Pacing-induced regional differences in adenosine receptors mRNA expression in a Swine model of dilated cardiomyopathy.

The adenosinergic system is essential in the mediation of intrinsic protection and myocardial resistance to insult; it may be considered a cardioprotective molecule and adenosine receptors (ARs) represent potential therapeutic targets in the setting of heart failure (HF). The aim of the study was to test whether differences exist between mRNA expression of ARs in the anterior left ventricle (LV) wall (pacing site: PS) compared to the infero septal wall (opposite region: OS) in an experimental model of dilated cardiomyopathy. Cardiac tissue was collected from LV PS and OS of adult male minipigs with pacing-induced HF (n = 10) and from a control group (C, n = 4). ARs and TNF-α mRNA expression was measured by Real Time-PCR and the results were normalized with the three most stably expressed genes (GAPDH, HPRT1, TBP). Immunohistochemistry analysis was also performed. After 3 weeks of pacing higher levels of expression for each analyzed AR were observed in PS except for A1R (A1R: C = 0.6±0.2, PS = 0.1±0.04, OS = 0.04±0.01, p<0.0001 C vs. PS and OS respectively; A2AR: C = 1.04±0.59, PS = 2.62±0.79, OS = 2.99±0.79; A2BR: C = 1.2±0.1, PS = 5.59±2.3, OS = 1.59±0.46; A3R: C = 0.76±0.18, PS = 8.40±3.38, OS = 4.40±0.83). Significant contractile impairment and myocardial hypoperfusion were observed at PS after three weeks of pacing as compared to OS. TNF-α mRNA expression resulted similar in PS (6.3±2.4) and in OS (5.9±2.7) although higher than in control group (3.4±1.5). ARs expression was mainly detected in cardiomyocytes. This study provided new information on ARs local changes in the setting of LV dysfunction and on the role of these receptors in relation to pacing-induced abnormalities of myocardial perfusion and contraction. These results suggest a possible therapeutic role of adenosine in patients with HF and dyssynchronous LV contraction

Halo abundances and counts-in-cells: The excursion set approach with correlated steps

The Excursion Set approach has been used to make predictions for a number of interesting quantities in studies of nonlinear hierarchical clustering. These include the halo mass function, halo merger rates, halo formation times and masses, halo clustering, analogous quantities for voids, and the distribution of dark matter counts in randomly placed cells. The approach assumes that all these quantities can be mapped to problems involving the first crossing distribution of a suitably chosen barrier by random walks. Most analytic expressions for these distributions ignore the fact that, although different k-modes in the initial Gaussian field are uncorrelated, this is not true in real space: the values of the density field at a given spatial position, when smoothed on different real-space scales, are correlated in a nontrivial way. As a result, the problem is to estimate first crossing distribution by random walks having correlated rather than uncorrelated steps. In 1990, Peacock & Heavens presented a simple approximation for the first crossing distribution of a single barrier of constant height by walks with correlated steps. We show that their approximation can be thought of as a correction to the distribution associated with what we call smooth completely correlated walks. We then use this insight to extend their approach to treat moving barriers, as well as walks that are constrained to pass through a certain point before crossing the barrier. For the latter, we show that a simple rescaling, inspired by bivariate Gaussian statistics, of the unconditional first crossing distribution, accurately describes the conditional distribution, independently of the choice of analytical prescription for the former. In all cases, comparison with Monte-Carlo solutions of the problem shows reasonably good agreement. (Abridged)Comment: 14 pages, 9 figures; v2 -- revised version with explicit demonstration that the original conclusions hold for LCDM, expanded discussion on stochasticity of barrier. Accepted in MNRA

An engineered escherichia coli strain with synthetic metabolism for in‐cell production of translationally active methionine derivatives

In the last decades, it has become clear that the canonical amino acid repertoire codified by the universal genetic code is not up to the needs of emerging biotechnologies. For this reason, extensive genetic code re‐engineering is essential to expand the scope of ribosomal protein translation, leading to reprogrammed microbial cells equipped with an alternative biochemical alphabet to be exploited as potential factories for biotechnological purposes. The prerequisite for this to happen is a continuous intracellular supply of noncanonical amino acids through synthetic metabolism from simple and cheap precursors. We have engineered an Escherichia coli bacterial system that fulfills these requirements through reconfiguration of the methionine biosynthetic pathway and the introduction of an exogenous direct trans‐sulfuration pathway. Our metabolic scheme operates in vivo, rescuing intermediates from core cell metabolism and combining them with small bio‐orthogonal compounds. Our reprogrammed E. coli strain is capable of the in‐cell production of L‐azidohomoalanine, which is directly incorporated into proteins in response to methionine codons. We thereby constructed a prototype suitable for economic, versatile, green sustainable chemistry, pushing towards enzyme chemistry and biotechnology‐based production

ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer

Activating mutations of fibroblast growth factor receptor 3 (FGFR3) are common in urothelial carcinoma of the bladder (UC). Silencing or inhibition of mutant FGFR3 in bladder cancer cell lines is associated with decreased malignant potential, confirming its important driver role in UC. However, understanding of how FGFR3 activation drives bladder malignant transformation remains limited. We have previously shown that mutant FGFR3 alters the cell-cell and cell-matrix adhesion properties of urothelial cells, resulting in loss of contact-inhibition of proliferation. In this study, we investigate a transcription factor of the ETS-family, ETV5, as a putative effector of FGFR3 signalling in bladder cancer. We show that FGFR3 signalling induces a MAPK/ERK-mediated increase in ETV5 levels, and that this results in increased level of TAZ, a co-transcriptional regulator downstream of the Hippo signalling pathway involved in cell-contact inhibition. We also demonstrate that ETV5 is a key downstream mediator of the oncogenic effects of mutant FGFR3, as its knockdown in FGFR3-mutant bladder cancer cell lines is associated with reduced proliferation and anchorage-independent growth. Overall this study advances our understanding of the molecular alterations occurring during bladder malignant transformation and indicates TAZ as a possible therapeutic target in FGFR3-dependent bladder tumours

A place for precision medicine in bladder cancer: targeting the FGFRs

Bladder tumors show diverse molecular features and clinical outcome. Muscle-invasive bladder cancer has poor prognosis and novel approaches to systemic therapy are urgently required. Non-muscle-invasive bladder cancer has good prognosis, but high recurrence rate and the requirement for life-long disease monitoring places a major burden on patients and healthcare providers. Studies of tumor tissues from both disease groups have identified frequent alterations of FGFRs, including mutations of FGFR3 and dysregulated expression of FGFR1 and FGFR3 that suggest that these may be valid therapeutic targets. We summarize current understanding of the molecular alterations affecting these receptors in bladder tumors, preclinical studies validating them as therapeutic targets, available FGFR-targeted agents and results from early clinical trials in bladder cancer patients

EVIDENCE OF ALTERED FEAR EXTINCTION LEARNING IN INDIVIDUALS WITH HIGH VACCINE HESITANCY DURING COVID-19 PANDEMIC

Objective: A relevance of fear and concerns about vaccine development and its side effects are suggested to explain COVID-19 vaccine hesitancy. However, evidence supporting the phobic origin hypothesis of hesitancy for COVID-19 and other vaccinations remains indirect and elusive. Method: We addressed this issue by investigating the existence of a relationship between fear conditioning, extinction, and the respective vaccination hesitancy and anxiety scores in a group of 25 individuals. Results: Overall, we show that the general mechanism of fear extinction learning is impaired in individuals with high vaccine hesitancy. State and trait anxiety scores do not account for this result. Conclusions: These findings suggest that attitudes against vaccination could be linked to an altered inhibitory learning process

Interdependent binary choices under social influence: phase diagram for homogeneous unbiased populations

Coupled Ising models are studied in a discrete choice theory framework, where they can be understood to represent interdependent choice making processes for homogeneous populations under social influence. Two different coupling schemes are considered. The nonlocal or group interdependence model is used to study two interrelated groups making the same binary choice. The local or individual interdependence model represents a single group where agents make two binary choices which depend on each other. For both models, phase diagrams, and their implications in socioeconomic contexts, are described and compared in the absence of private deterministic utilities (zero opinion fields).Comment: 17 pages, 3 figures. This is the pre-peer reviewed version of the following article: Ana Fern\'andez del R\'io, Elka Korutcheva and Javier de la Rubia, Interdependent binary choices under social influence, Wiley's Complexity, 2012; which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/cplx.21397/abstrac