Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists

BACKGROUND: Cytokine production is critical in ischemia/reperfusion (IR) injury. Acetylcholine binds to macrophages and inhibits cytokine synthesis, through the cholinergic anti-inflammatory pathway. This study examined the role of the cholinergic pathway in cytokine production and hepatic IR- injury. METHODS: Adult male mice underwent 90-min of partial liver ischemia followed by reperfusion. The AChR agonists (1,1-dimethyl-4-phenyl-L-pioperazinium-iodide [DMPP], and nicotine) or saline-vehicle were administered i.p. before ischemia. Plasma cytokine tumor necrosis factor (TNF)-α, macrophage inflammatory protein-2, and Interleukin-6 were measured. Liver injury was assessed by plasma alanine transaminase (ALT) and liver histopathology. RESULTS: A reperfusion time-dependent hepatocellular injury occurred as was indicated by increased plasma-ALT and histopathology. The injury was associated with marked elevation of plasma cytokines/chemokines. Pre-ischemic treatment of mice with DMPP or nicotine significantly decreased plasma-ALT and cytokines after 3 h of reperfusion. After 6 h of reperfusion, the protective effect of DMPP decreased and reached a negligible level by 24 h of reperfusion, despite significantly low levels of plasma cytokines. Histopathology showed markedly diminished hepatocellular injury in DMPP- and nicotine-pretreated mice during the early-phase of hepatic-IR, which reached a level comparable to saline-treated mice at late-phase of IR. CONCLUSION: Pharmacological modulation of the cholinergic pathway provides a means to modulate cytokine production and to delay IR-induced heaptocellular injury

Bill color, not badge size, indicates testosterone-related information in house sparrows

The honesty of ornamental signals of quality is often argued to be enforced via costs associated with testosterone. It is still poorly understood, however, how seasonal variation of testosterone within individuals is related to the timing and extent of ornament development. Here, we studied inter- and intra-individual variability of plasma testosterone levels in a population of 150 captive male house sparrows (Passer domesticus) through the course of a full year. We further analyzed the relationship between plasma testosterone levels and two sexually dimorphic ornaments: badge size and bill coloration. Also, because of a known negative relation between molt and circulating testosterone levels, we analyzed the relationship between ornamentation and molt status during the fall. We found that testosterone levels increased towards the breeding season and decreased before the onset of annual molt. However, within individuals, relative testosterone titers demonstrated low repeatability between seasons. Plasma testosterone levels were not correlated with badge size in any season but were correlated strongly with bill coloration during all periods, except the breeding season when variation in bill color was low. Finally, we found that bill coloration strongly correlated with molt status during fall. Our results indicate that bill coloration, not badge size, is the best ornamental indicator of a “running average” of male testosterone in house sparrows and therefore the best potential indicator of qualities and/or behavioral strategies associated with testosterone

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics

Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals

Measurement of the tt¯tt¯ production cross section in pp collisions at √s=13 TeV with the ATLAS detector

A measurement of four-top-quark production using proton-proton collision data at a centre-of-mass energy of 13 TeV collected by the ATLAS detector at the Large Hadron Collider corresponding to an integrated luminosity of 139 fb−1 is presented. Events are selected if they contain a single lepton (electron or muon) or an opposite-sign lepton pair, in association with multiple jets. The events are categorised according to the number of jets and how likely these are to contain b-hadrons. A multivariate technique is then used to discriminate between signal and background events. The measured four-top-quark production cross section is found to be 26+17−15 fb, with a corresponding observed (expected) significance of 1.9 (1.0) standard deviations over the background-only hypothesis. The result is combined with the previous measurement performed by the ATLAS Collaboration in the multilepton final state. The combined four-top-quark production cross section is measured to be 24+7−6 fb, with a corresponding observed (expected) signal significance of 4.7 (2.6) standard deviations over the background-only predictions. It is consistent within 2.0 standard deviations with the Standard Model expectation of 12.0 ± 2.4 fb

Search for dark matter in events with missing transverse momentum and a Higgs boson decaying into two photons in pp collisions at root s=13 TeV with the ATLAS detector

A search for dark-matter particles in events with large missing transverse momentum and a Higgs boson candidate decaying into two photons is reported. The search uses 139 fb−1 of proton-proton collision data collected at s√ = 13 TeV with the ATLAS detector at the CERN LHC between 2015 and 2018. No significant excess of events over the Standard Model predictions is observed. The results are interpreted by extracting limits on three simplified models that include either vector or pseudoscalar mediators and predict a final state with a pair of dark-matter candidates and a Higgs boson decaying into two photons

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Two-particle azimuthal correlations in photonuclear ultraperipheral Pb plus Pb collisions at 5.02 TeV with ATLAS

Two-particle long-range azimuthal correlations are measured in photonuclear collisions using 1.7 nb − 1 of 5.02 TeV Pb + Pb collision data collected by the ATLAS experiment at the CERN Large Hadron Collider. Candidate events are selected using a dedicated high-multiplicity photonuclear event trigger, a combination of information from the zero-degree calorimeters and forward calorimeters, and from pseudorapidity gaps constructed using calorimeter energy clusters and charged-particle tracks. Distributions of event properties are compared between data and Monte Carlo simulations of photonuclear processes. Two-particle correlation functions are formed using charged-particle tracks in the selected events, and a template-fitting method is employed to subtract the nonflow contribution to the correlation. Significant nonzero values of the second- and third-order flow coefficients are observed and presented as a function of charged-particle multiplicity and transverse momentum. The results are compared with flow coefficients obtained in proton-proton and proton-lead collisions in similar multiplicity ranges, and with theoretical expectations. The unique initial conditions present in this measurement provide a new way to probe the origin of the collective signatures previously observed only in hadronic collision

Medium-Induced Modification of Z-Tagged Charged Particle Yields in Pb+Pb Collisions at 5.02 TeV with the ATLAS Detector

The yield of charged particles opposite to a Z boson with large transverse momentum ( p T ) is measured in 260     pb − 1 of p p and 1.7     nb − 1 of Pb + Pb collision data at 5.02 TeV per nucleon pair recorded with the ATLAS detector at the Large Hadron Collider. The Z boson tag is used to select hard-scattered partons with specific kinematics, and to observe how their showers are modified as they propagate through the quark-gluon plasma created in Pb + Pb collisions. Compared with p p collisions, charged-particle yields in Pb + Pb collisions show significant modifications as a function of charged-particle p T in a way that depends on event centrality and Z boson p T . The data are compared with a variety of theoretical calculations and provide new information about the medium-induced energy loss of partons in a p T regime difficult to measure through other channels