Membrane-to-Nucleus Signaling in Human Blood Progenitor Cells Reveals an Efficient GM-Free Reprogramming to Pluripotency

The generation of induced pluripotent stem cells (iPSCs) by forced expression of defined transcription factors has revolutionized regenerative medicine. These cells have similar features to embryonic stem cells (ESCs) regarding self-renewal and their ability to differentiate into any cell type in the body. In spite of many improvements, in using nonviral delivery reprogramming methods, there are still challenges to overcome regarding safety before patient-made iPSCs can be used in regular clinical practice. We have recently reported about a gene manipulation-free method of generating human pluripotent stem cells (PSCs), based on activation of the novel human GPI-linked glycoprotein ACA. The process of dedifferentiation of blood progenitor cells that leads to the generation of blood-derived pluripotent stem cells (BD-PSCs) is initiated upon cross-linking of this protein via activation of PLCγ/PI3K/Akt pathway. These cells are mortal, express pluripotent markers, and redifferentiate in vitro into cells of all three germ layers. The ultrastructural analysis of BD-PSCs, by means of electron microscopy, revealed them similar to human ESCs with large dense nucleolus and scarce cytoplasm. BD-PSCs are autologous stem cells and while nonteratogenic offer a new alternative that overcomes immunological, ethical, and safety concerns and opens up a new avenue in treating contemporarily intractable diseases and generally in human therapeutics

Evolution of Vitamin B 2 Biosynthesis. A Novel Class of Riboflavin Synthase in Archaea †

The open reading frame MJ1184 of Methanococcus jannaschii with similarity to riboflavin synthase of Methanothermobacter thermoautotrophicus was cloned into an expression vector but was poorly expressed in an Escherichia coli host strain. However, a synthetic open reading frame that was optimized for expression in E. coli directed the synthesis of abundant amounts of a protein with an apparent subunit mass of 17.5 kDa. The protein was purified to apparent homogeneity. Hydrodynamic studies indicated a relative mass of 88 kDa suggesting a homopentamer structure. The enzyme was shown to catalyze the formation of riboflavin from 6,7-dimethyl-8-ribityllumazine at a rate of 24 nmol mg K1 min K1 at 40 8C. Divalent metal ions, preferably manganese or magnesium, are required for maximum activity. In contrast to pentameric archaeal type riboflavin synthases, orthologs from plants, fungi and eubacteria are trimeric proteins characterized by an internal sequence repeat with similar folding patterns. In these organisms the reaction is achieved by binding the two substrate molecules in an antiparallel orientation. With the enzyme of M. jannaschii, 13 C NMR spectroscopy with 13 C-labeled 6,7-dimethyl-8-ribityllumazine samples as substrates showed that the regiochemistry of the dismutation reaction is the same as observed in eubacteria and eukaryotes, however, in a non-pseudo-c 2 symmetric environment. Whereas the riboflavin synthases of M. jannaschii and M. thermoautotrophicus are devoid of similarity with those of eubacteria and eukaryotes, they have significant sequence similarity with 6,7-dimethyl-8-ribityllumazine synthases catalyzing the penultimate step of riboflavin biosynthesis. 6,7-Dimethyl-8-ribityllumazine synthase and the archaeal riboflavin synthase appear to have diverged early in the evolution of Archaea from a common ancestor. Some Archaea have eubacterial type riboflavin synthases which may have been acquired by lateral gene transfer

Transitkunst. Studien zur Literatur 1890-2010

Die Chiffre „Transit“ vereinigt mit Aspekten wie Mobilität, Flüchtigkeit und Vorläufigkeit zentrale Begriffe des Zeiterlebens zwischen 1890 und 2010. Vor dem Hintergrund mehrerer Krisen und Katastrophen sowie tiefgreifender Umwandlungsprozesse erscheint das Leben als Durchgangsstadium, in dem sich nur noch ein temporäres, fragmentarisches Netz von Orientierungspunkten entwerfen lässt. Das Transitäre durchdringt nahezu alle Facetten des Individuums und seiner Lebensbereiche: vom Wahrnehmen der Inkohärenz in der Folge gesellschaftlicher Umwälzungen, über den Verlust ‚sicherer‘ Orte bis zum Erfahren der eigenen Identität als provisorisch. Die Reaktion auf solche Übergangszustände ist oft eine Intensivierung der Suchbewegungen nach Sicherheit, Nähe und Glück, die jedoch selbst zunehmend transitive Zwischenstellungen markieren. Die Literatur zeichnet sich unter dieser Perspektive durch die Adaptation transittypischer Themen und Inhalte aus, desgleichen durch die autoreflexive Übertragung von Konzepten wie Momenthaftigkeit, Unvollständigkeit und Flexibilität in das eigene narrative Programm. Die Beiträge des Bandes nähern sich verschiedenen Formen eines solchen inhaltlichen und/oder formalen ‚Dazwischen‘ an. Die Idee des Transits erweist sich dabei für diese vielfältigen literatur- und kulturwissenschaftlichen Untersuchungen als ebenso funktionale wie inspirierende Klammer, der es gelingt, im bewussten Einlassen auf das im Durchgang Begriffene die heterogenen Facetten des 20. Jahrhunderts zu verbinden: zu einer Art Zeitbild und Ästhetik des Transits

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements