubertal status, vitamin D status, influence of parathyroid hormone status and the presence of nonalcoholic fatty liver disease. The few published clinical trials using vitamin D supplementation to improve insulin resistance and impaired glucose tolerance in obese adolescents have yielded beneficial effects. However, there is a need for more randomized controlled trials. Future investigations should involve larger sample sizes of obese adolescents with documented vitamin D deficiency, and careful selection of the dose, dosing regimen and achievement of target 25-hydroxyvitamn D serum concentrations. These trials should also include clamp-derived measures of in vivo sensitivity and β-cell function to more fully characterize the effects of vitamin D replenishment on insulin resistance.

The response of inertial particle detectors coupled to a scalar field satisfying nonlocal dynamics described by nonanalytic functions of the d'Alembertian operator $\Box$ is studied. We show that spontaneous emission processes of a low energy particle detector are very sensitive to high-energy nonlocality scales. This allows us to suggest a nuclear physics experiment ($\sim$ MeV energy scales) that outperforms the sensitivity of LHC experiments by many orders of magnitude. This may have implications for the falsifiability of theoretical proposals of quantum gravity., Comment: 5 pages, 1 figure. RevTeX 4.1. This version matches the published one in PRD Rapid Communications

Several quantum gravity scenarios lead to physics below the Planck scale characterised by nonlocal, Lorentz invariant equations of motion. We show that such non-local effective field theories lead to a modified Schr\"odinger evolution in the nonrelativistic limit. In particular, the nonlocal evolution of opto-mechanical quantum oscillators is characterised by a spontaneous periodic squeezing that cannot be generated by environmental effects. We discuss constraints on the nonlocality obtained by past experiments, and show how future experiments (already under construction) will either see such effects or otherwise cast severe bounds on the non-locality scale (well beyond the current limits set by the Large Hadron Collider). This paves the way for table top, high precision experiments on massive quantum objects as a promising new avenue for testing some quantum gravity phenomenology., Comment: 5 pages, 1 figure. Final version matching the published one in PRL

In order to understand the detailed mechanism by which a fundamental discreteness can provide a finite entanglement entropy, we consider the entanglement entropy of two classes of free massless scalar fields on causal sets that are well approximated by causal diamonds in Minkowski spacetime of dimensions 2,3 and 4. The first class is defined from discretised versions of the continuum retarded Green functions, while the second uses the causal set's retarded nonlocal d'Alembertians parametrised by a length scale $l_k$. In both cases we provide numerical evidence that the area law is recovered when the double-cutoff prescription proposed in arXiv:hep-th/1611.10281 is imposed. We discuss in detail the need for this double cutoff by studying the effect of two cutoffs on the quantum field and, in particular, on the entanglement entropy, in isolation. In so doing, we get a novel interpretation for why these two cutoff are necessary, and the different roles they play in making the entanglement entropy on causal sets finite., Comment: 36 pages, 14 figures

Causal set non-local wave operators allow both for the definition of an action for Causal set theory and the study of deviations from local physics that may have interesting phenomenological consequences. It was previously shown that, in all dimensions, the (unique) minimal discrete operators give averaged continuum non-local operators that reduce to $\Box-R/2$ in the local limit. Recently, dropping the constraint of minimality, it was shown that there exist an infinite number of discrete operators satisfying basic physical requirements and with the right local limit in flat spacetime. In this work, we consider this entire class of Generalized Causal set d'Alembertins in curved spacetimes and extend to them the result about the universality of the $-R/2$ factor. Finally, we comment on the relation of this result to the Einstein Equivalence principle., Comment: 31 pages, 1 figure. Some typos corrected, this version accepted for publication in Class.Quant.Grav

The continuum limit of a 4-dimensional, discrete d'Alembertian operator for scalar fields on causal sets is studied. The continuum limit of the mean of this operator in the Poisson point process in 4-dimensional Minkowski spacetime is shown to be the usual continuum scalar d'Alembertian $\Box$. It is shown that the mean is close to the limit when there exists a frame in which the scalar field is slowly varying on a scale set by the density of the Poisson process. The continuum limit of the mean of the causal set d'Alembertian in 4-dimensional curved spacetime is shown to equal $\Box - \frac{1}{2}R$, where $R$ is the Ricci scalar, under certain conditions on the spacetime and the scalar field., Comment: 31 pages, 2 figures. Slightly revised version, accepted for publication in Classical and Quantum Gravity

It is known that there is disruption of the blood–brain barrier during terminal AIDS encephalitis in both human immunodeficiency virus (HIV)-infected humans and simian immunodeficiency virus (SIV)-infected rhesus macaques. Much, although by no means all, of the neuropathological findings of HIV and SIV infection involves accumulation of monocytes/macrophages that have likely crossed the blood–brain barrier (BBB). There is no convincing, rigorous, demonstration of HIV (or SIV) infecting endothelial cells in vivo. However, this is not to say that HIV infection would not have any effects on the physiology of microvascular brain endothelial cells. Because of the elaborate nature of cerebral microvessels, previous studies of cerebral endothelial cells have been constrained by sectioning artifacts. Examination of freshly isolated cerebral microvessels allows investigation of extended lengths of vessels (>150 μm) without sectioning artifacts. These studies determine the changes in the expression of the tight junction protein zo-1 protein on the endothelial cells of cerebral capillaries at terminal acquired immune deficiency syndrome, demonstrating that there is a decreased expression of zo-1 protein over extended lengths of microvessels.

BACKGROUND Obese adolescents are at a greater risk of vitamin D deficiency because vitamin D is thought to be sequestered by excess adipose tissue. Poor vitamin D status has been associated with a higher prevalence of the metabolic syndrome, type 2 diabetes, or both in adults and adolescents. OBJECTIVE The objective was to determine in obese adolescents the efficacy and safety of 4000 IU vitamin D3/d and whether subsequent increased circulating concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with improved markers of insulin sensitivity and resistance and reduced inflammation. DESIGN Obese adolescent patients [n = 35; mean ± SD age: 14.1 ± 2.8 y; BMI (in kg/m(2)): 39.8 ± 6.1; 25(OH)D: 19.6 ± 7.1 ng/mL] were recruited from the University of Missouri Adolescent Diabetes and Obesity Clinic and were randomly assigned to receive either vitamin D3 (4000 IU/d) or placebo as part of their standard care. Anthropometric measurements, inflammatory markers (IL-6, TNF-α, C-reactive protein), adipokines (leptin, adiponectin), fasting glucose, fasting insulin, and HOMA-IR values were measured at baseline and at 2 follow-up visits (3 and 6 mo). RESULTS After 6 mo, there were no significant differences in BMI, serum inflammatory markers, or plasma glucose concentrations between groups. Participants supplemented with vitamin D3 had increases in serum 25(OH)D concentrations (19.5 compared with 2.8 ng/mL for placebo; P < 0.001), fasting insulin (-6.5 compared with +1.2 μU/mL for placebo; P = 0.026), HOMA-IR (-1.363 compared with +0.27 for placebo; P = 0.033), and leptin-to-adiponectin ratio (-1.41 compared with +0.10 for placebo; P = 0.045). Inflammatory markers remained unchanged. CONCLUSION The correction of poor vitamin D status through dietary supplementation may be an effective addition to the standard treatment of obesity and its associated insulin resistance. This trial was registered at clinicaltrials.gov as NCT00994396.

Most patients with adult respiratory distress syndrome (ARDS) survive the initial insult which caused respiratory failure only to succumb later to sepsis caused by nosocomial pneumonia or to pulmonary fibrosis. Clinical criteria and analysis of the tracheal aspirate are notoriously inadequate for establishing a diagnosis of ventilator-associated pneumonia. We implemented a comprehensive diagnostic protocol to determine the cause of sepsis in ARDS patients who had been ventilated for more than three days and who had no bronchoscopic evidence of pneumonia. Nine patients with late ARDS who had fever (89 percent), leukocytosis (89 percent), a new localized infiltrate (78 percent), purulent tracheal secretions (89 percent), low systemic vascular resistance (50 percent), and marked uptake of gallium in the lungs (100 percent) had no source of infection identified. Open-lung biopsy specimens from seven patients showed the fibroproliferative phase of diffuse alveolar damage and confirmed absence of pneumonia. Treatment with prolonged high doses of corticosteroids was associated with a marked and rapid improvement in lung injury score (p less than 0.003 at five days). Our findings indicate that the fibroproliferative process occurring in the lungs of patients with late ARDS gives rise to clinical manifestations identical to those of pneumonia and is potentially responsive to steroid treatment.

To evaluate the diagnostic value of gallium-67 scintigraphy in febrile ventilated patients by correlating the findings of 67Ga scintigraphy to sources of fever and pulmonary density, as determined by a comprehensive protocolized diagnostic evaluation.Prospective observational study.Thirty-two intubated patients on mechanical ventilation foror = 3 days with fever (or = 38.3 degrees C) and a new or progressive density on chest radiograph. Twenty patients (21 tests) had adult respiratory distress syndrome (ARDS).Diagnostic evaluation for fever included bronchoscopy with protected specimen brushing and (protected) bronchoalveolar lavage (BAL); computed tomography (CT) of sinuses; cultures of blood, urine, and central lines; and CT of the abdomen in high-risk patients.Uptake of 67Ga was reported as either focal or diffuse pulmonary uptake and extrapulmonary uptake. The combined causes of fever were pneumonia (9), fibroproliferation of late ARDS (7), abdominal process (4), sinusitis (4), urinary tract infection (3), and others (6). Causes of the pulmonary densities were pneumonia (9), ARDS (13), atelectasis (7), congestive heart failure (3), and empyema (1). Marked and diffuse pulmonary uptake was found only in patients with ARDS; however, it was not useful in discriminating those patients with pulmonary fibroproliferation as the sole cause of fever (p = 0.167) from those with infection. 67Ga scintigraphy was inadequate for detecting pneumonia but valuable in identifying extrapulmonary sites of infection in patients with ARDS (p = 0.021).67Ga scintigraphy should be considered only as an adjunct diagnostic test in the febrile, ventilated patient who has no obvious source of fever, despite a negative evaluation that includes testing for pneumonia, sinusitis, and urinary tract infection, conditions that are rarely detected by 67Ga scintigraphy.

Most Chlamydia pneumoniae infections are mild, but 10% develop into pneumonia. C. pneumoniae has been observed in hospital in intubated patients undergoing major surgery or admitted with severe trauma. A patient with squamous cell carcinoma in whom severe pneumonia developed postpneumonectomy and who required mechanical ventilation is presented. The patient was initially treated for nosocomial bacterial pneumonia with the broad spectrum antibiotics ceftazidime, amikacin, and vancomycin. The patient underwent a bronchoalveolar lavage, from which C. pneumoniae was grown. Generally, these patients are a high-risk mortality group. Only after substituting the above antibiotics with doxycycline, to which C. pneumoniae was sensitive, did the pneumonia respond. Whether this was a nosocomial or a community-acquired pneumonia is uncertain.

Most patients with adult respiratory distress syndrome (ARDS) survive the initial insult which caused respiratory failure only to succumb later to sepsis caused by nosocomial pneumonia or to pulmonary fibrosis. Clinical criteria and analysis of the tracheal aspirate are notoriously inadequate for establishing a diagnosis of ventilator-associated pneumonia. We implemented a comprehensive diagnostic protocol to determine the cause of sepsis in ARDS patients who had been ventilated for more than three days and who had no bronchoscopic evidence of pneumonia. Nine patients with late ARDS who had fever (89 percent), leukocytosis (89 percent), a new localized infiltrate (78 percent), purulent tracheal secretions (89 percent), low systemic vascular resistance (50 percent), and marked uptake of gallium in the lungs (100 percent) had no source of infection identified. Open-lung biopsy specimens from seven patients showed the fibroproliferative phase of diffuse alveolar damage and confirmed absence of pneumonia. Treatment with prolonged high doses of corticosteroids was associated with a marked and rapid improvement in lung injury score (p less than 0.003 at five days). Our findings indicate that the fibroproliferative process occurring in the lungs of patients with late ARDS gives rise to clinical manifestations identical to those of pneumonia and is potentially responsive to steroid treatment.