Quantitative Systems Pharmacology and Biased Agonism at Opioid Receptors: A Potential Avenue for Improved Analgesics

Chronic pain is debilitating and represents a significant burden in terms of personal and socio-economic costs. Although opioid analgesics are widely used in chronic pain treatment, many patients report inadequate pain relief or relevant adverse effects, highlighting the need to develop analgesics with improved efficacy/safety. Multiple evidence suggests that G protein-dependent signaling triggers opioid-induced antinociception, whereas arrestin-mediated pathways are credited with modulating different opioid adverse effects, thus spurring extensive research for G protein-biased opioid agonists as analgesic candidates with improved pharmacology. Despite the increasing expectations of functional selectivity, translating G protein-biased opioid agonists into improved therapeutics is far from being fully achieved, due to the complex, multidimensional pharmacology of opioid receptors. The multifaceted network of signaling events and molecular processes underlying therapeutic and adverse effects induced by opioids is more complex than the mere dichotomy between G protein and arrestin and requires more comprehensive, integrated, network-centric approaches to be fully dissected. Quantitative Systems Pharmacology (QSP) models employing multidimensional assays associated with computational tools able to analyze large datasets may provide an intriguing approach to go beyond the greater complexity of opioid receptor pharmacology and the current limitations entailing the development of biased opioid agonists as improved analgesics

Dagli osservatóri agli Osservatòri

Quelli che hanno avuto il Vesuvio negli occhi, le loro storie di scienziati e di uomini, sono il tema di questo breve racconto. Storie di osservatóri, quindi, che hanno studiato il vulcano con passione, affascinati e sedotti da una montagna umbratile e solenne. Ma anche storie di Osservatòri, di contesti e tempi, ovvero, anch’essi mutevoli, in cui la scienza si organizza e si disorganizza per comprendere, prevedere, provvedere

New concepts for light mechanical structures of cylindrical drift chambers

A significant reduction in the amount of material at the end plates of a drift chamber can be obtained by the simple consideration of separating, in the mechanical structure, the gas containment function from the wire tension support function. According to this scheme, the wires are anchored to a self-sustaining light structure ("wire cage") surrounded by a very thin skin ("gas envelope") of suitable profile to compensate for the gas differential pressure with respect to the outside. The "wire cage" is schematically made of a set of radial spokes, constrained into a polygonal shape at the inner ends and extended to the outer endplate rim, thus subdividing the chamber in identical sectors. The drift chamber is, then, built by stacking up radially, in each of the sectors and between adjacent spokes, printed circuit boards, where the ends of the wires are soldered, alternated with proper spacers, to define the cell width. A system of adjustable tie-rods steers the wire tension to the outer endplate rim, where a rigid cylindrical carbon fibre support structure, bearing the total wire load, is attached. Two thin carbon fibre domes, free to deform under the gas pressure without affecting the wire tension and conveniently shaped to minimize the stress at the inner rim, contribute to the "gas envelope" and, together with an inner thin cylindrical foil and with the outer structural support, enclose the gas volume

Role of Estimated Glomerular Filtration Rate in Clinical Research: The Never-Ending Matter

Background: Chronic kidney disease (CKD) burden is crucial both on a global scale and at individual patient level, affecting morbidity and mortality directly and through its effect on both cardiovascular damage and CKD progression to end-stage-kidney-disease (ESKD). Unfortunately, the awareness of CKD is poor, with few CKD patients conscious of the severity of their health status. The principal biomarker of kidney function is estimated glomerular filtration rate (eGFR). Methods: We searched the literature and present a review article with the aim of summarizing the role of eGFR in clinical research. In particular, we report the eGFR role as a prognostic, enrichment and endpoint biomarker and its role in the early detection of CKD. Results: eGFR has a major role as a biomarker in clinical research. As a prognostic marker, eGFR reduction is associated with cardiovascular events, ESKD and mortality. As an enrichment biomarker, eGFR values are pivotal for selecting patients to be included in randomized and observational studies; it helps to test a pre-defined drug in early CKD or in more advanced CKD allowing also to avoid screening failures and to shorten the duration of clinical trials. Moreover, eGFR decline (expressed as a percentage of reduction from baseline or continuous slope) can be considered a good endpoint in clinic trials overcoming delays whilst waiting for hard endpoints to develop. Conclusions: eGFR is a strong clinical measure for both observational and intervention studies. It is also helpful in screening the general population for kidney disease and, in particular, to increase awareness of CKD

A conserved role for Snail as a potentiator of active transcription

The transcription factors of the Snail family are key regulators of epithelial-mesenchymal transitions, cell morphogenesis, and tumor metastasis. Since its discovery in Drosophila ~25 years ago, Snail has been extensively studied for its role as a transcriptional repressor. Here we demonstrate that Drosophila Snail can positively modulate transcriptional activation. By combining information on in vivo occupancy with expression profiling of hand-selected, staged snail mutant embryos, we identified 106 genes that are potentially directly regulated by Snail during mesoderm development. In addition to the expected Snail-repressed genes, almost 50% of Snail targets showed an unanticipated activation. The majority of "Snail-activated" genes have enhancer elements cobound by Twist and are expressed in the mesoderm at the stages of Snail occupancy. Snail can potentiate Twist-mediated enhancer activation in vitro and is essential for enhancer activity in vivo. Using a machine learning approach, we show that differentially enriched motifs are sufficient to predict Snail's regulatory response. In silico mutagenesis revealed a likely causative motif, which we demonstrate is essential for enhancer activation. Taken together, these data indicate that Snail can potentiate enhancer activation by collaborating with different activators, providing a new mechanism by which Snail regulates development

Iloprost in Acute Post-kidney Transplant Atheroembolism: A Case Report of Two Successful Treatments

Cholesterol embolization (CE) is a rare and alarming post-transplant complication, responsible for primary non-function (PNF) or delayed graft function (DGF). Its incidence is expected to rise due to increasingly old donors and recipients and the extended criteria for donation. Therapy with statins and steroids has not been shown to be effective, while agonism of prostaglandin I2 has been reported to be useful in systemic CE. We report two cases of acute post-transplant CE in which intravenous iloprost (0.05 mg/kg/day) was added to standard statin and steroid therapy. In the first instance, CE was due to embolization from the kidney artery resulting in embolization of the small vessels; after a long DGF and 15 days of iloprost therapy, renal function recovered. The second instance is a case of embolization from the iliac artery of the recipient, where CE manifested as a partial renal infarction. After 5 days of iloprost administration, creatinine levels improved. Iloprost acts on vasodilation and on different inflammatory pathways, improving the anti-inflammatory profile. Post-transplant CE is difficult to diagnose and, if not treated, can lead to loss of function. Iloprost added to standard therapy could be beneficial in accelerating renal function recovery immediately after transplant

A 10-3 drift velocity monitoring chamber

The MEG-II experiment searches for the lepton flavor violating decay: mu in electron and gamma. The reconstruction of the positron trajectory uses a cylindrical drift chamber operated with a mixture of He and iC4H10 gas. It is important to provide a stable performance of the detector in terms of its electron transport parameters, avalanche multiplication, composition and purity of the gas mixture. In order to have a continuous monitoring of the quality of gas, we plan to install a small drift chamber, with a simple geometry that allows to measure very precisely the electron drift velocity in a prompt way. This monitoring chamber will be supplied with gas coming from the inlet and the outlet of the detector to determine if gas contaminations originate inside the main chamber or in the gas supply system. The chamber is a small box with cathode walls, that define a highly uniform electric field inside two adjacent drift cells. Along the axis separating the two drift cells, four staggered sense wires alternated with five guard wires collect the drifting electrons. The trigger is provided by two 90Sr weak calibration radioactive sources placed on top of a two thin scintillator tiles telescope. The whole system is designed to give a prompt response (within a minute) about drift velocity variations at the 0.001 level

A case report of IgG4-related disease: an insidious path to the diagnosis through kidney, heart and brain

BACKGROUND: IgG4-related disease, described around the years 2000 as a form of autoimmune pancreatitis, is now increasingly accepted as a systemic syndrome. The diagnosis is based on both comprehensive and organ-specific criteria. For the kidney, Mayo clinic classification and the guidelines of the Japanese Nephrology Society are used. Ultimately, together with parameters that characterize every organ or apparatus involved, the key element is the confirmation of growing levels of IgG4 in blood or in tissues. CASE PRESENTATION: We describe a male patient with chronic renal failure associated to hypertension without proteinuria. IgG4-related disease was diagnosed through renal biopsy. After an initial positive response to steroids, he presented tinnitus, and histological assessment showed cerebral and subsequently cardiac damage, both IgG4-related. This case appears unique for the type of histologically documented cardiac and neurological parenchymal involvement, and at the same time, exemplifies the subtle and pernicious course of the disease. Frequently, blurred and non-specific signs prevail. Here, kidney damage was associated with minimal urinary findings, slowly progressive renal dysfunction and other factors that can be equivocated in the differential diagnosis. Neurological involvement was represented by tinnitus alone, while cardiac alterations were completely asymptomatic. CONCLUSIONS: This report is representative of the neurological and cardiac changes described in the literature for IgG4-related disease, which may be correlated or not with the renal form and highlights the need, in some cases, of targeted therapeutic approaches. In addition to glucocorticoids, as in this case, rituximab may be necessary

The Tracking performance for the IDEA drift chamber

The IDEA detector concept for a future e+e- collider adopts an ultra-low mass drift chamber as a central tracking system. The He-based ultra-low mass drift chamber is designed to provide efficient tracking, a high-precision momentum measurement, and excellent particle identification by exploiting the cluster counting technique. This paper describes the expected tracking performance, obtained with full and fast simulation, for track reconstruction on detailed simulated physics events. Moreover, the details of the construction parameters of the drift chamber, including the inspection of new material for the wires, new techniques for soldering the wires, the development of an improved schema for the drift cell, and the choice of a gas mixture, will be described

Molecular diversity of Mycobacterium tuberculosis isolates from patients with pulmonary tuberculosis in Mozambique

<p>Abstract</p> <p>Background</p> <p>Mozambique is one of the countries with the highest burden of tuberculosis (TB) in Sub-Saharan Africa, and information on the predominant genotypes of <it>Mycobacterium tuberculosis </it>circulating in the country are important to better understand the epidemic. This study determined the predominant strain lineages that cause TB in Mozambique.</p> <p>Results</p> <p>A total of 445 <it>M. tuberculosis </it>isolates from seven different provinces of Mozambique were characterized by spoligotyping and resulting profiles were compared with the international spoligotyping database SITVIT2.</p> <p>The four most predominant lineages observed were: the Latin-American Mediterranean (LAM, n = 165 or 37%); the East African-Indian (EAI, n = 132 or 29.7%); an evolutionary recent but yet ill-defined T clade, (n = 52 or 11.6%); and the globally-emerging Beijing clone, (n = 31 or 7%). A high spoligotype diversity was found for the EAI, LAM and T lineages.</p> <p>Conclusions</p> <p>The TB epidemic in Mozambique is caused by a wide diversity of spoligotypes with predominance of LAM, EAI, T and Beijing lineages.</p