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Objective: The COVID-19 pandemic saw promotion of novel virus transmission-reduction behaviours, and discouragement of familiar transmission-conducive behaviours. Understanding changes in the automatic nature of such behaviours is important, because habitual behaviours may be more easily reactivated in future outbreaks and disrupting old habits may discontinue unwanted behaviours. Design: A repeated-measures, multi-national design tracked virus-transmission habits and behaviour fortnightly over six months (Apr-Sept 2020) among 517 participants (age M=42±16y, 79% female). Main outcome measures: Within-participant habit trajectories across all timepoints, and engagement in transmission-reduction behaviours (handwashing when entering home; handwashing with soap for 20 seconds; physical distancing) and transmission-conducive behaviours (coughing/sneezing into hands; making physical contact) summed over the final two timepoints. Results: Three habit trajectory types were observed. Habits that remained strong (‘stable strong habit’) and habits that strengthened (‘habit formation’) were most common for transmission-reduction behaviours. Erosion of initially strong habits (‘habit degradation’) was most common for transmission-conducive behaviours. Regression analyses showed ‘habit formation’ and ‘stable strong habit’ trajectories were associated with greater behavioural engagement at later timepoints. Conclusions: Participants typically maintained or formed transmission-reduction habits, which encouraged later performance, and degraded transmission-conducive habits, which decreased performance. Findings suggest COVID-19-preventive habits may be recoverable in future virus outbreaks.

Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.

SREBP2 is a master regulator of the mevalonate pathway (MVP), a biosynthetic process that drives the synthesis of dolichol, heme A, ubiquinone and cholesterol and also provides substrates for protein prenylation. Here, we identify SREBP2 as a novel substrate for USP28, a deubiquitinating enzyme that is frequently upregulated in squamous cancers. Our results show that silencing of USP28 reduces expression of MVP enzymes and lowers metabolic flux into this pathway. We also show that USP28 binds to mature SREBP2, leading to its deubiquitination and stabilisation. USP28 depletion rendered cancer cells highly sensitive to MVP inhibition by statins, which was rescued by the addition of geranyl-geranyl pyrophosphate. Analysis of human tissue microarrays revealed elevated expression of USP28, SREBP2 and MVP enzymes in lung squamous cell carcinoma (LSCC) compared to lung adenocarcinoma (LADC). Moreover, CRISPR/Cas-mediated deletion of SREBP2 selectively attenuated tumour growth in a KRas/p53/LKB1 mutant mouse model of lung cancer. Finally, we demonstrate that statins synergise with a dual USP28/25 inhibitor to reduce viability of SCC cells. Our findings suggest that combinatorial targeting of MVP and USP28 could be a therapeutic strategy for the treatment of squamous cell carcinomas.

The contribution of deubiquitylating enzymes to β-Catenin stabilisation in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, we report the deubiquitylase USP10 as an APC-truncation- specific enhancer of β-Catenin stability, potentiating WNT signalling and cancer stem cells and CRC. Mechanistically, interaction and in vitro binding studies, together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and requires the absence of full-length APC. Reduction of USP10 induces the expression of differentiation genes and opposes the APC-truncated phenotype in an intestinal hyperplasia model. Notably, loss of USP10 in CRISPR engineered intestinal organoids opposed the super competitor-signalling and reduced tumorigenic properties of APC-mutated CRC. Taken together, our findings reveal USP10s role in CRC cell identity, stemness and tumour growth by stabilising β-Catenin, leading to aberrant WNT signalling, and implicate USP10 as a cancer specific therapeutic vulnerability in Apc truncated CRC.

Der folgende Beitrag zeichnet die Anfänge der Behandlung des Bodens in der Geschichte der ökonomischen Theorie und in der dazu korrespondierenden politischen Praxis nach. Eine zentrale Rolle spielt die Kritik am Privatbesitz am Boden, aus der dann die Forderung nach einer Besteuerung des Wertzuwachses abgeleitet wurde. Gezeigt wird die Rezeption von Henry George und dessen Konzept einer "single tax" in den ersten Organisationen der Bodenreform-Bewegung; verdeutlicht wird dann der Einfluss von Adolf Damaschke und dessen Wirken in der Vereinigung der Bewegung zum "Bund deutscher Bodenreformer", der schließlich Spuren in der Weimarer Reichsverfassung und im Reichsheimstättengesetz hinterließ. Der Nationalsozialismus führte zu einem Ende der Bewegung. Aber auch nach dem Ende des 2. Weltkriegs wurde eine Bodenreform zum Teil als Voraussetzung für einen planvollen Wiederaufbau gefordert. Wesentliche Argumentationslinien – etwa zur Grundlage einer Besteuerung – erscheinen bis heute aktuell. The following article traces the beginnings of the treatment of land in the history of economic theory and in the corresponding political practice. A central role is played by the criticism of private ownership of land, from which the demand for taxation of the increase in value was derived. The reception of Henry George and his concept of a "single tax" in the first organisations of the land reform movement is shown; the influence of Adolf Damaschke and his work in uniting the movement to form the "Bund deutscher Bodenreformer" (Association of German Land Reformers), which finally left its mark in the Weimar Constitution and the Reich Homestead Act, is then clarified. Nationalsocialism led to the end of the movement. But even after the end of the Second World War, land reform was demanded in part as a prerequisite for a planned reconstruction of cities. Essential lines of argumentation – for example on the basis of taxation – appear to be still relevant today.

Legends for Supplementary Figures S1-S4.

The stability of several oncoproteins, including c-Myc, is regulated by ubiquitin-dependent degradation mediated by the SCF(Fbw7) ubiquitin ligase. This activity is antagonized by the deubiquitinase Usp28, which is highly expressed in murine and human intestinal cancers. Usp28 was previously shown to interact with its substrates via a “piggyback” interaction with Fbw7, which suggested that Fbw7 is required for Usp28 activity. Unexpectedly, we found that genetic deletion of Usp28 rescued the lethality of Fbw7-deficient primary fibroblasts. Moreover, Usp28 inactivation in the intestine (Usp28ΔIEC) ameliorated the hyperproliferation and the impaired goblet and Paneth cell differentiation observed in Fbw7ΔIEC mice. The aggressive intestinal tumor formation of APCMin/+; Fbw7ΔIEC mice was restrained when Usp28 was inactivated concomitantly. In both fibroblasts and intestinal cells, Usp28 deficiency corrected the accumulation of SCF(Fbw7) substrate proteins, including NICD1, c-Jun, and c-Myc. These findings suggested that Usp28 function does not depend on the presence of Fbw7, but instead independently recognizes and deubiquitylates the same substrates as SCF(Fbw7). Fbw7 binds to a phosphorylated motif termed the phosphodegron and we found that Usp28 also interacted with this same motif, but only when it is unphosphorylated, offering a mechanistic explanation for identical substrate selection by Fbw7 and Usp28. Our results indicate an unusually direct antagonism between an E3 ligase and a deubiquitinase, Fbw7 and Usp28, in modulating intestinal homeostasis and cancer. Cancer Res; 75(7); 1181–6. ©2015 AACR.

Supplementary Methods and References. Description of additional methods and procedures used in the study. Also includes Supplementary References.

Supplementary Figures S1-S4. Loss of Usp28 ameliorates the Fbw7 inactivation phenotype and partly restores cell differentiation in the intestine (S1); Deletion of Usp28 prolongs life expectancy and reduces tumor burden in the Fbw7-deleted APCmin/+ intestinal tumour model (S2); The interaction between Usp28 and its substrate c-Myc is independent of Fbw7 (S3); Schematic representation of Usp28-Fbw7-substrate crosstalk in Fbw7-proficient and deficient cells and speculative model of the consequences of this crosstalk in the intestinal crypt (S4).

SummaryThe contribution of deubiquitylating enzymes to β-Catenin stabilisation in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, we report the deubiquitylase USP10 as an APC-truncation- specific enhancer of β-Catenin stability, potentiating WNT signalling in CRC and cancer stem cells. Mechanistically, interaction studies in various CRC cell lines and in vitro binding studies, together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and requires the absence of full-length APC. Notably, loss of USP10 in CRISPR engineered intestinal organoids reduces tumorigenic properties of CRC and blocks the super competitor-signalling of APC-mutated CRC. Furthermore, reduction of USP10 induces the expression of differentiation genes, and opposes the APC-truncated phenotype in an intestinal hyperplasia model ofD.melanogaster.Taken together, our findings reveal USP10s role in intestinal tumourigenesis by stabilising β-Catenin, leading to aberrant WNT signalling, enhancing cancer cell stemness and implicate the DUB USP10 as a cancer specific therapeutic vulnerability inApctruncated CRC.

Der Nationale Wohlfahrtsindex (NWI) möchte Einblicke bezüglich der Fragen bieten, wie sich die Wohlfahrt in den letzten Jahrzehnten in Deutschland entwickelt hat und wie nachhaltige Wege zu deren Steigerung aussehen könnten. Der NWI zielt dabei auf einen Perspektivwechsel gegenüber dem Bruttoinlandsprodukt (BIP) ab, indem er den Blick um wohlfahrtsrelevante ökonomische, ökologische und soziale Aspekte erweitert. Der vorliegende Bericht geht dabei zunächst auf die Wohlfahrtsentwicklung im Jahr 2021 ein. Die Wohlfahrt ging, maßgeblich verursacht durch die Flutkatastrophe an Ahr und Erft und gegensätzlich zum BIP, zurück. Der Bericht zeigt weiter auf, dass sich die Entwicklungen von NWI und BIP in den letzten 30 Jahren deutlich unterscheiden: Während das BIP um über 40% angewachsen ist, hat sich die Wohlfahrt gemäß NWI kaum erhöht und liegt 2021 niedriger als zur Jahrtausendwende Der konsumgetriebene Anstieg im Zeitraum 2013 bis 2019 wurde dabei im Jahr 2020 jäh durch die Corona-Pandemie - deren Effekte der NWI nur teilweise abzubilden vermag - unterbrochen. Hingewiesen wird zudem darauf, dass die Aussagekraft des NWI eingeschränkt ist, solange planetare Belastungsgrenzen überschritten sind. Nachhaltig gesteigert werden könnte die Wohlfahrt - wie durch Szenariorechnungen veranschaulicht wird - durch eine Reduktion der Umweltkosten und der Einkommensungleichheit.