Letrozole treatment of pubertal female mice results in activational effects on reproduction, metabolism and the gut microbiome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women that is comprised of two out of the following three features: hyperandrogenism, oligo- or amenorrhea, or polycystic ovaries. In addition to infertility, many women with PCOS have metabolic dysregulation that increases the risk of developing type 2 diabetes, hypertension, and non-alcoholic fatty liver disease. Changes in the gut microbiome are associated with PCOS and gut microbes may be involved in the pathology of this disorder. Since PCOS often manifests in the early reproductive years, puberty is considered to be a critical time period for the development of PCOS. Exposure to sex steroid hormones during development results in permanent, organizational effects, while activational effects are transient and require the continued presence of the hormone. Androgens exert organizational effects during prenatal or early post-natal development, but it is unclear whether androgen excess results in organizational or activational effects during puberty. We recently developed a letrozole-induced PCOS mouse model that recapitulates both reproductive and metabolic phenotypes of PCOS. In this study, we investigated whether letrozole treatment of pubertal female mice exerts organizational or activational effects on host physiology and the gut microbiome. Two months after letrozole removal, we observed recovery of reproductive and metabolic parameters, as well as diversity and composition of the gut microbiome, indicating that letrozole treatment of female mice during puberty resulted in predominantly activational effects. These results suggest that if exposure to excess androgens during puberty leads to the development of PCOS, reduction of androgen levels during this time may improve reproductive and metabolic phenotypes in women with PCOS. These results also imply that continuous letrozole exposure is required to model PCOS in pubertal female mice since letrozole exerts activational rather than organizational effects during puberty

Microvascular dysfunction in the immediate aftermath of chronic total coronary occlusion recanalization

Objectives The aim of this study was to compare microvascular resistance under both baseline and hyperemic conditions immediately after percutaneous coronary intervention (PCI) of a chronic total occlusion (CTO) with an unobstructed reference vessel in the same patient. Background Microvascular dysfunction has been reported to be prevalent immediately after CTO PCI. However, previous studies have not made comparison with a reference vessel. Patients with a CTO may have global microvascular and/or endothelial dysfunction, making comparison with established normal values misleading. Methods After successful CTO PCI in 21 consecutive patients, coronary pressure and flow velocity were measured at baseline and hyperemia in distal segments of the CTO/target vessel and an unobstructed reference vessel. Hemodynamics including hyperemic microvascular resistance (HMR), basal microvascular resistance (BMR), and instantaneous minimal microvascular resistance at baseline and hyperemia were calculated and compared between reference and target/CTO vessels. Results After CTO PCI, BMR was reduced in the target/CTO vessel compared with the reference vessel: 3.58 mm Hg/cm/s vs 4.94 mm Hg/cm/s, difference −1.36 mm Hg/cm/s (−2.33 to −0.39, p = 0.008). We did not detect a difference in HMR: 1.82 mm Hg/cm/s vs 2.01 mm Hg/cm/s, difference −0.20 (−0.78 to 0.39, p = 0.49). Instantaneous minimal microvascular resistance correlated strongly with the length of stented segment at baseline (r = 0.63, p = 0.005) and hyperemia (r = 0.68, p = 0.002). Conclusions BMR is reduced in a recanalized CTO in the immediate aftermath of PCI compared to an unobstructed reference vessel; however, HMR appears to be preserved. A longer stented segment is associated with increased microvascular resistance

Collateral donor artery physiology and the influence of a chronic total occlusion on fractional flow reserve

Background— The presence of a concomitant chronic total coronary occlusion (CTO) and a large collateral contribution might alter the fractional flow reserve (FFR) of an interrogated vessel, rendering the FFR unreliable at predicting ischemia should the CTO vessel be revascularized and potentially affecting the decision on optimal revascularization strategy. We tested the hypothesis that donor vessel FFR would significantly change after percutaneous coronary intervention of a concomitant CTO. Methods and Results— In consecutive patients undergoing percutaneous coronary intervention of a CTO, coronary pressure and flow velocity were measured at baseline and hyperemia in proximal and distal segments of both nontarget vessels, before and after percutaneous coronary intervention. Hemodynamics including FFR, absolute coronary flow, and the coronary flow velocity–pressure gradient relation were calculated. After successful percutaneous coronary intervention in 34 of 46 patients, FFR in the predominant donor vessel increased from 0.782 to 0.810 (difference, 0.028 [0.012 to 0.044]; P=0.001). Mean decrease in baseline donor vessel absolute flow adjusted for rate pressure product: 177.5 to 139.9 mL/min (difference −37.6 [−62.6 to −12.6]; P=0.005), mean decrease in hyperemic flow: 306.5 to 272.9 mL/min (difference, −33.5 [−58.7 to −8.3]; P=0.011). Change in predominant donor vessel FFR correlated with angiographic (%) diameter stenosis severity (r=0.44; P=0.009) and was strongly related to stenosis severity measured by the coronary flow velocity–pressure gradient relation (r=0.69; P<0.001). Conclusions— Recanalization of a CTO results in a modest increase in the FFR of the predominant collateral donor vessel associated with a reduction in coronary flow. A larger increase in FFR is associated with greater coronary stenosis severity

Biomarkers of coronary endothelial health: correlation with invasive measures of collateral function, flow and resistance in chronically occluded coronary arteries and the effect of recanalization

Objectives: In the presence of a chronically occluded coronary artery, the collateral circulation matures by a process of arteriogenesis; however, there is considerable variation between individuals in the functional capacity of that collateral network. This could be explained by differences in endothelial health and function. We aimed to examine the relationship between the functional extent of collateralization and levels of biomarkers that have been shown to relate to endothelial health. Methods: We measured four potential biomarkers of endothelial health in 34 patients with mature collateral networks who underwent a successful percutaneous coronary intervention (PCI) for a chronic total coronary occlusion (CTO) before PCI and 6-8 weeks after PCI, and examined the relationship of biomarker levels with physiological measures of collateralization. Results: We did not find a significant change in the systemic levels of sICAM-1, sE-selectin, microparticles or tissue factor 6-8 weeks after PCI. We did find an association between estimated retrograde collateral flow before CTO recanalization and lower levels of sICAM-1 (r=0.39, P=0.026), sE-selectin (r=0.48, P=0.005) and microparticles (r=0.38, P=0.03). Conclusion: Recanalization of a CTO and resultant regression of a mature collateral circulation do not alter systemic levels of sICAM-1, sE-selectin, microparticles or tissue factor. The identified relationship of retrograde collateral flow with sICAM-1, sE-selectin and microparticles is likely to represent an association with an ability to develop collaterals rather than their presence and extent

Introducing Psychological Concepts and Methods to Cybersecurity Students

This chapter will begin with a brief review of the literature that highlights what psychology research and practice can offer to cybersecurity education. The authors draw on their wide-ranging inter-disciplinary teaching experience and in this chapter they discuss their observations gained from teaching psychological principles and methods to undergraduate and postgraduate cybersecurity students. The authors pay special attention to the consideration of the characteristics of cybersecurity students, so that psychology is taught in a way that is accessible and engaging. Finally, the authors offer some practical suggestions for academics to help them incorporate psychology into the cybersecurity curriculum

Prion-induced neurotoxicity: Possible role for cell cycle activity and DNA damage response.

Protein misfolding neurodegenerative diseases arise through neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, motor neuron disease, tauopathies and prion diseases. Collectively, these conditions are a challenge to society because of the increasing aged population and through the real threat to human food security by animal prion diseases. It is therefore important to understand the cellular and molecular mechanisms that underlie protein misfolding-induced neurotoxicity as this will form the basis for designing strategies to alleviate their burden. Prion diseases are an important paradigm for neurodegenerative conditions in general since several of these maladies have now been shown to display prion-like phenomena. Increasingly, cell cycle activity and the DNA damage response are recognised as cellular events that participate in the neurotoxic process of various neurodegenerative diseases, and their associated animal models, which suggests they are truly involved in the pathogenic process and are not merely epiphenomena. Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases, and suggest that these events contribute towards prion-induced neurotoxicity. In doing so, we highlight PrP transgenic Drosophila as a tractable model for the genetic analysis of transmissible mammalian prion disease.Supported by The NC3Rs No. NC/K000462/1 (in part).This is the final published version. It first appeared at http://dx.doi.org/10.5501/wjv.v4.i3.188

Teaching Psychological Principles to Cybersecurity Students

This paper will discuss our observations gained from teaching psychological principles and methods to undergraduate and postgraduate cybersecurity students. We will draw on and extend our previous work encouraging the teaching of psychology in computing and cybersecurity education. We pay special attention to the consideration of characteristics of cybersecurity students in terms of teaching psychology in a way that will be accessible and engaging. We then discuss the development and use of an online training tool which draws on psychology to help educators and companies to raise awareness of cybersecurity risks in students and employees. Finally, we offer some practical suggestions to incorporate psychology into the cybersecurity curriculum

Hypergraph models of biological networks to identify genes critical to pathogenic viral response

BACKGROUND: Representing biological networks as graphs is a powerful approach to reveal underlying patterns, signatures, and critical components from high-throughput biomolecular data. However, graphs do not natively capture the multi-way relationships present among genes and proteins in biological systems. Hypergraphs are generalizations of graphs that naturally model multi-way relationships and have shown promise in modeling systems such as protein complexes and metabolic reactions. In this paper we seek to understand how hypergraphs can more faithfully identify, and potentially predict, important genes based on complex relationships inferred from genomic expression data sets. RESULTS: We compiled a novel data set of transcriptional host response to pathogenic viral infections and formulated relationships between genes as a hypergraph where hyperedges represent significantly perturbed genes, and vertices represent individual biological samples with specific experimental conditions. We find that hypergraph betweenness centrality is a superior method for identification of genes important to viral response when compared with graph centrality. CONCLUSIONS: Our results demonstrate the utility of using hypergraphs to represent complex biological systems and highlight central important responses in common to a variety of highly pathogenic viruses