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Abstract Background Acute myeloid leukemia (AML) patients with a high allelic burden of an internal tandem duplication (ITD)-mutated FMS-like Tyrosine Kinase-3 (FLT3) have a dismal outcome. FLT3ITD triggers the proliferation of the quiescent hematopoietic stem cell (HSC) pool but fails to directly transform HSCs. While the inflammatory transcription factor nuclear factor of activated T-cells 2 (NFAT2, NFATC1) is overexpressed in AML, it is unknown whether it plays a role in FLT3ITD-induced HSC transformation. Methods We generated a triple transgenic mouse model, in which tamoxifen-inducible Cre-recombinase targets expression of a constitutively nuclear transcription factor NFATC1 to FLT3 ITD positive HSC. Emerging genotypes were phenotypically, biochemically, and also transcriptionally characterized using RNA sequencing. We also retrospectively analyzed the overall survival of AML patients with different NFATC1 expression status. Results We find that NFATC1 governs FLT3ITD-driven precursor cell expansion and transformation, causing a fully penetrant lethal AML. FLT3ITD/NFATC1-AML is re-transplantable in secondary recipients and shows primary resistance to the FLT3ITD-kinase inhibitor quizartinib. Mechanistically, NFATC1 rewires FLT3ITD-dependent signaling output in HSC, involving augmented K-RAS signaling and a selective de novo recruitment of key HSC-transforming signaling pathways such as the Hedgehog- and WNT/B-Catenin signaling pathways. In human AML, NFATC1 overexpression is associated with poor overall survival. Conclusions NFATC1 expression causes FLT3ITD-induced transcriptome changes, which are associated with HSC transformation, quizartinib resistance, and a poor prognosis in AML.

There has been a lack of multi-year landscape-scale studies on the effect of neonicotinoids on honeybee health. Here, Osterman et al. show that clothianidin exposure via seed-treated rapeseed has no negative impact on honeybee colony development, microbial pathogens/symbionts or immune gene expression.

The potential impact of neonicotinoid field exposure on bumblebee microbiota remains unclear. In a landscape—scale study, Wintermantel et al. show that whilst exposure to clothianidin impacts Bombus terrestris performance, it does not affect levels of gut bacteria, viruses or intracellular parasites.

Numerous microbial symbionts, both commensal and pathogenic, are associated with honey bees. Here, the authors genomically characterize this ‘metagenome’ of the British honey bee, identifying a diversity of commensal microbes as well as known and putative pathogens

Numerous studies have recently reported on the discovery of bee viruses in different arthropod species and their possible transmission routes, vastly increasing our understanding of these viruses and their distribution. Here, we review the current literature on the recent advances in understanding the transmission of viruses, both on the presence of bee viruses in Apis and non-Apis bee species and on the discovery of previously unknown bee viruses. The natural transmission of bee viruses will be discussed among different bee species and other insects. Finally, the research potential of in vivo (host organisms) and in vitro (cell lines) serial passages of bee viruses is discussed, from the perspective of the host-virus landscape changes and potential transmission routes for emerging bee virus infections.

Background: Renal artery stenosis (RAS) can lead to hypertension and renal failure. Nevertheless, its treatment by percutaneous transluminal renal angioplasty (PTRA) remains controversial. It is unknown, whether patients with global kidney ischemia (GKI), that means patients with bilateral RAS or RAS with a single functioning kidney, may benefit from PTRA or not. Methods: We retrospectively analyzed 93 patients with RAS (25 bilateral or single functioning kidney) undergoing PTRA. Patients had refractory hypertension (≥3 medications). Blood pressure, antihypertensive drugs and serum-creatinine were compared pre-/post-intervention and at 1 year’s follow-up. Results: At 1 year after PTRA of patients with GKI, systolic and diastolic blood pressure were significantly reduced compared to patients with unilateral PTRA (systolic: −19.1 ± 10.5 [bilateral] vs. −11.4 ± 12.1 mmHg [unilateral], P

Abstract Background Therapeutic targeting of tumour necrosis factor (TNF)-α is highly effective in ankylosing spondylitis (AS) patients. However, since one-third of anti-TNF-treated AS patients do not show an adequate clinical response there is an urgent need for new biomarkers that would aid clinicians in their decision-making to select appropriate therapeutic options. Thus, the aim of this explorative study was to identify cell-based biomarkers in peripheral blood that could be used for a pre-treatment stratification of AS patients. Methods A high-dimensional, multi-parametric flow cytometric approach was applied to identify baseline predictors in 31 AS patients before treatment with the TNF blockers adalimumab (TNF-neutralisation) and etanercept (soluble TNF receptor). Results As the major result, the frequencies of natural killer (NK) cells, and in particular CD8-positive (CD8+) NK cell subsets, were most predictive for therapeutic outcome in AS patients. While an inverse correlation between classical CD56+/CD16+ NK cells and reduction of disease activity was observed, the CD8+ NK cell subset behaved in the opposite direction. At baseline, responders showed significantly increased frequencies of CD8+ NK cells compared with non-responders. Conclusions This is the first study demonstrating that the composition of the NK cell compartment has predictive power for prediction of therapeutic outcome for anti-TNF-α blockers, and we identified CD8+ NK cells as a potential new player in the TNF-α-driven chronic inflammatory immune response of AS.

Chronic viral infections are frequently associated with the dysfunction of CD8+ T cells which includes loss of function and results in CD8+ T cell exhaustion. Here the authors show a role of CEACAM1 in promoting responsive CD8+ T cells in the context of a chronic lymphocytic choriomeningitis virus (LCMV) infection model.

Personalised medicine requires cell cultures from defined genetic backgrounds, but providing sufficient numbers of cells is a challenge. Here the authors develop gene cocktails to expand primary cells from a variety of different tissues and species, and show that expanded endothelial and hepatic cells retain properties of the differentiated phenotype.

Focal adhesion kinase (FAK) plays a critical role during vascular development because knockout of FAK in endothelial cells (ECs) is embryonic lethal. Surprisingly, tamoxifen-inducible conditional knockout of FAK in adult blood vessels (inducible EC-specific FAK knockout [i-EC-FAK-KO]) produces no vascular phenotype, and these animals are capable of developing a robust growth factor-induced angiogenic response. Although angiogenesis in wild-type mice is suppressed by pharmacological inhibition of FAK, i-EC-FAK-KO mice are refractory to this treatment, which suggests that adult i-EC-FAK-KO mice develop a compensatory mechanism to bypass the requirement for FAK. Indeed, expression of the FAK-related proline-rich tyrosine kinase 2 (Pyk2) is elevated and phosphorylated in i-EC-FAK-KO blood vessels. In cultured ECs, FAK knockdown leads to increased Pyk2 expression and, surprisingly, FAK kinase inhibition leads to increased Pyk2 phosphorylation. Pyk2 can functionally compensate for the loss of FAK because knockdown or pharmacological inhibition of Pyk2 disrupts angiogenesis in i-EC-FAK-KO mice. These studies reveal the adaptive capacity of ECs to switch to Pyk2-dependent signaling after deletion or kinase inhibition of FAK.

Inflammation-induced thrombosis represents a severe complication in patients with myeloproliferative neoplasms (MPN) and in those with kidney dysfunction. Overlapping disease-specific attributes suggest common mechanisms involved in MPN pathogenesis, kidney dysfunction, and thrombosis. Data from 1420 patients with essential thrombocythemia (ET, 33.7%), polycythemia vera (PV, 38.5%), and myelofibrosis (MF, 27.9%) were extracted from the bioregistry of the German Study Group for MPN. The total cohort was subdivided according to the calculated estimated glomerular filtration rate (eGFR, (mL/min/1.73 m2)) into eGFR1 (≥90, 21%), eGFR2 (60–89, 56%), and eGFR3 (

This work presents a method for reducing acoustic resonances in ferroelectric barium strontium titanate (BST)-based bulk ceramic varactors, which are capable of operation in high-power matching circuits. Two versions of parallel-plate varactors are manufactured here: one with pure BST and one with 10 vol-% magnesium borate, Mg3B2O6 (MBO). Each varactor includes a 0.85-mm-thick ferroelectric layer. Acoustic resonances that are present in the pure BST varactor are strongly suppressed in the BST-MBO varactor and, hence, the Q-factor is increased over a wide frequency range by the addition of small amounts of a low-dielectric-constant (LDK) MBO. Although the tunability is reduced due to the presence of non-tunable MBO, the increased Q-factor extends the varactor’s availability for low-loss and high-power applications.