Extension of the Segatella copri complex to 13 species with distinct large extrachromosomal elements and associations with host conditions

The Segatella copri (formerly Prevotella copri) complex (ScC) comprises taxa that are key members of the human gut microbiome. It was previously described to contain four distinct phylogenetic clades. Combining targeted isolation with large-scale metagenomic analysis, we defined 13 distinct Segatella copri-related species, expanding the ScC complex beyond four clades. Complete genome reconstruction of thirteen strains from seven species unveiled the presence of genetically diverse large circular extrachromosomal elements. These elements are consistently present in most ScC species, contributing to intra- and inter-species diversities. The nine species-level clades present in humans display striking differences in prevalence and intraspecies genetic makeup across human populations. Based on a meta-analysis, we found reproducible associations between members of ScC and the male sex and positive correlations with lower visceral fat and favorable markers of cardiometabolic health. Our work uncovers genomic diversity within ScC, facilitating a better characterization of the human microbiome

6-OHDA-induced dopaminergic neurodegeneration in <i>Caenorhabditis elegans</i> is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33

<div><p>Oxidative stress is linked to many pathological conditions including the loss of dopaminergic neurons in Parkinson’s disease. The vast majority of disease cases appear to be caused by a combination of genetic mutations and environmental factors. We screened for genes protecting <i>Caenorhabditis elegans</i> dopaminergic neurons from oxidative stress induced by the neurotoxin 6-hydroxydopamine (6-OHDA) and identified the <u>t</u>rans<u>t</u>hyretin-<u>r</u>elated gene <i>ttr-33</i>. The only described <i>C</i>. <i>elegans</i> transthyretin-related protein to date, TTR-52, has been shown to mediate corpse engulfment as well as axon repair. We demonstrate that TTR-52 and TTR-33 have distinct roles. TTR-33 is likely produced in the posterior arcade cells in the head of <i>C</i>. <i>elegans</i> larvae and is predicted to be a secreted protein. TTR-33 protects <i>C</i>. <i>elegans</i> from oxidative stress induced by paraquat or H₂O₂ at an organismal level. The increased oxidative stress sensitivity of <i>ttr-33</i> mutants is alleviated by mutations affecting the KGB-1 MAPK kinase pathway, whereas it is enhanced by mutation of the JNK-1 MAPK kinase. Finally, we provide genetic evidence that the <i>C</i>. <i>elegans</i> cell corpse engulfment pathway is required for the degeneration of dopaminergic neurons after exposure to 6-OHDA. In summary, we describe a new neuroprotective mechanism and demonstrate that TTR-33 normally functions to protect dopaminergic neurons from oxidative stress-induced degeneration, potentially by acting as a secreted sensor or scavenger of oxidative stress.</p></div

Immediate Drop on Demand Technology (I-DOT): Poster presented Forum Life Science 2015, 9th International Congress and Exhibition, 11-12 March 2015, Garching, Germany

The handling and dosing of cells is the most critical step in the microfabrication of 3D-cell-based assay systems for screening and toxicity testing applications. The use of robotic workstations for liquid handling has increased enormously over the last decades, in order to meet the requirements for high accuracy and high throughput of current bioanalytics. The immediate drop on demand technology (I-DOT) overcomes the challenge of dispensing cells in a small volume precisely and with low shear stress. I-DOT provides a fast and flexible non-contact liquid handling system enabling dispensing cells and liquid without the risk of cross-contamination to a precise volume even in nanoliter range

Sensitivity analysis of climate-related transition risks in the German financial sector

Climate-related risks arising from the transition to a low-carbon economy may expose potential vulnerabilities in the financial system. In this article, we develop and describe a set of tools for analysing these risks and apply them to the German financial system. The use of longterm, consistent climate scenarios that have been developed as part of the joint work of the Network for Greening the Financial System (NGFS) allows the effects of the transition to be modelled and then mapped to the financial system. We use a comprehensive dataset in terms of the financial intermediaries and financial instruments reviewed, and demonstrate that the aggregated potential portfolio losses from an unexpected change in climate policy are within the low to medium single-digit percentage range for individual financial sectors. Individual financial intermediaries are more severely affected by transition risks. Uncertainty about the current expectations of market participants leads to results that may deviate by up to 40% from the potential portfolio losses calculated.Klimabezogene Risiken aus der Transition zu einem CO2-armen Wirtschaftssystem können potentielle Verwundbarkeiten des Finanzsystems offenlegen. Wir entwickeln und beschreiben in diesem Artikel ein Instrumentarium zur Analyse dieser Risiken und wenden es auf das deutsche Finanzsystem an. Die Verwendung langfristiger, konsistenter Klimaszenarien, die im Rahmen der gemeinsamen Arbeiten des Network for Greening the Financial System (NGFS) entstanden sind, erlauben die Modellierung der Auswirkungen der Transition und die anschließende Abbildung in das Finanzsystem. Wir nutzen eine umfassende Datenbasis hinsichtlich der einbezogenen Finanzintermediäre und -instrumente und zeigen, dass sich die potentiellen Portfolioverluste aus einem unerwarteten Klimapolitikwechsel im Aggregat für die einzelnen Finanzsektoren im geringen bis mittleren einstelligen Prozentbereich bewegen. Einzelne Finanzintermediäre sind dabei stärker von Transitionsrisiken betroffen. Die Unsicherheit über die aktuellen Erwartungen der Marktakteure führt zu Ergebnissen, welche von den abgeleiteten potentiellen Portfolioverlusten um bis zu 40 % abweichen können

Sensitivity analysis of climate-related transition risks in the German financial sector

Klimabezogene Risiken aus der Transition zu einem CO2-armen Wirtschaftssystem können potentielle Verwundbarkeiten des Finanzsystems offenlegen. Wir entwickeln und beschreiben in diesem Artikel ein Instrumentarium zur Analyse dieser Risiken und wenden es auf das deutsche Finanzsystem an. Die Verwendung langfristiger, konsistenter Klimaszenarien, die im Rahmen der gemeinsamen Arbeiten des Network for Greening the Financial System (NGFS) entstanden sind, erlauben die Modellierung der Auswirkungen der Transition und die anschließende Abbildung in das Finanzsystem. Wir nutzen eine umfassende Datenbasis hinsichtlich der einbezogenen Finanzintermediäre und -instrumente und zeigen, dass sich die potentiellen Portfolioverluste aus einem unerwarteten Klimapolitikwechsel im Aggregat für die einzelnen Finanzsektoren im geringen bis mittleren einstelligen Prozentbereich bewegen. Einzelne Finanzintermediäre sind dabei stärker von Transitionsrisiken betroffen. Die Unsicherheit über die aktuellen Erwartungen der Marktakteure führt zu Ergebnissen, welche von den abgeleiteten potentiellen Portfolioverlusten um bis zu 40 % abweichen können.Climate-related risks arising from the transition to a low-carbon economy may expose potential vulnerabilities in the financial system. In this article, we develop and describe a set of tools for analysing these risks and apply them to the German financial system. The use of longterm, consistent climate scenarios that have been developed as part of the joint work of the Network for Greening the Financial System (NGFS) allows the effects of the transition to be modelled and then mapped to the financial system. We use a comprehensive dataset in terms of the financial intermediaries and financial instruments reviewed, and demonstrate that the aggregated potential portfolio losses from an unexpected change in climate policy are within the low to medium single-digit percentage range for individual financial sectors. Individual financial intermediaries are more severely affected by transition risks. Uncertainty about the current expectations of market participants leads to results that may deviate by up to 40% from the potential portfolio losses calculated

Orai1 Boosts SK3 Channel Activation

The interplay of SK3, a Ca2+ sensitive K+ ion channel, with Orai1, a Ca2+ ion channel, has been reported to increase cytosolic Ca2+ levels, thereby triggering proliferation of breast and colon cancer cells, although a molecular mechanism has remained elusive to date. We show in the current study, via heterologous protein expression, that Orai1 can enhance SK3 K+ currents, in addition to constitutively bound calmodulin (CaM). At low cytosolic Ca2+ levels that decrease SK3 K+ permeation, co-expressed Orai1 potentiates SK3 currents. This positive feedback mechanism of SK3 and Orai1 is enabled by their close co-localization. Remarkably, we discovered that loss of SK3 channel activity due to overexpressed CaM mutants could be restored by Orai1, likely via its interplay with the SK3–CaM binding site. Mapping for interaction sites within Orai1, we identified that the cytosolic strands and pore residues are critical for a functional communication with SK3. Moreover, STIM1 has a bimodal role in SK3–Orai1 regulation. Under physiological ionic conditions, STIM1 is able to impede SK3–Orai1 interplay by significantly decreasing their co-localization. Forced STIM1–Orai1 activity and associated Ca2+ influx promote SK3 K+ currents. The dynamic regulation of Orai1 to boost endogenous SK3 channels was also determined in the human prostate cancer cell line LNCaP

Protective T cell receptor identification for orthotopic reprogramming of immunity in refractory virus infections

Viral infections cause life-threatening disease in immunocompromised patients and especially following transplantation. T cell receptor (TCR) engineering redirects specificity and can bring significant progress to emerging adoptive T cell transfer (ACT) approaches. T cell epitopes are well described, although knowledge is limited on which TCRs mediate protective immunity. In this study, refractory adenovirus (AdV) infection after hematopoietic stem cell transplantation (HSCT) was treated with ACT of highly purified Hexon5-specific T cells using peptide major histocompatibility complex (pMHC)-Streptamers against the immunodominant human leukocyte antigen (HLA)-A∗0101-restricted peptide LTDLGQNLLY. AdV was successfully controlled through this oligoclonal ACT. Novel protective TCRs were isolated ex vivo and preclinically engineered into the TCR locus of allogeneic third-party primary T cells by CRISPR-Cas9-mediated orthotopic TCR replacement. Both TCR knockout and targeted integration of the new TCR in one single engineering step led to physiological expression of the transgenic TCR. Reprogrammed TCR-edited T cells showed strong virus-specific functionality such as cytokine release, effector marker upregulation, and proliferation capacity, as well as cytotoxicity against LTDLGQNLLY-presenting and AdV-infected targets. In conclusion, ex vivo isolated TCRs with clinical proven protection through ACT could be redirected into T cells from naive third-party donors. This approach ensures that transgenic TCRs are protective with potential off-the-shelf use and widened applicability of ACT to various refractory emerging viral infections