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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.

Diabetic cardiomyopathy refers to a unique set of heart-specific pathological variables induced by hyperglycemia and insulin resistance. Given that cardiovascular disease (CVD) is the leading cause of death in the world, and type 2 diabetes incidence continues to rise, understanding the complex interplay between these two morbidities and developing novel therapeutic strategies is vital. Two hallmark characteristics specific to diabetic cardiomyopathy are diastolic dysfunction and cardiac structural mal-adaptations, arising from cardiac cellular responses to the complex toxicity induced by hyperglycemia with or without hyperinsulinemia. While type 2 diabetes is more prevalent in men compared to women, cardiovascular risk is higher in diabetic women than in diabetic men, suggesting that diabetic women take a steeper path to cardiomyopathy and heart failure. Accumulating evidence from randomized clinical trials indicate that although pre-menopausal women have lower risk of CVDs, compared to age-matched men, this advantage is lost in diabetic pre-menopausal women, which suggests estrogen availability does not protect from increased cardiovascular risk. Notably, few human studies have assessed molecular and cellular mechanisms regarding similarities and differences in the progression of diabetic cardiomyopathy in men versus women. Additionally, most pre-clinical rodent studies fail to include female animals, leaving a void in available data to truly understand the impact of biological sex differences in diabetes-induced dysfunction of cardiovascular cells. Elegant reviews in the past have discussed in detail the roles of estrogen-mediated signaling in cardiovascular protection, sex differences associated with telomerase activity in the heart, and cardiac responses to exercise. In this review, we focus on the emerging cellular and molecular markers that define sex differences in diabetic cardiomyopathy based on the recent clinical and pre-clinical evidence. We also discuss miR-208a, MED13, and AT2R, which may provide new therapeutic targets with hopes to develop novel treatment paradigms to treat diabetic cardiomyopathy uniquely between men and women.

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.

Rapamycin (Rap), an inhibitor of mTORC1, reduces obesity and improves lifespan in mice. However, hyperglycemia and lipid disorders are adverse side effects in patients receiving Rap treatment. We previously reported that diabetes induces pansuppression of cardiac cytokines in Zucker obese rats (ZO-C). Rap treatment (750 μg/kg/day for 12 weeks) reduced their obesity and cardiac fibrosis significantly; however, it increased their hyperglycemia and did not improve their cardiac diastolic parameters. Moreover, Rap treatment of healthy Zucker lean rats (ZL-C) induced cardiac fibrosis. Rap-induced changes in ZL-C’s cardiac cytokine profile shared similarities with that of diabetes-induced ZO-C. Therefore, we hypothesized that the cardiac microRNA transcriptome induced by diabetes and Rap treatment could share similarities. Here, we compared the cardiac miRNA transcriptome of ZL-C to ZO-C, Rap-treated ZL (ZL-Rap), and ZO (ZO-Rap). We report that 80% of diabetes-induced miRNA transcriptome (40 differentially expressed miRNAs by minimum 1.5-fold in ZO-C versus ZL-C; p≤0.05) is similar to 47% of Rap-induced miRNA transcriptome in ZL (68 differentially expressed miRNAs by minimum 1.5-fold in ZL-Rap versus ZL-C; p≤0.05). This remarkable similarity between diabetes-induced and Rap-induced cardiac microRNA transcriptome underscores the role of miRNAs in Rap-induced insulin resistance. We also show that Rap treatment altered the expression of the same 17 miRNAs in ZL and ZO hearts indicating that these 17 miRNAs comprise a unique Rap-induced cardiac miRNA signature. Interestingly, only four miRNAs were significantly differentially expressed between ZO-C and ZO-Rap, indicating that, unlike the nondiabetic heart, Rap did not substantially change the miRNA transcriptome in the diabetic heart. In silico analyses showed that (a) mRNA-miRNA interactions exist between differentially expressed cardiac cytokines and miRNAs, (b) human orthologs of rat miRNAs that are strongly correlated with cardiac fibrosis may modulate profibrotic TGF-β signaling, and (c) changes in miRNA transcriptome caused by diabetes or Rap treatment include cardioprotective miRNAs indicating a concurrent activation of an adaptive mechanism to protect the heart in conditions that exacerbate diabetes.

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.

Modifications of Einstein's theory of gravitation have been extensively considered in the past years, in connection to both cosmology and quantum gravity. Higher-curvature and higher-derivative gravity theories constitute the main examples of such modifications. These theories exhibit, in general, more degrees of freedom than those found in standard General Relativity; counting, identifying, and retrieving the description/representation of such dynamical variables is currently an open problem, and a decidedly nontrivial one. In this work we review, via both formal arguments and custom-made examples, the most relevant methods to unveil the gravitational degrees of freedom of a given model, discussing the merits, subtleties and pitfalls of the various approaches., 85 pages; typos corrected, references added; conclusions improved

PURPOSE: Maternal vitamin D deficiency during pregnancy is a widespread issue that may have long-lasting consequences on offspring adiposity. We sought to determine how maternal vitamin D deficiency during the perinatal period would affect offspring adipose tissue development and gene expression. METHODS: Female C57BL/6 J mice were fed either a vitamin D deficient (VDD) or control diet from 4 weeks before pregnancy (periconception) until 7 days postparturition. Male offspring were weighed and euthanized at 75 days of age (early adult period), at which point serum was collected for biochemical analyses, and perigonadal and subcutaneous white adipose tissue (PGAT and SQAT, respectively) were excised, weighed, then flash-frozen for later histology and analyses of adipogenic gene expression. RESULTS: All adult male offspring were nonobese; there were no significant differences in body weight, adipose pad weight, or adipocyte size. However, VDD-exposed offspring had greater expression of the adipogenic-regulating genes peroxisome proliferator-activated receptor gamma (Pparg) and vitamin D receptor (Vdr). CONCLUSIONS: This study suggests that exposure to vitamin D deficiency during the perinatal period can directly affect genes involved in the development of adipose tissue in non-obese offspring. These novel findings invite further investigation into the mechanisms by which maternal vitamin D status during pregnancy affects adipose development and metabolic health of offspring.

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

We revisit here the naturalness problem of Lorentz invariance violations on a simple toy model of a scalar field coupled to a fermion field via a Yukawa interaction. We first review some well-known results concerning the low-energy percolation of Lorentz violation from high energies, presenting some details of the analysis not explicitly discussed in the literature and discussing some previously unnoticed subtleties. We then show how a separation between the scale of validity of the effective field theory and that one of Lorentz invariance violations can hinder this low-energy percolation. While such protection mechanism was previously considered in the literature, we provide here a simple illustration of how it works and of its general features. Finally, we consider a case in which dissipation is present, showing that the dissipative behaviour does not percolate generically to lower mass dimension operators albeit dispersion does. Moreover, we show that a scale separation can protect from unsuppressed low-energy percolation also in this case., Comment: 33 pages, 5 figures. Some typos corrected, this version accepted for publication in JHEP

This proceeding is based on a talk prepared for the XIV Marcel Grossmann meeting. We review some results on causal set inspired non-local theories as well as work in progress concerning their phenomenology., 6 pages, 3 figures. Prepared for the Proceedings of the 14th Marcel Grossmann meeting

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

We investigate the spectral dimension obtained from non-local continuum d'Alembertians derived from causal sets. We find a universal dimensional reduction to 2 dimensions, in all dimensions. We conclude by discussing the validity and relevance of our results within the broader context of quantum field theories based on these nonlocal dynamics., 7 pages, 2 figures, version accepted for publication in Phys. Rev. D

We study a non-local scalar quantum field theory in flat spacetime derived from the dynamics of a scalar field on a causal set. We show that this non-local QFT contains a continuum of massive modes in any dimension. In 2 dimensions the Hamiltonian is positive definite and therefore the quantum theory is well-defined. In 4-dimensions, we show that the unstable modes of the non-local d'Alembertian are propagated via the so called Wheeler propagator and hence do not appear in the asymptotic states. In the free case studied here the continuum of massive mode are shown to not propagate in the asymptotic states. However the Hamiltonian is not positive definite, therefore potential issues with the quantum theory remain. Finally, we conclude with hints toward what kind of phenomenology one might expect from such non-local QFTs., Comment: 24 pages, 7 figures. Published in JHEP 1503 (2015) 036

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.