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Background Activation of the oncogene yes-associated protein (YAP) is frequently detected in intrahepatic cholangiocarcinoma (iCCA); however, the expression pattern and the functional impact of its paralogue WW domain-containing transcription regulator 1 (WWTR1; synonym: TAZ) are not well described in different CCA subtypes. Methods Immunohistochemical analysis of YAP and TAZ in iCCA and extrahepatic CCA (eCCA) cohorts was performed. YAP/TAZ shuttling and their functional impact on CCA cell lines were investigated. Target genes expression after combined YAP/TAZ inhibition was analyzed. Results Immunohistochemical analysis of iCCA and eCCA revealed YAP or TAZ positivity in up to 49.2%; however, oncogene co-expression was less frequent (up to 23%). In contrast, both proteins were jointly detectable in most CCA cell lines and showed nuclear/cytoplasmic shuttling in a cell density-dependent manner. Next to the pro-proliferative function of YAP/TAZ, both transcriptional co-activators cooperated in the regulation of a gene signature that indicated the presence of chromosomal instability (CIN). A correlation between YAP and the CIN marker phospho-H2A histone family member X (pH2AX) was particularly observed in tissues from iCCA and distal CCA (dCCA). The presence of the CIN genes in about 25% of iCCA was statistically associated with worse prognosis. Conclusions YAP and TAZ activation is not uncoupled from cell density in CCA cells and both factors cooperatively contribute to proliferation and expression of CIN-associated genes. The corresponding group of CCA patients is characterized by CIN and may benefit from YAP/TAZ-directed therapies.

Forecasting the geomagnetic effects of solar coronal mass ejections (CMEs) is currently an unsolved problem. CMEs, responsible for the largest values of the north‐south component of the interplanetary magnetic field, are the key driver of intense and extreme geomagnetic activity. Observations of southward interplanetary magnetic fields are currently only accessible directly through in situ measurements by spacecraft in the solar wind. On 10–12 May 2024, the strongest geomagnetic storm since 2003 took place, caused by five interacting CMEs. We clarify the relationship between the CMEs, their solar source regions, and the resulting signatures at the Sun–Earth L1 point observed by the ACE spacecraft at 1.00 AU. The STEREO‐A spacecraft was situated at 0.956 AU and 12.6° ^{\\circ}$ west of Earth during the event, serving as a fortuitous sub‐L1 monitor providing interplanetary magnetic field measurements of the solar wind. We demonstrate an extension of the prediction lead time, as the shock was observed 2.57 hr earlier at STEREO‐A than at L1, consistent with the measured shock speed at L1, 710 kms−1 $\\,{\\mathrm{s}}^{-1}$, and the radial distance of 0.043 AU. By deriving the geomagnetic indices based on the STEREO‐A beacon data, we show that the strength of the geomagnetic storm would have been decently forecasted, with the modeled minimum SYM‐H=−478.5 $\\,=-\\,478.5$ nT, underestimating the observed minimum by only 8%. Our study sets an unprecedented benchmark for future mission design using upstream monitoring for space weather prediction.

Coronal mass ejections (CMEs) drive space weather throughout the heliosphere so knowledge of their internal properties is key to understanding and eventually forecasting their effects. Typically observations are limited to single‐spacecraft encounters sampling one path that may or may not be representative of the overall structure. Many catalogs exist listing the observed boundaries of a CME ejecta and any CME‐driven sheath. Often there are large differences in the reported boundaries across different catalogs. We introduce the Living List of Attributes Measured in Any In situ CME Encounter (LLAMAICE), which collects and collates existing near‐Earth catalogs into a new meta‐catalog. We have added a new set of boundaries, building upon the existing information that includes additional mixed regions containing mixed signatures of the pristine sheath and ejecta core (EC). This first version of LLAMAICE covers February 1995 to December 2006, corresponding to 1,516 entries for 396 unique CMEs. We use LLAMAICE to quantify the variation in mean sheath/ejecta properties from using boundaries from different catalogs and/or data from using ACE versus Wind data. We also reconstruct flux rope (FR) orientation for each set of bounds/spacecraft, which are well‐known to be quite sensitive. For both studies, the cross‐catalog variations exceed the cross‐spacecraft variations. The reconstructed FR handedness agrees 77% of the time between spacecraft but only 47% across catalogs. The orientations vary between spacecraft by 2.2°^{\\circ}$ /3.4°^{\\circ}$in inclination/longitude but 4/10 times that between catalogs.

Background Overexpression and nuclear enrichment of the oncogene yes-associated protein (YAP) cause tumor initiation and support tumor progression in human hepatocellular carcinoma (HCC) via cell autonomous mechanisms. However, how YAP expression in tumor cells affects intercellular communication within the tumor microenvironment is not well understood. Methods To investigate how tumor cell-derived YAP is changing the paracrine communication network between tumor cells and non-neoplastic cells in hepatocarcinogenesis, the expression and secretion of cytokines, growth factors and chemokines were analyzed in transgenic mice with liver-specific and inducible expression of constitutively active YAP (YAP S127A ). Transcriptomic and proteomic analyses were performed using primary isolated hepatocytes and blood plasma. In vitro, RNAinterference (RNAi), expression profiling, functional analyses and chromatin immunoprecipitation (ChIP) analyses of YAP and the transcription factor TEA domain transcription factor 4 (TEAD4) were performed using immortalized cell lines. Findings were confirmed in cohorts of HCC patients at the transcript and protein levels. Results YAP overexpression induced the expression and secretion of many paracrine-acting factors with potential impact on tumorous or non-neoplastic cells (e.g. plasminogen activator inhibitor-1 (PAI-1), C-X-C motif chemokine ligand 13 (CXCL13), CXCL16). Expression analyses of human HCC patients showed an overexpression of PAI-1 in human HCC tissues and a correlation with poor overall survival as well as early cancer recurrence. PAI-1 statistically correlated with genes typically induced by YAP, such as connective tissue growth factor (CTGF) and cysteine rich angiogenic inducer 61 (CYR61) or YAP-dependent gene signatures (CIN4/25). In vitro, YAP inhibition diminished the expression and secretion of PAI-1 in murine and human liver cancer cell lines. PAI-1 affected the expression of genes involved in cellular senescence and oncogene-induced senescence was confirmed in YAP S127A transgenic mice. Silencing of TEAD4 as well as treatment with the YAP/TEAD interfering substance Verteporfin reduced PAI-1 expression. ChIP analyses confirmed the binding of YAP and TEAD4 to the gene promoter of PAI-1 (SERPINE1). Conclusions These results demonstrate that the oncogene YAP changes the secretome response of hepatocytes and hepatocyte-derived tumor cells. In this context, the secreted protein PAI-1 is transcriptionally regulated by YAP in hepatocarcinogenesis. Perturbation of these YAP-dependent communication hubs including PAI-1 may represent a promising pharmacological approach in tumors with YAP overexpression. 99z8_srgZpQ-KvP6pFLwuF Video abstract

Background Adherens junctions (AJs) facilitate cell–cell contact and contribute to cellular communication as well as signaling under physiological and pathological conditions. Aberrant expression of AJ proteins is frequently observed in human cancers; however, how these factors contribute to tumorigenesis is poorly understood. In addition, for some factors such as α‐catenin contradicting data has been described. In this study we aim to decipher how the AJ constituent α‐catenin contributes to liver cancer formation. Methods TCGA data was used to detect transcript changes in 23 human tumor types. For the detection of proteins, liver cancer tissue microarrays were analyzed by immunohistochemistry. Liver cancer cell lines (HLF, Hep3B, HepG2) were used for viability, proliferation, and migration analyses after RNA interference -mediated gene silencing. To investigate the tumor initiating potential, vectors coding for α‐catenin and myristoylated AKT were injected in mice by hydrodynamic gene delivery. A BioID assay combined with mass spectrometry was performed to identify α‐catenin binding partners. Results were confirmed by proximity ligation and co-immunoprecipitation assays. Binding of transcriptional regulators at gene promoters was investigated using chromatin-immunoprecipitation. Results α‐catenin mRNA was significantly reduced in many human malignancies (e.g., colon adenocarcinoma). In contrast, elevated α‐catenin expression in other cancer entities was associated with poor clinical outcome (e.g., for hepatocellular carcinoma; HCC). In HCC cells, α‐catenin was detectable at the membrane as well as cytoplasm where it supported tumor cell proliferation and migration. In vivo, α‐catenin facilitated moderate oncogenic properties in conjunction with AKT overexpression. Cytokinesis regulator centrosomal protein 55 (CEP55) was identified as a novel α‐catenin-binding protein in the cytoplasm of HCC cells. The physical interaction between α‐catenin and CEP55 was associated with CEP55 stabilization. CEP55 was highly expressed in human HCC tissues and its overexpression correlated with poor overall survival and cancer recurrence. Next to the α‐catenin-dependent protein stabilization, CEP55 was transcriptionally induced by a complex consisting of TEA domain transcription factors (TEADs), forkhead box M1 (FoxM1), and yes-associated protein (YAP). Surprisingly, CEP55 did not affect HCC cell proliferation but significantly supported migration in conjunction with α‐catenin. Conclusion Migration-supporting CEP55 is induced by two independent mechanisms in HCC cells: stabilization through interaction with the AJ protein α‐catenin and transcriptional activation via the FoxM1/TEAD/YAP complex. Plain English Summary Cell–cell contact in epithelial cells is important for cell polarity, cellular compartmentalisation, as well as tissue architecture during development, homeostasis, and regeneration of adult tissues in metazoans. In this context, adherens junctions (AJs) mechanically sense cell contact information with direct impact on cytoskeletal remodelling, the regulation of signalling pathways, and eventually cell biology. Indeed, the loss of cell–cell contact and cellular polarity are key features in human carcinogenesis and important pathological parameters for the identification of many epithelial tumors. We demonstrate in this study, that overexpression of the AJ constituent α‐catenin is frequently observed in human hepatocellular carcinoma (HCC). α‐catenin supports HCC cell proliferation and migration. Together with the oncogene AKT, α‐catenin moderately facilitates tumor initiation in mouse livers. Using mass spectrometry, we identified several new α‐catenin interaction partners in the cytosol of liver cancer cells, including the cytokinesis regulator centrosomal protein 55 (CEP55). CEP55 mediates pro-migratory effects and its overexpression in HCC cells is controlled by two molecular mechanisms: α‐catenin-dependent protein stabilization and transcriptional induction by the TEA domain transcription factors (TEADs)/forkhead box M1 (FoxM1)/yes-associated protein (YAP) complex. In summary, we here describe a new mechanism how changes in cell–cell contact support liver cancer formation and progression. This study demonstrates that dysregulation of the AJ component α‐catenin contributes to liver carcinogenesis via distinct molecular mechanisms. -S16VsLzM44GwwAKkQYCqU Video Abstract

Physical properties, distribution, and abundance of natural hard substrates are important variables modulating the potential distribution of sessile aquatic species. In this study, we analyze the effects of the geological origin of different rock types common in intertidal environments of Argentina on the recruitment success of the nonindigenous Pacific oyster Crassostreagigas, accounting for spatial and interannual variation. A series of experiments showed that although recruitment occurs on all of the five most widespread hard substrates in the region (i.e., pelitic mudstone, limestone, conglomeradic sabulitic sandstone, gray sandstone, and volcanic rock) it is significantly higher on pelitic mudstone. Accounting for the geographic distribution of these substrate types along the coast of Argentina, it is concluded that the Valdés Peninsula and central San Jorge Gulf areas, where pelitic mudstone outcrops are the dominant intertidal hard substrate, are the regions with highest potential for C. gigas intertidal reef formation. Pelitic mudstone displayed the highest mean values of specific heat and porosity as well as high values of luminosity.

The Solar TErrestrial RElations Observatory (STEREO) mission has laid a foundation for advancing real‐time space weather forecasting by enabling the evaluation of heliospheric imager (HI) data for predicting coronal mass ejection (CME) arrivals at Earth. This study employs the ELEvoHI model to assess how incorporating STEREO/HI data from the Lagrange 5 (L5) perspective can enhance prediction accuracy for CME arrival times and speeds. Our investigation, preparing for the upcoming ESA Vigil mission, explores whether the progressive incorporation of HI data in real‐time enhances the forecasting accuracy. The role of human tracking variability is evaluated by comparing predictions based on observations by three different scientists, highlighting the influence of manual biases on forecasting outcomes. Furthermore, the study examines the efficacy of deriving CME propagation directions using HI‐specific methods versus coronagraph‐based techniques, emphasizing the trade‐offs in prediction accuracy. Our results demonstrate the potential of HI data to significantly improve operational space weather forecasting when integrated with other observational platforms, especially when HI data from beyond 35°^{\\circ}$elongation are used. These findings pave the way for optimizing real‐time prediction methodologies, providing valuable groundwork for the forthcoming Vigil mission and enhancing preparedness for CME‐driven space weather events.

The Hippo pathway transducers yes-associated protein (YAP) and WW-domain containing transcription regulator 1 (WWTR1/TAZ) are key regulators of liver tumorigenesis, promoting tumor formation and progression. Although the first inhibitors are in clinical trials, targeting the relevant upstream regulators of YAP/TAZ activity could prove equally beneficial. To identify regulators of YAP/TAZ activity in hepatocarcinoma (HCC) cells, we carried out a proximity labelling approach (BioID) coupled with mass spectrometry. We verified CRK-like proto-oncogene adaptor protein (CRKL) as a new YAP-exclusive interaction partner. CRKL is highly expressed in HCC patients, and its expression is associated with YAP activity as well as poor survival prognosis. In vitro experiments demonstrated CRKL-dependent cell survival and the loss of YAP binding induced through actin disruption. Moreover, we delineated the activation of the JNK/JUN pathway by CRKL, which promoted YAP transcription. Our data illustrate that CRKL not only promoted YAP activity through its binding but also through the induction of YAP transcription by JNK/JUN activation. This emphasizes the potential use of targeting the JNK/JUN pathway to suppress YAP expression in HCC patients.

A highly sensitive and accurate multiplex gas chromatography—tandem mass spectrometry (GC-MS/MS) technique is reported for indole-3-acetic acid, abscisic acid, jasmonic acid, 12-oxo-phytodienoic acid and salicylic acid. The optimized setup allows the routine processing and analysis of up to 60 plant samples of between 20 and 200 mg of fresh weight per day. The protocol was designed and the equipment used was chosen to facilitate implementation of the method into other laboratories and to provide access to state-of-the-art analytical tools for the acidic phytohormones and related signalling molecules. Whole-plant organ-distribution maps for indole-3-acetic acid, abscisic acid, jasmonic acid, 12-oxo-phytodienoic acid and salicylic acid were generated for Arabidopsis thaliana (L.) Heynh. For leaves of A. thaliana, a spatial resolution of hormone quantitation down to approximately 2 mm2 was achieved.

The genes of two closely related 12-oxo-phytodienoic acid reductases (EC 1.3.1.42), OPR1 and OPR2, were identified on a 7079-bp-long genomic fragment from Arabidopsis thaliana (L.) Heynh. The organization of these two genes was determined and putative cis elements were identified. Promoter-β-glucuronidase (GUS) fusions expressed in transgenic Arabidopsis thaliana and Nicotiana tabacum L. plants revealed differences in OPR-promoter-driven GUS expression in flowers. While the OPR1 promoter directed GUS expression in young seeds, the OPR2 promoter directed pollen-specific expression. Both OPR1 and OPR2, were predominantly expressed in roots. Stress treatments, like local and systemic wounding, UV-C illumination and coldness, resulted in transient changes in steady-state OPR mRNA levels, but no concurrent changes in polypeptide level or enzyme activity were detected.