The Isl1/Ldb1 complex orchestrates heart-specific chromatin organization and transcriptional regulation

Cardiac stem/progenitor cells hold great potential for regenerative therapies however the mechanisms regulating their expansion and differentiation remain insufficiently defined. Here we show that the multi-adaptor protein Ldb1 is a central regulator of cardiac progenitor cell differentiation and second heart field (SHF) development. Mechanistically, we demonstrate that Ldb1 binds to the key regulator of SHF progenitors Isl1 and protects it from proteasomal degradation. Furthermore, the Isl1/Ldb1 complex promotes long-range promoter-enhancer interactions at the loci of the core cardiac transcription factors Mef2c and Hand2. Chromosome conformation capture followed by sequencing identified surprisingly specific, Ldb1-mediated interactions of the Isl1/Ldb1 responsive Mef2c anterior heart field enhancer with genes which play key roles in cardiac progenitor cell function and cardiovascular development. Importantly, the expression of these genes was downregulated upon Ldb1 depletion and Isl1/Ldb1 haplodeficiency. In conclusion, the Isl1/Ldb1 complex orchestrates a network for heart-specific transcriptional regulation and coordination in three-dimensional space during cardiogenesis

Testing the inverse-Compton catastrophe scenario in the intra-day variable blazar S5 0716+71. I. Simultaneous broadband observations during November 2003

Some intra-day variable, compact extra-galactic radio sources show brightness temperatures severely exceeding 10^{12} K, the limit set by catastrophic inverse-Compton (IC) cooling in sources of incoherent synchrotron radiation. The violation of the IC limit, possible under non-stationary conditions, would lead to IC avalanches in the soft-gamma-ray energy band during transient periods. For the first time, broadband signatures of possible IC catastrophes were searched for in S5 0716+71. A multifrequency observing campaign targetting S5 0716+71 was carried out in November 2003 under the framework of the European Network for the Investigation of Galactic nuclei through Multifrequency Analysis (ENIGMA) together with a campaign by the Whole Earth Blazar Telescope (WEBT), involving a pointing by the soft-gamma-ray satellite INTEGRAL, optical, near-infrared, sub-millimeter, millimeter, radio, and Very Long Baseline Array (VLBA) monitoring. S5 0716+71 was very bright at radio frequencies and in a rather faint optical state during the INTEGRAL pointing; significant inter-day and low intra-day variability was recorded in the radio regime, while typical fast variability features were observed in the optical band. No correlation was found between the radio and optical emission. The source was not detected by INTEGRAL, neither by the X-ray monitor JEM-X nor by the gamma-ray imager ISGRI, but upper limits to the source emission in the 3-200 keV energy band were estimated. A brightness temperature Tb>2.1x10^{14} K was inferred from the radio variability, but no corresponding signatures of IC avalanches were recorded at higher energies. The absence of IC-catastrophe signatures provides either a lower limit delta>8 to the Doppler factor affecting the radio emission or strong constraints for modelling of the Compton catastrophes in S5 0716+71.Comment: 15 pages, 3 EPS figures, 3 tables, to appear in A&

Multifrequency variability of the blazar AO 0235+164. The WEBT campaign in 2004-2005 and long-term SED analysis

A huge multiwavelength campaign targeting the blazar AO 0235+164 was organized by the Whole Earth Blazar Telescope (WEBT) in 2003-2005 to study the variability properties of the source. Monitoring observations were carried out at cm and mm wavelengths, and in the near-IR and optical bands, while three pointings by the XMM-Newton satellite provided information on the X-ray and UV emission. We present the data acquired during the second observing season, 2004-2005, by 27 radio-to-optical telescopes. They reveal an increased near-IR and optical activity with respect to the previous season. Increased variability is also found at the higher radio frequencies, down to 15 GHz, but not at the lower ones. The radio (and optical) outburst predicted to peak around February-March 2004 on the basis of the previously observed 5-6 yr quasi-periodicity did not occur. The analysis of the optical light curves reveals now a longer characteristic time scale of 8 yr, which is also present in the radio data. The spectral energy distributions corresponding to the XMM-Newton observations performed during the WEBT campaign are compared with those pertaining to previous pointings of X-ray satellites. Bright, soft X-ray spectra can be described in terms of an extra component, which appears also when the source is faint through a hard UV spectrum and a curvature of the X-ray spectrum. Finally, there might be a correlation between the X-ray and optical bright states with a long time delay of about 5 yr, which would require a geometrical interpretation.Comment: 14 pages, 10 figures (8 included in the text and 2 PNG files), in press for A&

Multifrequency variability of the blazar AO 0235+164 the WEBT campaign in 2004-2005 and long-term SED analysis

A huge multiwavelength campaign targeting the blazar AO 0235+164 was organized by the Whole Earth Blazar Telescope (WEBT) in 2003-2005 to study the variability properties of the source. Monitoring observations were carried out at cm and mm wavelengths, and in the near-IR and optical bands, while three pointings by the XMM-Newton satellite provided information on the X-ray and UV emission. We present the data acquired during the second observing season, 2004-2005, by 27 radio-to-optical telescopes. They reveal an increased near-IR and optical activity with respect to the previous season. Increased variability is also found at the higher radio frequencies, down to 15 GHz, but not at the lower ones. The radio (and optical) outburst predicted to peak around February-March 2004 on the basis of the previously observed 5-6 yr quasi-periodicity did not occur. The analysis of the optical light curves reveals now a longer characteristic time scale of 8 yr, which is also present in the radio data. The spectral energy distributions corresponding to the XMM-Newton observations performed during the WEBT campaign are compared with those pertaining to previous pointings of X-ray satellites. Bright, soft X-ray spectra can be described in terms of an extra component, which appears also when the source is faint through a hard UV spectrum and a curvature of the X-ray spectrum. Finally, there might be a correlation between the X-ray and optical bright states with a long time delay of about 5 yr, which would require a geometrical interpretation

Reduced Lipid Peroxidation Predicts Unfavorable Prognosis in Hepatocellular Carcinoma, but Not Intrahepatic Cholangiocarcinoma

Primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), remains a significant contributor to cancer-related mortality worldwide. Oxidative stress and lipid peroxidation play a key role in chronic liver diseases and have been shown to be pivotal for tumor initiation and progression. 4-hydroxy-nonenal (4-HNE), one of the major mediators of oxidative stress and a well-established biomarker for lipid peroxidation, can act as a signal transducer, inducing inflammation and exerting carcinogenic effects. However, the role of 4-HNE in primary liver cancer remains poorly explored. In this study, we investigated 4-HNE levels in 797 liver carcinomas, including 561 HCC and 236 iCCA, by immunohistochemistry. We then correlated 4-HNE levels with comprehensive clinical data and survival outcomes. In HCC, lower expression levels of 4-HNE were associated with vascular invasion, a high tumor grade, a macrotrabecular-massive HCC subtype, and poor overall survival. Concerning iCCA, large duct iCCA showed significantly higher 4-HNE levels when compared to small duct iCCA. Yet, in iCCA, 4-HNE levels did not correlate with known prognostic parameters or survival outcomes. To conclude, in HCC but not in iCCA, low amounts of 4-HNE predict unfavorable survival outcomes and are associated with aggressive tumor behavior. These findings provide insights into the role of 4-HNE in liver cancer progression and may enable novel therapeutic strategies

N-Cadherin Distinguishes Intrahepatic Cholangiocarcinoma from Liver Metastases of Ductal Adenocarcinoma of the Pancreas

Carcinomas of the pancreatobiliary system confer an especially unfavorable prognosis. The differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) and its subtypes versus liver metastasis of ductal adenocarcinoma of the pancreas (PDAC) is clinically important to allow the best possible therapy. We could previously show that E-cadherin and N-cadherin, transmembrane glycoproteins of adherens junctions, are characteristic features of hepatocytes and cholangiocytes. We therefore analyzed E-cadherin and N-cadherin in the embryonally related epithelia of the bile duct and pancreas, as well as in 312 iCCAs, 513 carcinomas of the extrahepatic bile ducts, 228 gallbladder carcinomas, 131 PDACs, and precursor lesions, with immunohistochemistry combined with image analysis, fluorescence microscopy, and immunoblots. In the physiological liver, N-cadherin colocalizes with E-cadherin in small intrahepatic bile ducts, whereas larger bile ducts and pancreatic ducts are positive for E-cadherin but contain decreasing amounts of N-cadherin. N-cadherin was highly expressed in most iCCAs, whereas in PDACs, N-cadherin was negative or only faintly expressed. E- and N-cadherin expression in tumors of the pancreaticobiliary tract recapitulate their expression in their normal tissue counterparts. N-cadherin is a helpful marker for the differential diagnosis between iCCA and PDAC, with a specificity of 96% and a sensitivity of 67% for small duct iCCAs and 50% for large duct iCCAs

The WEBT campaign to observe AO 0235+16 in the 2003-2004 observing season. Results from radio-to-optical monitoring and XMM-Newton observations

Peer reviewe

[Accepted Article Manuscript Version (Postprint)] Testing the Inverse-Compton Catastrophe Scenario in the Intra-Day Variable Blazar s5 0716+71. I. Simultaneous Broadband Observations During November 2003

Context. Some intra-day variable, compact extra-galactic radio sources show brightness temperatures severely exceeding 1012 K, the limit set by catastrophic inverse-Compton (IC) cooling in sources of incoherent synchrotron radiation. The violation of the IC limit, actually possible under non-stationary conditions, would lead to IC avalanches in the soft-γ-ray energy band during transient periods.Aims. For the first time, broadband signatures of possible IC catastrophes were searched for in a prototypical source, S5 0716+71.Methods. A multifrequency observing campaign targetting S5 0716+71 was carried out during November 06-20, 2003. The observations, organized under the framework of the European Network for the Investigation of Galactic nuclei through Multifrequency Analysis (ENIGMA) together with a campaign by the Whole Earth Blazar Telescope (WEBT), involved a pointing by the soft-γ-ray satellite INTEGRAL, optical, near-infrared, sub-millimeter, millimeter, radio, as well as Very Long Baseline Array (VLBA) monitoring.Results. S5 0716+71 was very bright at radio frequencies and in a rather faint optical state () during the INTEGRAL pointing; significant inter-day and low intra-day variability was recorded in the radio regime, while typical fast variability features were observed in the optical band. No obvious correlation was found between the radio and optical emission. The source was not detected by INTEGRAL, neither by the X-ray monitor JEM-X nor by the γ-ray imager ISGRI, but upper limits to the source emission in the 3-200 keV energy band were estimated. A brightness temperature K (violating the IC limit) was inferred from the variability observed in the radio regime, but no corresponding signatures of IC avalanches were recorded at higher energies.Conclusions. In the most plausible scenario of negligible contribution of the interstellar scintillation to the observed radio variability, the absence of the signatures of IC catastrophes provides either a lower limit to the Doppler factor affecting the radio emission or strong constraints for modelling of the Compton-catastrophe scenario in S5 0716+71