Requirement for LIM kinases in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive disease for which only few targeted therapies are available. Using high-throughput RNA interference (RNAi) screening in AML cell lines, we identified LIM kinase 1 (LIMK1) as a potential novel target for AML treatment. HighLIMK1expression was significantly correlated with shorter survival of AML patients and coincided withFLT3mutations,KMT2Arearrangements, and elevatedHOXgene expression. RNAi- and CRISPR-Cas9-mediated suppression as well as pharmacologic inhibition of LIMK1 and its close homolog LIMK2 reduced colony formation and decreased proliferation due to slowed cell-cycle progression ofKMT2A-rearranged AML cell lines and patient-derived xenograft (PDX) samples. This was accompanied by morphologic changes indicative of myeloid differentiation. Transcriptome analysis showed upregulation of several tumor suppressor genes as well as downregulation of HOXA9 targets and mitosis-associated genes in response to LIMK1 suppression, providing a potential mechanistic basis for the anti-leukemic phenotype. Finally, we observed a reciprocal regulation between LIM kinases (LIMK) and CDK6, a kinase known to be involved in the differentiation block ofKMT2A-rearranged AML, and addition of the CDK6 inhibitor palbociclib further enhanced the anti-proliferative effect of LIMK inhibition. Together, these data suggest that LIMK are promising targets for AML therapy

Radiochirurgie vs. Ganzhirnbestrahlung– mehr Lebensqualität, mehr Leistungsfähigkeit?

Hintergrund: Lebensqualität und Neurokognition rückt zunehmend in den klinischen und wissenschaftlichen Fokus in der Behandlung von Hirnmetastasen. Ziel: Die vorliegende Arbeit basiert auf einer selektiven Literaturrecherche in der Datenbank PubMed zum Thema neurokognitive Veränderungen und Lebensqualität nach zerebraler Radiotherapie. Es wird eine Übersicht über die aktuelle Datenlage gegeben. Ergebnisse und Schlussfolgerung: Die technischen Verbesserungen in der Radioonkologie führen zu schneller und effektiver Hochpräzisionsbestrahlung. Die potenziell geringere intrakranielle Kontrolle nach stereotaktischer Radiochirurgie („stereotactic radiosurgery“, SRS) scheint im Vergleich zur Ganzhirnbestrahlung („whole brain radiation therapy“, WBRT) keinen relevanten Einfluss auf das Überleben zu haben. Daher ist die Erhaltung der Neurokognition und der Lebensqualität zentrales Ziel der Behandlung und Gegenstand der aktuellen Forschung

High-resolution spatiotemporal modeling of daily near-surface air temperature in Germany over the period 2000–2020.

The commonly used weather stations cannot fully capture the spatiotemporal variability of near-surface air temperature (Tair), leading to exposure misclassification and biased health effect estimates. We aimed to improve the spatiotemporal coverage of Tair data in Germany by using multi-stage modeling to estimate daily 1 × 1 km minimum (Tmin), mean (Tmean), maximum (Tmax) Tair and diurnal Tair range during 2000–2020. We used weather station Tair observations, satellite-based land surface temperature (LST), elevation, vegetation and various land use predictors. In the first stage, we built a linear mixed model with daily random intercepts and slopes for LST adjusted for several spatial predictors to estimate Tair from cells with both Tair and LST available. In the second stage, we used this model to predict Tair for cells with only LST available. In the third stage, we regressed the second stage predictions against interpolated Tair values to obtain Tair countrywide. All models achieved high accuracy (0.91 ≤ R2 ≤ 0.98) and low errors (1.03 °C ≤ Root Mean Square Error (RMSE) ≤ 2.02 °C). Validation with external data confirmed the good performance, locally, i.e., in Augsburg for all models (0.74 ≤ R2 ≤ 0.99, 0.87 °C ≤ RMSE ≤ 2.05 °C) and countrywide, for the Tmean model (0.71 ≤ R2 ≤ 0.99, 0.79 °C ≤ RMSE ≤ 1.19 °C). Annual Tmean averages ranged from 8.56 °C to 10.42 °C with the years beyond 2016 being constantly hotter than the 21-year average. The spatial variability within Germany exceeded 15 °C annually on average following patterns including mountains, rivers and urbanization. Using a case study, we showed that modeling leads to broader Tair variability representation for exposure assessment of participants in health cohorts. Our results indicate the proposed models as suitable for estimating nationwide Tair at high resolution. Our product is critical for temperature-based epidemiological studies and is also available for other research purposes

TET1 promotes growth of T-cell acute lymphoblastic leukemia and can be antagonized via PARP inhibition.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer characterized by skewed epigenetic patterns, raising the possibility of therapeutically targeting epigenetic factors in this disease. Here we report that among different cancer types, epigenetic factor TET1 is highly expressed in T-ALL and is crucial for human T-ALL cell growth in vivo. Knockout of TET1 in mice and knockdown in human T cell did not perturb normal T-cell proliferation, indicating that TET1 expression is dispensable for normal T-cell growth. The promotion of leukemic growth by TET1 was dependent on its catalytic property to maintain global 5-hydroxymethylcytosine (5hmC) marks, thereby regulate cell cycle, DNA repair genes, and T-ALL associated oncogenes. Furthermore, overexpression of the Tet1-catalytic domain was sufficient to augment global 5hmC levels and leukemic growth of T-ALL cells in vivo. We demonstrate that PARP enzymes, which are highly expressed in T-ALL patients, participate in establishing H3K4me3 marks at the TET1 promoter and that PARP1 interacts with the TET1 protein. Importantly, the growth related role of TET1 in T-ALL could be antagonized by the clinically approved PARP inhibitor Olaparib, which abrogated TET1 expression, induced loss of 5hmC marks, and antagonized leukemic growth of T-ALL cells, opening a therapeutic avenue for this disease

Bernstein inequality in L^α norms.

The classical Bernstein inequality estimates the derivative of a polynomial at a fixed point with the supremum norm and a factor depending on the point only. Recently, this classical inequality was generalized to arbitrary compact subsets on the real line. That generalization is sharp and naturally introduces potential theoretical quantities. It also gives a hint how a sharp L α Bernstein inequality should look like. In this paper we prove this conjectured Lα Bernstein type inequality and we also prove its sharpness

Condensed tannins as antioxidants that protect poplar against oxidative stress from drought and UV-B.

Condensed tannins (CTs, proanthocyanidins) are widespread polymeric flavan-3-ols known for their ability to bind proteins. In poplar (Populus spp.), leaf condensed tannins are induced by both biotic and abiotic stresses, suggesting diverse biological functions. Here we demonstrate the ability of CTs to function as physiological antioxidants, preventing oxidative and cellular damage in response to drought and UV-B irradiation. Chlorophyll fluorescence was used to monitor photosystem II performance, and both hydrogen peroxide and malondialdehyde content was assayed as a measure of oxidative damage. Transgenic MYB-overexpressing poplar (Populus tremula x tremuloides) with high CT content showed reduced photosystem damage and lower hydrogen peroxide and malondialdehyde content after drought and UV-B stress. This antioxidant effect of CT was observed using two different poplar MYB CT regulators, in multiple independent lines and different genetic backgrounds. Additionally, low-CT MYB134-RNAi transgenic poplars showed enhanced susceptibility to drought-induced oxidative stress. UV-B radiation had different impacts than drought on chlorophyll fluorescence, but all high-CT poplar lines displayed reduced sensitivity to both stresses. Our data indicate that CTs are significant defenses against oxidative stress. The broad distribution of CTs in forest systems which are exposed to diverse abiotic stresses suggests that these compounds have wider functional roles than previously realized. This article is protected by copyright. All rights reserved

Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with acute myeloid leukemia.

Previous studies demonstrated that splicing factor mutations are recurrent events in hematopoietic malignancies with both clinical and functional implications. However, their aberrant splicing patterns in acute myeloid leukemia remain largely unexplored. In this study, we characterized mutations in SRSF2, U2AF1, and SF3B1, the most commonly mutated splicing factors. In our clinical analysis of 2678 patients, splicing factor mutations showed inferior relapse-free and overall survival, however, these mutations did not represent independent prognostic markers. RNA-sequencing of 246 and independent validation in 177 patients revealed an isoform expression profile which is highly characteristic for each individual mutation, with several isoforms showing a strong dysregulation. By establishing a custom differential splice junction usage pipeline, we accurately detected aberrant splicing in splicing factor mutated samples. A large proportion of differentially used junctions were novel, including several junctions in leukemia-associated genes. In SRSF2(P95H) mutants, we further explored the possibility of a cascading effect through the dysregulation of the splicing pathway. Furthermore, we observed a validated impact on overall survival for two junctions overused in SRSF2(P95H) mutants. We conclude that splicing factor mutations do not represent independent prognostic markers. However, they do have genome-wide consequences on gene splicing leading to dysregulated isoform expression of several genes

Isolation of nuclei from flash-frozen liver tissue for single-cell multiomics.

The liver is a complex and heterogenous tissue responsible for carrying out many critical physiological functions, such as the maintenance of energy homeostasis and the metabolism of xenobiotics, among others. These tasks are performed through tight coordination between hepatic parenchymal and non-parenchymal cells. Additionally, various metabolic activities are confined to specific areas of the hepatic lobule-a phenomenon called liver zonation. Recent advances in single-cell sequencing technologies have empowered researchers to investigate tissue heterogeneity at a single-cell resolution. In many complex tissues, including the liver, harsh enzymatic and/or mechanical dissociation protocols can negatively affect the viability or the quality of the single-cell suspensions needed to comprehensively characterize this organ in health and disease. This paper describes a robust and reproducible protocol for isolating nuclei from frozen, archived liver tissues. This method yields high-quality nuclei that are compatible with downstream, single-cell omics approaches, including single-nucleus RNA-seq, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), as well as multimodal omics (joint RNA-seq and ATAC-seq). This method has been successfully used for the isolation of nuclei from healthy and diseased human, mouse, and non-human primate frozen liver samples. This approach allows the unbiased isolation of all the major cell types in the liver and, therefore, offers a robust methodology for studying the liver at the single-cell resolution

Investigation of COVID-19-related lockdowns on the air pollution changes in augsburg in 2020, Germany.

The COVID-19 pandemic in Germany in 2020 brought many regulations to impede its transmission such as lockdown. Hence, in this study, we compared the annual air pollutants (CO, NO, NO2, O3, PM10, PM2.5, and BC) in Augsburg in 2020 to the record data in 2010–2019. The annual air pollutants in 2020 were significantly (p < 0.001) lower than that in 2010–2019 except O3, which was significantly (p = 0.02) higher than that in 2010–2019. In a depth perspective, we explored how lockdown impacted air pollutants in Augsburg. We simulated air pollutants based on the meteorological data, traffic density, and weekday and weekend/holiday by using four different models (i.e. Random Forest, K-nearest Neighbors, Linear Regression, and Lasso Regression). According to the best fitting effects, Random Forest was used to predict air pollutants during two lockdown periods (16/03/2020–19/04/2020, 1st lockdown and 02/11/2020–31/12/2020, 2nd lockdown) to explore how lockdown measures impacted air pollutants. Compared to the predicted values, the measured CO, NO2, and BC significantly reduced 18.21%, 21.75%, and 48.92% in the 1st lockdown as well as 7.67%, 32.28%, and 79.08% in the 2nd lockdown. It could be owing to the reduction of traffic and industrial activities. O3 significantly increased 15.62% in the 1st lockdown but decreased 40.39% in the 2nd lockdown, which may have relations with the fluctuations the NO titration effect and photochemistry effect. PM10 and PM2.5 were significantly increased 18.23% an 10.06% in the 1st lockdown but reduced 34.37% and 30.62% in the 2nd lockdown, which could be owing to their complex generation mechanisms