Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure, mainly as a result of mutations in cardiac desmosomal genes. Desmosomes are ...cell-cell junctions mediating adhesion of cardiomyocytes; however, the molecular and cellular mechanisms underlying the disease remain widely unknown. Desmocollin-2 is a desmosomal cadherin serving as an anchor molecule required to reconstitute homeostatic intercellular adhesion with desmoglein-2. Cardiac specific lack of desmoglein-2 leads to severe cardiomyopathy, whereas overexpression does not. In contrast, the corresponding data for desmocollin-2 are incomplete, in particular from the view of protein overexpression. Therefore, we developed a mouse model overexpressing desmocollin-2 to determine its potential contribution to cardiomyopathy and intercellular adhesion pathology.
We generated transgenic mice overexpressing DSC2 in cardiac myocytes. Transgenic mice developed a severe cardiac dysfunction over 5 to 13 weeks as indicated by 2D-echocardiography measurements. Corresponding histology and immunohistochemistry demonstrated fibrosis, necrosis and calcification which were mainly localized in patches near the epi- and endocardium of both ventricles. Expressions of endogenous desmosomal proteins were markedly reduced in fibrotic areas but appear to be unchanged in non-fibrotic areas. Furthermore, gene expression data indicate an early up-regulation of inflammatory and fibrotic remodeling pathways between 2 to 3.5 weeks of age.
Cardiac specific overexpression of desmocollin-2 induces necrosis, acute inflammation and patchy cardiac fibrotic remodeling leading to fulminant biventricular cardiomyopathy.
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Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations ...have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients.
We sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons.
The analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations.
Clinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation.
In recent years the UN Commission on Human Rights has been widely and severely castigated for its failures to live up to the vision of being a genuine protector of victims of human rights abuses and ...instead becoming a shield for the violators. This article provides an assessment of these criticisms of the Commission by exploring its historical beginnings, its notable achievements, and its manifest shortcomings, and then analyzes how these and other factors came into play when the membership of the United Nations decided to replace the Commission with the new Human Rights Council.
This widely acclaimed and highly regarded book, used extensively by students, scholars, policymakers, and activists, now appears in a new third edition. Focusing on the theme of visions seen by those ...who dreamed of what might be, Lauren explores the dramatic transformation of a world patterned by centuries of human rights abuses into a global community that now boldly proclaims that the way governments treat their own people is a matter of international concern-and sets the goal of human rights "for all peoples and all nations." He reveals the truly universal nature of this movement, places contemporary events within their broader historical contexts, and explains the relationship between individual cases and larger issues of human rights with insight. This new edition incorporates material from recently declassified documents and the most recent scholarship relating to the creation of the new Human Rights Council and its Universal Periodic Review, the International Criminal Court, the Responsibility to Protect (R2P), terrorism and torture, the impact of globalization and modern technology, and activists in NGOs devoted to human rights. It provides perceptive assessments of the process of change, the power of visions and visionaries, politics and political will, and the evolving meanings of sovereignty, security, and human rights themselves.
Accurate detection of somatic mutations is a crucial step toward understanding cancer. Various tools have been developed to detect somatic mutations from cancer genome sequencing data by mapping ...reads to a universal reference genome and inferring likelihoods from complex statistical models. However, read mapping is frequently obstructed by mismatches between germline and somatic mutations on a read and the reference genome. Previous attempts to develop personalized genome tools are not compatible with downstream statistical models for somatic mutation detection.
We present PRESM, a tool that builds personalized reference genomes by integrating germline mutations into the reference genome. The aforementioned obstacle is circumvented by using a two-step germline substitution procedure, maintaining positional fidelity using an innovative workaround. Reads derived from tumor tissue can be positioned more accurately along a personalized reference than a universal reference due to the reduced genetic distance between the subject (tumor genome) and the target (the personalized genome). Application of PRESM's personalized genome reduced false-positive (FP) somatic mutation calls by as much as 55.5%, and facilitated the discovery of a novel somatic point mutation on a germline insertion in PDE1A, a phosphodiesterase associated with melanoma. Moreover, all improvements in calling accuracy were achieved without parameter optimization, as PRESM itself is parameter-free. Hence, similar increases in read mapping and decreases in the FP rate will persist when PRESM-built genomes are applied to any user-provided dataset.
The software is available at https://github.com/precisionomics/PRESM.
Supplementary data are available at Bioinformatics online.
The Diplomats, 1939-1979 Craig, Gordon A; Loewenheim, Francis L
2019, 20190115, 1994, 2019-10-04, Letnik:
5254
eBook
This volume offers a unique perspective on a turbulent and dangerous age by focusing on the activities and accomplishments of its diplomats. Its twenty-three interconnected essays discuss the ...politics of ambassadors, foreign ministers, and heads of state from Acheson and Adenauer to Sadat and Gromyko, as well as the special problems of the professionals in the foreign offices and the role of the media in modern diplomacy. Among its contributors are such distinguished international scholars as Akira Iriye, Michael Brecher, Stanley Hoffmann, W.W. Rostow, and Norman Stone. Expanding the field of inquiry covered by its acclaimed predecessor, The Diplomats, 1919-1939, which concentrated on Europe and the coming of the Second World War, these essays showcase the major diplomatic practitioners of the period against the broader background of the problems and crises that confronted them-among others, the Polish question at the end of World War II, the onset of the Cold War, the defeat of EDC in 1954, the Suez crisis, Kruschchev's Berlin note in 1958, the Middle East War of 1967 and the oil shock of 1973, the Iranian revolution, and the Soviet invasion of Afghanistan. This account of the pendular swing from crisis and detente and back again is given a global perspective by careful treatment of the diplomacy of new nations like India, Communist China, and Israel, and the transformation of the Middle East and Japan. Among the new perspectives offered here are Geoffrey Warner's critical view of Ernest Bevin's attitude toward the United States, John Lewis Gaddis's judgment of Henry Kissinger's detente policy, W.W. Rostow's analysis of the diplomatic method of Paul Monnnet, Rena Fonseca's assessment of Nehru's policy of nonalignment, Shu Guang Zhang's fresh look at the relationship between Zhou Enlai and Mao, and Paul Gordon Lauren's critique of U.N. crisis management from Trygve Lie to Perez de Cuellar. Highly original also are Steven Miner's portrait of Molotov, Michael Brecher's pioneering study of the diplomacy of Abba Eben, and James McAdams's analysis of German Ostpolitik.
Originally published in 1994.
ThePrinceton Legacy Library uses the latest print-on-demand technology to again make available previously out-of-print books from the distinguished backlist of Princeton University Press. These editions preserve the original texts of these important books while presenting them in durable paperback and hardcover editions. The goal of the Princeton Legacy Library is to vastly increase access to the rich scholarly heritage found in the thousands of books published by Princeton University Press since its founding in 1905.
ABSTRACT
Power estimations are important for optimizing genotype‐phenotype association study designs. However, existing frameworks are designed for common disorders, and thus ill‐suited for the ...inherent challenges of studies for low‐prevalence conditions such as rare diseases and infrequent adverse drug reactions. These challenges include small sample sizes and the need to leverage genetic annotation resources in association analyses for the purpose of ranking potential causal genes. We present SimPEL, a simulation‐based program providing power estimations for the design of low‐prevalence condition studies. SimPEL integrates the usage of gene annotation resources for association analyses. Customizable parameters, including the penetrance of the putative causal allele and the employed pathogenic scoring system, allow SimPEL to realistically model a large range of study designs. To demonstrate the effects of various parameters on power, we estimated the power of several simulated designs using SimPEL and captured power trends in agreement with observations from current literature on low‐frequency condition studies. SimPEL, as a tool, provides researchers studying low‐frequency conditions with an intuitive and highly flexible avenue for statistical power estimation. The platform‐independent “batteries included” executable and default input files are available at https://github.com/precisionomics/SimPEL.
THE FIRST OCCUPANT of this position in diplomacy ominously described it as “the most impossible job in the world.”¹ “It was a challenge A beyond my wildest dreams,” he later wrote, “a nightmare” and ...“the target of criticism from right, left and center” from the great and the small powers of the world alike.² His successor stated publicly, “Nobody, I think, can accept this position … knowing what it means, except from a sense of duty.”³ Others who followed used similar language, describing their job as a “cockpit of world tensions” and the center of heavy burdens of international politics.⁴
The history of human rights is complex and often appears to be confusing and even contradictory. This article seeks to explain why this is so, and why there are both successes and failures, by ...focusing upon paradoxes in the interactions among people and forces. In doing so, it pays particular attention to individual men and women and the roles played by religious belief, ideas and philosophical opinion, technology, violence and upheavals, and human catastrophes or atrocities, noting that each of these has contributed not only to the promotion of human rights but to the abuse of human rights as well.
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