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Liquid crystal elastomers (LCEs) are innovative materials best known for their reversible shape and optical property changes in response to external stimuli such as heat, light, and mechanical forces. These unique features position them as promising candidates for applications in emerging technologies. The determination of the mechanical properties of these materials is important for the study of the interaction between orientational and mechanical deformations of LCEs. Importantly, thoroughly characterizing the mechanical and elastic properties of LCEs is essential for their efficient design and integration into various devices. In this study, a full elastic characterization of promising acrylate-based LCE materials that are auxetic above a material-dependent strain threshold (~0.4 for the material studied here) was carried out. Highly aligned macroscopic samples were fabricated, allowing us to determine, for the first time, the five elasticity coefficients that enter into the elastic-free energy density of acrylate-based LCE materials, as well as the Young’s moduli and Poisson ratios. Our approach involves connecting measured strains with elasticity coefficients and using data obtained from three tensile experiments. Specifically, the measured Young’s moduli are on the order of MPa, with an anisotropy ratio (E‖/E⊥) of ~4.5. Moreover, the longitudinal Poisson ratios are both close to 0.5, confirming a uniaxial elastic response at low strains in these LCE samples. These findings align with theoretical predictions, indicating a good correspondence between experimental results and established theories.

Liquid crystal elastomers are attractive materials featuring promising applications in emerging technologies, but their structure–property relationship has yet to be thoroughly explored. Some mechanical properties of these materials are the focus of this article. Three tensile experiments of monodomain nematic liquid crystal elastomers have been theoretically analyzed using a free energy density expression describing mechanical and orientational deformations and their interaction. As a result, a theoretical relation is obtained that relates the quantities measured in experiments with the elasticity coefficients entering the expression of the free energy density. Five of these elasticity coefficients were estimated for monodomain nematic liquid crystal elastomers with different compositions using available experimental data from the literature.

The prime function of nucleoli is ribogenesis, however, several other, non-canonical functions have recently been identified, including a role in genotoxic stress response. Upon DNA damage, numerous proteins shuttle dynamically between the nucleolus and the nucleoplasm, yet the underlying molecular mechanisms are incompletely understood. Here, we demonstrate that PARP1 and PARylation contribute to genotoxic stress-induced nucleolar-nucleoplasmic shuttling of key genome maintenance factors in HeLa cells. Our work revealed that the RECQ helicase, WRN, translocates from nucleoli to the nucleoplasm upon treatment with the oxidizing agent H 2 O 2 , the alkylating agent 2-chloroethyl ethyl sulfide (CEES), and the topoisomerase inhibitor camptothecin (CPT). We show that after treatment with H 2 O 2 and CEES, but not CPT, WRN translocation was dependent on PARP1 protein, yet independent of its enzymatic activity. In contrast, nucleolar-nucleoplasmic translocation of the base excision repair protein, XRCC1, was dependent on both PARP1 protein and its enzymatic activity. Furthermore, gossypol, which inhibits PARP1 activity by disruption of PARP1-protein interactions, abolishes nucleolar-nucleoplasmic shuttling of WRN, XRCC1 and PARP1, indicating the involvement of further upstream factors. In conclusion, this study highlights a prominent role of PARP1 in the DNA damage-induced nucleolar-nucleoplasmic shuttling of genome maintenance factors in HeLa cells in a toxicant and protein-specific manner.

Background The JAK2-V617F mutation is the most frequent driver mutation in a group of malignant hematopoietic disorders called myeloproliferative neoplasms (MPN). JAK2-V617F is a somatic mutation originating in a hematopoietic stem cell and results in constitutively activated JAK-STAT signaling. High levels of pro-inflammatory cytokines in the blood are a hallmark of MPN patients and are a key factor in the severe clinical symptoms seen in these patients. The molecular mechanisms underlying the up-regulation of inflammatory cytokines in JAK2-V617F mutated hematopoietic cells remain to be elucidated. Methods 32D myeloid progenitor cells expressing JAK2-wildtype (WT) and JAK2-V617F, respectively were employed. In addition, primary hematopoietic cells from the JAK2-V617F knock-in MPN mouse model were investigated. Integrin outside-in signaling upon binding of cells to the adhesion molecules VCAM-1/ICAM-1 was characterized by Western blotting of phosphorylated FAK, STAT3, p65, SYK and JNK. Regulation of mRNA and protein expression of IL-1α, IL-1β, IL-6, TNF and CXCL10 was measured by qPCR and ELISA. RNAseq and DNA methylation analysis in primary mouse JAK2-V617F granulocytes was performed. In JAK2-V617F knock-in mice, anti-integrin treatment was applied to evaluate the impact of activated integrin signaling on IL-1 blood levels in vivo. Results Integrin stimulation via the adhesion molecules VCAM-1/ICAM-1 activated integrin outside-in signaling including FAK, SYK, NFκB, and JNK. This induced strong mRNA expression of IL-1α, IL-1β, IL-6, TNF and CXCL10. In 32D cells, the presence of the JAK2-V617F mutation further increased VCAM-1/ICAM-1-induced mRNA and protein levels of IL-1α and IL-1β, and active caspase 1 expression. In primary granulocytes, integrin stimulation resulted in an activated mRNA signature of inflammatory cytokines. Consistent with the mRNA results, adhesion to VCAM-1/ICAM-1 induced an increase in intracellular IL-1α and IL-1β protein levels in 32D cells. However, in primary hematopoietic cells, up-regulation of inflammatory cytokines was not observed at the protein level in vitro, whereas, in vivo, blocking of integrin binding to VCAM-1/ICAM-1 was sufficient to reduce elevated IL-1α levels in the blood of JAK2-V617F mice. Conclusions We conclude that integrin stimulation via the adhesion molecules VCAM-1/ICAM-1 activates integrin outside-in signaling, leading to the up-regulation of pro-inflammatory cytokines in both JAK2-mutated and non-mutated mouse hematopoietic cells.

Impaired differentiation a key feature of many hematopoietic malignancies. To decipher the molecular processes underlying malignant transformation, it is important to understand the mechanisms regulating hematopoietic differentiation. Cell lines derived from transformed hematopoietic progenitors or from leukemia patients have proven to be valuable model systems for mechanistic investigations of hematopoiesis. In the present work, we investigated the cell-intrinsic differentiation capacity of the interleukin 3 (IL-3) dependent murine myeloid progenitor cell line 32D. We demonstrated that 32D cells have a cell-intrinsic granulocytic differentiation potential which requires the presence of high IL-3 concentrations in order to induce granulocytic priming. We also show that 32D cells still proliferate at comparable rates but lack granulocytic priming in the presence of intermediate IL-3 concentrations. This phenotypic plasticity is fully reversible and entirely depends on the IL-3 concentrations present in the culture media. RNA-seq analysis revealed that, among other myeloid genes, the expression of Csf3r is strongly induced exclusively in the presence of high IL-3 concentrations, likely explaining the granulocytic differentiation in response to G-CSF treatment. Together, our work provides detailed cellular and molecular insights into the phenotypic plasticity of 32D cells driven by different IL-3 concentrations and suggest culture conditions for different experimental set ups.Competing Interest StatementD.B.L. receives honoraria from Infectopharm. All other authors report having no conflicts of interest.

Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML. This study examines the consequences of structural alterations and demonstrates that proto-oncogene activation by enhancer hijacking is an overlooked pathomechanism in AML. MNX1 overexpression demonstrates that deletions on chromosome 7q can not only lead to haploinsufficiency, but also to activation of oncogenes by enhancer hijacking, providing a novel leukemogenic mechanism.