ACE2 and AT4R are present in diseased human blood vessels

A growing body of evidence suggests that the angiotensin II fragments, Ang(1-7) and Ang(3-8), have a vasoactive role, however ACE2, the enzyme that produces Ang(1-7), or AT4R, the receptor that binds Ang (3-8), have yet been simultaneously localised in both normal and diseased human conduit blood vessels. We sought to determine the immunohistochemical distribution of ACE2 and the AT4R in human internal mammary and radial arteries from patients undergoing coronary artery bypass surgery.We found that ACE2 positive cells were abundant in both normal and diseased vessels, being present in neo-intima and in media. ACE2 positive immunoreactivity was not present in the endothelial layer of the conduit vessels, but was clearly evident in small newly formed angiogenic vessels as well as the vaso vasorum. Endothelial AT4R immunoreactivity were rarely observed in either normal and diseased arteries, but AT4R positive cells were observed adjacent to the internal elastic lamine in the internal mammary artery, in the neo-intima of radial arteries, as well as in the media of both internal mammary artery and radial artery. AT4R was abundant in vaso vasorum and within small angiogenic vessels. Both AT4R and ACE2 colocalised with smooth muscle cell a actin. This study identifies smooth muscle cell a actin positive ACE2 and AT4R in human blood vessels as well as in angiogenic vessels, indicating a possible role for these enzymes in pathological disease

The e-Index, Complementing the h-Index for Excess Citations

BACKGROUND: The h-index has already been used by major citation databases to evaluate the academic performance of individual scientists. Although effective and simple, the h-index suffers from some drawbacks that limit its use in accurately and fairly comparing the scientific output of different researchers. These drawbacks include information loss and low resolution: the former refers to the fact that in addition to h(2) citations for papers in the h-core, excess citations are completely ignored, whereas the latter means that it is common for a group of researchers to have an identical h-index. METHODOLOGY/PRINCIPAL FINDINGS: To solve these problems, I here propose the e-index, where e(2) represents the ignored excess citations, in addition to the h(2) citations for h-core papers. Citation information can be completely depicted by using the h-index together with the e-index, which are independent of each other. Some other h-type indices, such as a and R, are h-dependent, have information redundancy with h, and therefore, when used together with h, mask the real differences in excess citations of different researchers. CONCLUSIONS/SIGNIFICANCE: Although simple, the e-index is a necessary h-index complement, especially for evaluating highly cited scientists or for precisely comparing the scientific output of a group of scientists having an identical h-index

The Carbon_h-Factor: Predicting Individuals' Research Impact at Early Stages of Their Career

Assessing an individual's research impact on the basis of a transparent algorithm is an important task for evaluation and comparison purposes. Besides simple but also inaccurate indices such as counting the mere number of publications or the accumulation of overall citations, and highly complex but also overwhelming full-range publication lists in their raw format, Hirsch (2005) introduced a single figure cleverly combining different approaches. The so-called h-index has undoubtedly become the standard in scientometrics of individuals' research impact (note: in the present paper I will always use the term “research impact” to describe the research performance as the logic of the paper is based on the h-index, which quantifies the specific “impact” of, e.g., researchers, but also because the genuine meaning of impact refers to quality as well). As the h-index reflects the number h of papers a researcher has published with at least h citations, the index is inherently positively biased towards senior level researchers. This might sometimes be problematic when predictive tools are needed for assessing young scientists' potential, especially when recruiting early career positions or equipping young scientists' labs. To be compatible with the standard h-index, the proposed index integrates the scientist's research age (Carbon_h-factor) into the h-index, thus reporting the average gain of h-index per year. Comprehensive calculations of the Carbon_h-factor were made for a broad variety of four research-disciplines (economics, neuroscience, physics and psychology) and for researchers performing on three high levels of research impact (substantial, outstanding and epochal) with ten researchers per category. For all research areas and output levels we obtained linear developments of the h-index demonstrating the validity of predicting one's later impact in terms of research impact already at an early stage of their career with the Carbon_h-factor being approx. 0.4, 0.8, and 1.5 for substantial, outstanding and epochal researchers, respectively

DOK3 Negatively Regulates LPS Responses and Endotoxin Tolerance

Innate immune activation via Toll-like receptors (TLRs), although critical for host defense against infection, must be regulated to prevent sustained cell activation that can lead to cell death. Cells repeatedly stimulated with lipopolysaccharide (LPS) develop endotoxin tolerance making the cells hypo-responsive to additional TLR stimulation. We show here that DOK3 is a negative regulator of TLR signaling by limiting LPS-induced ERK activation and cytokine responses in macrophages. LPS induces ubiquitin-mediated degradation of DOK3 leading to SOS1 degradation and inhibition of ERK activation. DOK3 mice are hypersensitive to sublethal doses of LPS and have altered cytokine responses in vivo. During endotoxin tolerance, DOK3 expression remains stable, and it negatively regulates the expression of SHIP1, IRAK-M, SOCS1, and SOS1. As such, DOK3-deficient macrophages are more sensitive to LPS-induced tolerance becoming tolerant at lower levels of LPS than wild type cells. Taken together, the absence of DOK3 increases LPS signaling, contributing to LPS-induced tolerance. Thus, DOK3 plays a role in TLR signaling during both naïve and endotoxin-induced tolerant conditions

The chemical signatures underlying host plant discrimination by aphids

The diversity of phytophagous insects is largely attributable to speciation involving shifts between host plants. These shifts are mediated by the close interaction between insects and plant metabolites. However, there has been limited progress in understanding the chemical signatures that underlie host preferences. We use the pea aphid (Acyrthosiphon pisum) to address this problem. Host-associated races of pea aphid discriminate between plant species in race-specific ways. We combined metabolomic profiling of multiple plant species with behavioural tests on two A. pisum races, to identify metabolites that explain variation in either acceptance or discrimination. Candidate compounds were identified using tandem mass spectrometry. Our results reveal a small number of compounds that explain a large proportion of variation in the differential acceptability of plants to A. pisum races. Two of these were identified as L-phenylalanine and L-tyrosine but it may be that metabolically-related compounds directly influence insect behaviour. The compounds implicated in differential acceptability were not related to the set correlated with general acceptability of plants to aphids, regardless of host race. Small changes in response to common metabolites may underlie host shifts. This study opens new opportunities for understanding the mechanistic basis of host discrimination and host shifts in insects

Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure

Background-Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants.Methods and Results-We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression.Conclusions-Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure