Federalism and Recent Political Dynamics in Austria

From a comparative perspective, the Austrian Federal Constitution appears rather centralized, given that the majority of legislative competences are allocated at the federal level. However, a closer look indicates that the Länder (the federal units) gain considerable political weight by serving as the administrative centre of gravity; namely, the Länder execute their own laws and most of the laws based on the federation’s subject-matters. Hence, one might speak of “administrative federalism”. History shows that Austrian politics resemble a tug-of-war over the federal division of (legislative) competences. The newly elected coalition government’s program joins the ranks of long-winded discussions on how to make Austrian federalism more efficient. Even if pro-federal by rhetoric, the actual content of the government program is either conceptually ambivalent or substantially in favour of increased (legislative) centralization, especially in the realm of social and educational policy

Federalism and Recent Political Dynamics in Austria

From a comparative perspective, the Austrian Federal Constitution appears rather centralized, given that the majority of legislative competences are allocated at the federal level. However, a closer look indicates that the Länder (the federal units) gain considerable political weight by serving as the administrative centre of gravity; namely, the Länder execute their own laws and most of the laws based on the federation’s subject-matters. Hence, one might speak of “administrative federalism”. History shows that Austrian politics resemble a tug-of-war over the federal division of (legislative) competences. The newly elected coalition government’s program joins the ranks of long-winded discussions on how to make Austrian federalism more efficient. Even if pro-federal by rhetoric, the actual content of the government program is either conceptually ambivalent or substantially in favour of increased (legislative) centralization, especially in the realm of social and educational policy

Federalism and Recent Political Dynamics in Austria

From a comparative perspective, the Austrian Federal Constitution appears rather centralized, given that the majority of legislative competences are allocated at the federal level. However, a closer look indicates that the Länder (the federal units) gain considerable political weight by serving as the administrative centre of gravity; namely, the Länder execute their own laws and most of the laws based on the federation’s subject-matters. Hence, one might speak of “administrative federalism”. History shows that Austrian politics resemble a tug-of-war over the federal division of (legislative) competences. The newly elected coalition government’s program joins the ranks of long-winded discussions on how to make Austrian federalism more efficient. Even if pro-federal by rhetoric, the actual content of the government program is either conceptually ambivalent or substantially in favour of increased (legislative) centralization, especially in the realm of social and educational policy

Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer.

Despite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities in KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the cell surface of intestinal epithelial cells. Here we show that oncogenic KRAS alters the expression of a myriad of cell-surface proteins implicated in diverse biological functions, and identify many potential surface-accessible therapeutic targets. Cell surface-based loss-of-function screens reveal that ATP7A, a copper-exporter upregulated by mutant KRAS, is essential for neoplastic growth. ATP7A is upregulated at the surface of KRAS-mutated CRC, and protects cells from excess copper-ion toxicity. We find that KRAS-mutated cells acquire copper via a non-canonical mechanism involving macropinocytosis, which appears to be required to support their growth. Together, these results indicate that copper bioavailability is a KRAS-selective vulnerability that could be exploited for the treatment of KRAS-mutated neoplasms

Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer

The oncogene KRAS is frequently mutated in cancer, including colorectal cancer. Here, using a cell-surface proteomics approach, KRAS-mutated colorectal cancer cells are shown to express high levels of the copper transporter ATP7A, which has an essential roles in cancer cell survival and proliferation

Isotopologue Profiling of Triterpene Formation under Physiological Conditions. Biosynthesis of Lupeol-3-(3′‑<i>R</i>‑hydroxy)-stearate in <i>Pentalinon andrieuxii</i>

The biosynthesis of lupeol-3-(3′<i>R</i>-hydroxy)-stearate (procrim b, <b>1</b>) was investigated in the Mexican medicinal plant <i>Pentalinon andrieuxii</i> by ¹³CO₂ pulse-chase experiments. NMR analyses revealed positional enrichments of ¹³C₂-isotopologues in both the triterpenoid and the hydroxystearate moieties of <b>1</b>. Five of the six isoprene units reflected a pattern with [1,2-¹³C₂]- and [3,5-¹³C₂]-isotopologues from the respective C₅-precursors, IPP and DMAPP, whereas one isoprene unit in the ring E of <b>1</b> showed only the [3,5-¹³C₂]-connectivity of the original C₅-precursor, due to rearrangement of the dammarenyl cation intermediate during the cyclization process. The presence of ¹³C₂-isotopologues was indicative of [¹³C₂]­acetyl-CoA being the precursor units in the formation of the fatty acid moiety and of the triterpene via the mevalonate route. The observed labeling pattern was in agreement with a chair-chair-chair-boat conformation of the (<i>S</i>)-2,3-oxidosqualene precursor during the cyclization process, suggesting that the lupeol synthase from <i>P. andrieuxii</i> is of the same type as that from <i>Olea europea</i> and <i>Taraxacum officinale</i>, but different from that of <i>Arabidopsis thaliana</i>. The study shows that ¹³CO₂ pulse-chase experiments are powerful in elucidating, under <i>in vivo</i> conditions and in a single experiment, the biosynthesis of complex plant products including higher terpenes

Phosphorylation-dependent binding of 14-3-3 terminates signalling by the Gab2 docking protein

Grb2-associated binder (Gab)2 functions downstream of a variety of receptor and cytoplasmic tyrosine kinases as a docking platform for specific signal transducers and performs important functions in both normal physiology and oncogenesis. Gab2 signalling is promoted by its association with specific receptors through the adaptor Grb2. However, the molecular mechanisms that attenuate Gab2 signals have remained unclear. We now demonstrate that growth factor-induced phosphorylation of Gab2 on two residues, S210 and T391, leads to recruitment of 14-3-3 proteins. Together, these events mediate negative-feedback regulation, as Gab2S210A/T391A exhibits sustained receptor association and signalling and promotes cell proliferation and transformation. Importantly, introduction of constitutive 14-3-3-binding sites into Gab2 renders it refractory to receptor activation, demonstrating that site-selective binding of 14-3-3 proteins is sufficient to terminate Gab2 signalling. Furthermore, this is associated with reduced binding of Grb2. This leads to a model where signal attenuation occurs because 14-3-3 promotes dissociation of Gab2 from Grb2, and thereby uncouples Gab2 from the receptor complex. This represents a novel regulatory mechanism with implications for diverse tyrosine kinase signalling systems