Nebenwirkungen umgehen: Nanocontainer bringen Wirkstoffe direkt ans Ziel

Mithilfe von Nanopartikeln konnte ein Jenaer Forschungsteam einen Wirkstoff zielgerichtet ins Lebergewebe transportieren. Dies gelang durch die Markierung mit einem Farbstoff, der spezifisch von Leberzellen aufgenommen wird. Dort hemmt der Wirkstoff das Signalprotein PI3Kinase γ, das bei einer Sepsis zum Leberversagen beiträgt. Die außerhalb der Leberzellen erwünschte Aktivität des Signalproteins in der Bekämpfung der Infektionserreger bleibt ungehindert. Diesen neuartigen Ansatz zur Behandlung des septischen Leberversagens beschreibt das Team in einer jetzt im EMBO Molecular Medicine Journal erschienenen Arbeit.

Quelle: IDW Informationsdienst Wissenschaft

Paradigmenwechsel in der Immunologie: „Adaptive Toleranz“ balanciert Autoimmunreaktion aus

Ein neues immunologisches Modell aus Ulm könnte einen Paradigmenwechsel bei der Behandlung von Autoimmunerkrankungen auslösen. Im EMBO Journal beschreiben Forschende um Prof. Hassan Jumaa den bislang unbekannten Mechanismus der „adaptiven Toleranz“. Demnach sind autoreaktive Antikörper keineswegs schädlich und so schnell wie möglich vom Organismus zu eliminieren. Vielmehr stoßen sie die Bildung von so genannten igM-Antikörpern an, die körperliche Schäden abwenden. Anwendungsgebiete dieses dynamischen immunologischen Modells reichen von der Entwicklung neuer Diabetes-Therapien bis hin zur Impfstoff-Forschung.

Quelle: IDW Informationsdienst Wissenschaft

Neutralizing the SARS-CoV-2 sugar coat

Researchers identify two sugar-binding proteins that impede the viral entry of circulating SARS-CoV-2 variants. The team, spearheaded by researchers at IMBA – Institute of Molecular Biotechnology of the Austrian Academy of Sciences – may have found the “Achilles’ heel” of the virus, with potential for pan-variant therapeutic interventions. The findings are now published in the EMBO Journal.

Quelle: IDW Informationsdienst Wissenschaft

Wiener Forscher finden eine mögliche Achillesferse des Coronavirus: die Neutralisierung der SARS-CoV-2-Zuckerhülle

Ein Team unter der Leitung von Forschern des Wiener IMBA (Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften) hat möglicherweise die Achillesferse des Coronavirus gefunden: Zwei zuckerbindende Proteine behindern SARS-CoV-2-Varianten am Eindringen. Die Ergebnisse, die das Potenzial für variantenübergreifende Therapien haben, wurden jetzt im renommierten EMBO Journal veröffentlicht.

Quelle: IDW Informationsdienst Wissenschaft

Dipeptide als Retter in der Not – Wie kleine Moleküle Pflanzen bei ihrer Stressbewältigung helfen

Ein Team von Wissenschaftler*innen um Dr. Aleksandra Skirycz – bis vor kurzem Gruppenleiterin am Max-Planck-Institut für molekulare Pflanzenphysiologie, nun Professorin am Boyce Thompson Institute (BTI) in den USA – hat in einer aktuellen Studie ein neuartiges regulatorisches kleines Molekül untersucht und beschrieben, das die Toleranz von Pflanzen gegenüber Umweltstress verbessert (Moreno et al. 2021, EMBO Journal).

Quelle: IDW Informationsdienst Wissenschaft

Dipeptides to the rescue – How small molecules help plants cope with stress

A team of scientists led by Dr. Aleksandra Skirycz, until recently a group leader at the Max Planck Institute of Molecular Plant Physiology, now a professor at the Boyce Thompson Institute (BTI) in the USA, has investigated and described in a recent study a novel regulatory small molecule that improves plant tolerance to environmental stress (Moreno et al., 2021, EMBO Journal).

Quelle: IDW Informationsdienst Wissenschaft

Wie SARS-Coronaviren die menschliche Zelle zum eigenen Vorteil umfunktionieren

Coronavirus-Forscherinnen und -Forscher um Prof. Rolf Hilgenfeld von der Universität zu Lübeck und Privatdozent Dr. Albrecht von Brunn von der Ludwigs-Maximilians-Universität München, beides Forscher am Deutschen Zentrum für Infektionsforschung (DZIF), konnten einen Forschungserfolg im angesehenen „EMBO Journal“ publizieren: Sie fanden heraus, wie SARS-Viren die Herstellung viraler Proteine in infizierten Zellen so anregen, dass viele neue Kopien des Virus gebildet werden können. Andere Coronaviren als SARS-CoV und SARS-CoV-2 verfügen nicht über diesen Mechanismus, so dass hier eine Erklärung für die ungleich höhere Pathogenität der SARS-Viren liegen könnte.

Quelle: IDW Informationsdienst Wissenschaft

How SARS-Coronaviruses reprogram the human cell to their own benefit

Coronavirus researchers under Prof. Rolf Hilgenfeld of the University of Lübeck and Dr. Albrecht von Brunn of the Ludwig-Maximilians University of Munich published a research breakthrough in the highly ranked „EMBO Journal“. They discovered how SARS viruses enhance the production of viral proteins in infected cells, so that many new copies of the virus can be generated. Other coronaviruses apart from SARS-CoV and SARS-CoV-2 do not use this mechanism, thereby providing a possible explanation for the much higher pathogenicity of the SARS viruses.

Quelle: IDW Informationsdienst Wissenschaft

Facundo Batista appointed Chief Editor of The EMBO Journal

Heidelberg/Germany and Cambridge/USA, 4 February 2021 – EMBO Press announces the appointment of immunologist Facundo Batista, PhD, as Chief Editor of The EMBO Journal. Facundo Batista, who is a Professor at Harvard Medical School and the first Associate Director of the Ragon Institute of MGH, MIT and Harvard, Cambridge/USA, takes up the appointment with immediate effect. He takes over from Bernd Pulverer, Head of Scientific Publishing at EMBO after a decade in the role, who will lead EMBO Reports as Chief Editor.

Quelle: IDW Informationsdienst Wissenschaft

A global assessment of cancer genomic alterations in epigenetic mechanisms

Muhammad A Shah, Emily L Denton, Cheryl H Arrowsmith, Mathieu Lupien and Matthieu Schapira

Abstract

Background

The notion that epigenetic mechanisms may be central to cancer initiation and progression is supported by recent next-generation sequencing efforts revealing that genes involved in chromatin-mediated signaling are recurrently mutated in cancer patients.

Results

Here, we analyze mutational and transcriptional profiles from TCGA and the ICGC across a collection 441 chromatin factors and histones. Chromatin factors essential for rapid replication are frequently overexpressed, and those that maintain genome stability frequently mutated. We identify novel mutation hotspots such as K36M in histone H3.1, and uncover a general trend in which transcriptional profiles and somatic mutations in tumor samples favor increased transcriptionally repressive histone methylation, and defective chromatin remodeling.

Conclusions

This unbiased approach confirms previously published data, uncovers novel cancer-associated aberrations targeting epigenetic mechanisms, and justifies continued monitoring of chromatin-related alterations as a class, as more cancer types and distinct cancer stages are represented in cancer genomics data repositories.

Continue reading „A global assessment of cancer genomic alterations in epigenetic mechanisms“

Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci

3D-SIM-based DAPI intensity classification in the Barr body versus the entire nucleus of C2C12 cells. (A) Mid z-section of a DAPI-stained nucleus. The area below the dashed line illustrates the resolution level obtained by wide-field deconvolution microscopy, for comparison. Inset magnifications show the non-uniformly compacted structure of the Barr body resolvable with 3D-SIM (1) and an arbitrary autosomal region with CDCs (2). Scale bars: 5 μm, insets 1 μm. (B) X chromosome-specific painting (green) of Xi (left) and Xa territories (right) of the same nucleus in different z-sections. Note the high convergence between the painted Xi and the DAPI visualized Barr body (arrowheads). Scale bars: 2 μm, insets 1 μm. (C) 3D DAPI intensity classification exemplified for the nucleus shown in (A). Seven DAPI intensity classes displayed in false-color code ranging from class 1 (blue) representing pixels close to background intensity, largely representing the IC, up to class 7 (white) representing pixels with highest density, mainly associated with chromocenters. Framed areas of the Barr body (inset 1) and a representative autosomal region (inset 2) are shown on the right at resolution levels of 3D-SIM, deconvolution and conventional wide-field microscopy. The Xi territory pervaded by lower DAPI intensities becomes evident only at 3D-SIM resolution, whereas both wide-field and deconvolution microscopy imply a concentric increase of density in the Barr body. In the autosomal region, chromatin assigned to classes 2 to 3 lines compacted CDCs, represented by classes 4 to 6. (D) Left: average DAPI intensity classification profiles with standard deviations evaluated for entire nuclear volumes or the Barr body region only (dark grey bars). Right: over/underrepresentation of the average DAPI intensity class fraction sizes in the Barr body versus entire nuclear volumes (n = 12). Distribution differences on classes between Xi and entire nucleus P <0.001. 3D-SIM, three-dimensional structured illumination microscopy; CDC, chromatin domain cluster; DAPI, 4',6-diamidino-2-phenylindole; FISH, fluorescence in situ hybridization; IC, interchromatin compartment; Xa, active X chromosome; Xi, inactive X chromosome. Smeets et al. Epigenetics & Chromatin 2014 7:8   doi:10.1186/1756-8935-7-8
3D-SIM-based DAPI intensity classification in the Barr body versus the entire nucleus of C2C12 cells. (A) Mid z-section of a DAPI-stained nucleus. The area below the dashed line illustrates the resolution level obtained by wide-field deconvolution microscopy, for comparison. Inset magnifications show the non-uniformly compacted structure of the Barr body resolvable with 3D-SIM (1) and an arbitrary autosomal region with CDCs (2). Scale bars: 5 μm, insets 1 μm. (B) X chromosome-specific painting (green) of Xi (left) and Xa territories (right) of the same nucleus in different z-sections. Note the high convergence between the painted Xi and the DAPI visualized Barr body (arrowheads). Scale bars: 2 μm, insets 1 μm. (C) 3D DAPI intensity classification exemplified for the nucleus shown in (A). Seven DAPI intensity classes displayed in false-color code ranging from class 1 (blue) representing pixels close to background intensity, largely representing the IC, up to class 7 (white) representing pixels with highest density, mainly associated with chromocenters. Framed areas of the Barr body (inset 1) and a representative autosomal region (inset 2) are shown on the right at resolution levels of 3D-SIM, deconvolution and conventional wide-field microscopy. The Xi territory pervaded by lower DAPI intensities becomes evident only at 3D-SIM resolution, whereas both wide-field and deconvolution microscopy imply a concentric increase of density in the Barr body. In the autosomal region, chromatin assigned to classes 2 to 3 lines compacted CDCs, represented by classes 4 to 6. (D) Left: average DAPI intensity classification profiles with standard deviations evaluated for entire nuclear volumes or the Barr body region only (dark grey bars). Right: over/underrepresentation of the average DAPI intensity class fraction sizes in the Barr body versus entire nuclear volumes (n = 12). Distribution differences on classes between Xi and entire nucleus P Smeets et al. Epigenetics & Chromatin 2014 7:8 doi:10.1186/1756-8935-7-8

Daniel Smeets, Yolanda Markaki, Volker J Schmid, Felix Kraus, Anna Tattermusch, Andrea Cerase, Michael Sterr, Susanne Fiedler, Justin Demmerle, Jens Popken, Heinrich Leonhardt, Neil Brockdorff, Thomas Cremer1, Lothar Schermelleh and Marion Cremer

Abstract

Background

A Xist RNA decorated Barr body is the structural hallmark of the compacted inactive X territory in female mammals. Using super-resolution three-dimensional structured illumination microscopy (3D-SIM) and quantitative image analysis, we compared its ultrastructure with active chromosome territories (CTs) in human and mouse somatic cells, and explored the spatio-temporal process of Barr body formation at onset of inactivation in early differentiating mouse embryonic stem cells (ESCs).

Results

We demonstrate that all CTs are composed of structurally linked chromatin domain clusters (CDCs). In active CTs the periphery of CDCs harbors low-density chromatin enriched with transcriptionally competent markers, called the perichromatin region (PR). The PR borders on a contiguous channel system, the interchromatin compartment (IC), which starts at nuclear pores and pervades CTs. We propose that the PR and macromolecular complexes in IC channels together form the transcriptionally permissive active nuclear compartment (ANC). The Barr body differs from active CTs by a partially collapsed ANC with CDCs coming significantly closer together, although a rudimentary IC channel system connected to nuclear pores is maintained. Distinct Xist RNA foci, closely adjacent to the nuclear matrix scaffold attachment factor-A (SAF-A) localize throughout Xi along the rudimentary ANC. In early differentiating ESCs initial Xist RNA spreading precedes Barr body formation, which occurs concurrent with the subsequent exclusion of RNA polymerase II (RNAP II). Induction of a transgenic autosomal Xist RNA in a male ESC triggers the formation of an ‘autosomal Barr body’ with less compacted chromatin and incomplete RNAP II exclusion.

Conclusions

3D-SIM provides experimental evidence for profound differences between the functional architecture of transcriptionally active CTs and the Barr body. Basic structural features of CT organization such as CDCs and IC channels are however still recognized, arguing against a uniform compaction of the Barr body at the nucleosome level. The localization of distinct Xist RNA foci at boundaries of the rudimentary ANC may be considered as snap-shots of a dynamic interaction with silenced genes. Enrichment of SAF-A within Xi territories and its close spatial association with Xist RNA suggests their cooperative function for structural organization of Xi.

Continue reading „Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci“