Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease.Marianne Barrie Philanthropic Fund; Canadian Institutes of Health Research [RN332805]; Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation; Dutch Federation of University Medical Centers; Netherlands Organisation for Health Research and Development; Royal Netherlands Academy of Sciences [CVON-PREDICT 2012-10]; Netherlands Cardiovascular Research Initiative - Dutch Heart Foundation [CVON2012-10 PREDICT CVON2018-30 PREDICT2, CVON2015-12 eDETECT]; Netherlands Organization for Scientific Research (NWO) [040.11.586]; Fondation Leducq [16 CVD 02]; Dr. Francis P. Chiramonte Private Foundation; Leyla Erkan Family Fund for ARVD Research; Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; NIH [HL135754, HL134824, HL139348, HL135096, HL114383, HL114893, HL137331, HL137325, 2UM1HG006542, UL1 TR 001079]; Ohio State Frick Center; JB ProjectOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Modified reaction centers from Rhodobacter sphaeroides R26

Incubation of photosynthetic reaction centers from Rhodobacter sphaeroides R26 with exogenous 132-OH-bacteriochlorophyll ap or aGG according to Scheer et al. (1987) results in the exchange of endogenous bacteriochlorophyll ap. The exchange amounts to less-than-or-equals, slant 50% according to HPLC analysis, corresponding to a complete replacement of the ‘monomeric’ bacteriochlorophylls, bm and bl, by exogenous pigment. The absorption spectra show small, but distinct changes in the Qx-region of the bacteriochlorophylls, and bleaching of the modified reaction centers is retained. The corresponding binding sites must be accessible from the exterior, and allow for the introduction of a polar residue at C-132. This is supported by the observation of side reactions of the endogenous ‘monomeric’ bacteriochlorophylls within the reaction center pigments, e.g. epimerization and hydroxylation at C-132

Adaptation and enslavement in endosymbiont-host associations

The evolutionary persistence of symbiotic associations is a puzzle. Adaptation should eliminate cooperative traits if it is possible to enjoy the advantages of cooperation without reciprocating - a facet of cooperation known in game theory as the Prisoner's Dilemma. Despite this barrier, symbioses are widespread, and may have been necessary for the evolution of complex life. The discovery of strategies such as tit-for-tat has been presented as a general solution to the problem of cooperation. However, this only holds for within-species cooperation, where a single strategy will come to dominate the population. In a symbiotic association each species may have a different strategy, and the theoretical analysis of the single species problem is no guide to the outcome. We present basic analysis of two-species cooperation and show that a species with a fast adaptation rate is enslaved by a slowly evolving one. Paradoxically, the rapidly evolving species becomes highly cooperative, whereas the slowly evolving one gives little in return. This helps understand the occurrence of endosymbioses where the host benefits, but the symbionts appear to gain little from the association.Comment: v2: Correction made to equations 5 & 6 v3: Revised version accepted in Phys. Rev. E; New figure adde

Cumulant Expansions and the Spin-Boson Problem

The dynamics of the dissipative two-level system at zero temperature is studied using three different cumulant expansion techniques. The relative merits and drawbacks of each technique are discussed. It is found that a new technique, the non-crossing cumulant expansion, appears to embody the virtues of the more standard cumulant methods.Comment: 26 pages, LaTe

Development of a post-mortem procedure to reduce the uncertainty regarding causes of death in developing countries

A major failure of our global society in the 21st century is that many people in developing countries are not only born and live without any official record of their existence a flagrant deprivation of an essential human right but also die without having been seen by medically qualified personnel. The resultant uncertainty about the real burden of specific causes of death is being increasingly recognised by international health and funding agencies as a crucial limitation in the prioritisation of effective public health programmes and assessment of their effect

Pathophysiological role of prostanoids in coagulation of the portal venous system in liver cirrhosis

BACKGROUND: Prostanoids are important regulators of platelet aggregation and thrombotic arterial diseases. Their involvement in the development of portal vein thrombosis, frequent in decompensated liver cirrhosis, is still not investigated. METHODS: Therefore, we used pro-thrombotic venous milieu generation by bare metal stent transjugular intrahepatic portosystemic shunt insertion, to study the role of prostanoids in decompensated liver cirrhosis. Here, 89 patients receiving transjugular intrahepatic portosystemic shunt insertion were included in the study, and baseline levels of thromboxane B2, prostaglandin D2 and prostaglandin E2 were measured in the portal and the hepatic vein. RESULTS: While the hepatic vein contained higher levels of thromboxane B2 than the portal vein, levels of prostaglandin E2 and D2 were higher in the portal vein (all P<0.0001). Baseline concentrations of thromboxane B2 in the portal vein were independently associated with an increase of portal hepatic venous pressure gradient during short term follow-up, as an indirect sign of thrombogenic potential (multivariable P = 0.004). Moreover, severity of liver disease was inversely correlated with portal as well as hepatic vein levels of prostaglandin D2 and E2 (all P<0.0001). CONCLUSIONS: Elevated portal venous thromboxane B2 concentrations are possibly associated with the extent of thrombogenic potential in patients with decompensated liver cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03584204

The HIPASS Catalogue - II. Completeness, Reliability, and Parameter Accuracy

The HI Parkes All Sky Survey (HIPASS) is a blind extragalactic HI 21-cm emission line survey covering the whole southern sky from declination -90 to +25. The HIPASS catalogue (HICAT), containing 4315 HI-selected galaxies from the region south of declination +2, is presented in Meyer et al. (2004a, Paper I). This paper describes in detail the completeness and reliability of HICAT, which are calculated from the recovery rate of synthetic sources and follow-up observations, respectively. HICAT is found to be 99 per cent complete at a peak flux of 84 mJy and an integrated flux of 9.4 Jy km/s. The overall reliability is 95 per cent, but rises to 99 per cent for sources with peak fluxes >58 mJy or integrated flux > 8.2 Jy km/s. Expressions are derived for the uncertainties on the most important HICAT parameters: peak flux, integrated flux, velocity width, and recessional velocity. The errors on HICAT parameters are dominated by the noise in the HIPASS data, rather than by the parametrization procedure.Comment: Accepted for publication in MNRAS. 12 pages, 11 figures. Paper with higher resolution figures can be downloaded from http://hipass.aus-vo.or

Does publication bias inflate the apparent efficacy of psychological treatment for major depressive disorder? A systematic review and meta-analysis of US national institutes of health-funded trials

Background The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. Methods and Findings We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972–2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta-analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges’ g = 0.20; CI95% -0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. Conclusion The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression

Cosmogenic radionuclides reveal an extreme solar particle storm near a solar minimum 9125 years BP

During solar storms, the Sun expels large amounts of energetic particles (SEP) that can react with the Earth’s atmospheric constituents and produce cosmogenic radionuclides such as 14C, 10Be and 36Cl. Here we present 10Be and 36Cl data measured in ice cores from Greenland and Antarctica. The data consistently show one of the largest 10Be and 36Cl production peaks detected so far, most likely produced by an extreme SEP event that hit Earth 9125 years BP (before present, i.e., before 1950 CE), i.e., 7176 BCE. Using the 36Cl/10Be ratio, we demonstrate that this event was characterized by a very hard energy spectrum and was possibly up to two orders of magnitude larger than any SEP event during the instrumental period. Furthermore, we provide 10Be-based evidence that, contrary to expectations, the SEP event occurred near a solar minimum