Trehalose-6-phosphate-mediated toxicity determines essentiality of OtsB2 in Mycobacterium tuberculosis in vitro and in mice

Trehalose biosynthesis is considered an attractive target for the development of antimicrobials against fungal, helminthic and bacterial pathogens including Mycobacterium tuberculosis. The most common biosynthetic route involves trehalose-6-phosphate (T6P) synthase OtsA and T6P phosphatase OtsB that generate trehalose from ADP/UDP-glucose and glucose-6-phosphate. In order to assess the drug target potential of T6P phosphatase, we generated a conditional mutant of M. tuberculosis allowing the regulated gene silencing of the T6P phosphatase gene otsB2. We found that otsB2 is essential for growth of M. tuberculosis in vitro as well as for the acute infection phase in mice following aerosol infection. By contrast, otsB2 is not essential for the chronic infection phase in mice, highlighting the substantial remodelling of trehalose metabolism during infection by M. tuberculosis. Blocking OtsB2 resulted in the accumulation of its substrate T6P, which appears to be toxic, leading to the self-poisoning of cells. Accordingly, blocking T6P production in a ΔotsA mutant abrogated otsB2 essentiality. T6P accumulation elicited a global upregulation of more than 800 genes, which might result from an increase in RNA stability implied by the enhanced neutralization of toxins exhibiting ribonuclease activity. Surprisingly, overlap with the stress response caused by the accumulation of another toxic sugar phosphate molecule, maltose-1-phosphate, was minimal. A genome-wide screen for synthetic lethal interactions with otsA identified numerous genes, revealing additional potential drug targets synergistic with OtsB2 suitable for combination therapies that would minimize the emergence of resistance to OtsB2 inhibitors

The KMT2A recombinome of acute leukemias in 2023

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5’-KMT2A, two patients had a 5’-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.publishedVersionPeer reviewe

Marketing in One Person Libraries

In times of budget restraints and limited capacities it is important to use the available resources strictly market-oriented - in other words focused on the client's needs - and with a view to the company's targets. Even for a One Person Library, a marketing concept is essential in order to optimize the work of the library. This article introduces the different stages of the marketing management process. Hereby, the analysis of strengths and weaknesses and strategic marketing planning build the core area.In Zeiten knapper Etats und geringer Personalkapazitäten ist es wichtig, die vorhandenen Ressourcen marktorientiert, d. h. an den Bedürfnissen der Kunden orientiert, und auf die eigenen Unternehmensziele hin einzusetzen. Auch für One Person Libraries ist ein Marketingkonzept unerlässlich, um die Arbeit der Bibliothek zu optimieren. Der Artikel stellt die Stationen des Marketing-Managementprozesses vor. Der Schwerpunkt liegt dabei auf der Stärken-Schwächen-Analyse und der strategischen Marketingplanung

Protocol for High-Throughput Electron Tomography Exemplified on Centrioles in Primary Human Plasma Cells

This dataset provides additional data, code and scripts to Köhrer, Dittrich et al.: Protocol for High-Throughput Electron Tomography Exemplified on Centrioles in Primary Human Plasma Cells. STAR Protocols, 2023

Protocol for High-Throughput Electron Tomography Exemplified on Centrioles in Primary Human Plasma Cells

This dataset provides additional data, code and scripts to Köhrer, Dittrich et al.: Protocol for High-Throughput Electron Tomography Exemplified on Centrioles in Primary Human Plasma Cells. STAR Protocols, 2023.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV