The Idea of Social Life

This paper reclaims the idea that human society is a form of life, an idea once vibrant in the work of Toennies, Durkheim, Simmel, Le Bon, Kroeber, Freud, Bion, and Follett but moribund today. Despite current disparagements, this idea remains the only and best answer to our primary experience of society as vital feeling. The main obstacle to conceiving society as a life is linguistic; the logical form of life is incommensurate with the logical form of language. However, it is possible to extend our conceptual reach by appealing to alternative symbolisms more congenial to living form such as, and especially, art.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68336/2/10.1177_004839319502500201.pd

Murine liver organoids as a genetically flexible system to study liver cancer <em>in vivo</em> and<em> in vitro</em>.

The rising incidence of cholangiocarcinoma (CCA) coupled with a low 5-year survival rate that remains below 10% delineates the urgent need for more effective treatment strategies. Although several recent studies provided detailed information on the genetic landscape of this fatal malignancy, versatile model systems to functionally dissect the immediate clinical relevance of the identified genetic alterations are still missing. To enhance our understanding of CCA pathophysiology and facilitate rapid functional annotation of putative CCA driver and tumor maintenance genes, we developed a tractable murine CCA model by combining the cyclization recombination (Cre)-lox system, RNA interference, and clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology with liver organoids, followed by subsequent transplantation into immunocompetent, syngeneic mice. Histologically, resulting tumors displayed cytokeratin 19-positive ductal structures surrounded by a desmoplastic stroma-hallmark features of human CCAs. Despite their initial biliary phenotype organoids retained the plasticity to induce a broader differentiation spectrum of primary liver cancers following transplantation into recipient mice, depending on their genetic context. Thus, the organoid system combines the advantage of using nontransformed, premalignant cells to recapitulate liver tumorigenesis as a multistep process, with the advantage of a reproducible and expandable cell culture system that abrogates the need for recurrent isolations of primary cells. Genetically modified liver organoids are able to transform into histologically accurate CCAs. Depending on the oncogenic context, they are also able to give rise to liver cancers that show features of hepatocellular carcinomas. The model can be used to functionally explore candidate cancer genes of primary liver cancers in immunocompetent animals and evaluate novel treatment regimens

Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing.

Beyond the nearly uniform presence of KRAS mutations, pancreatic cancer is increasingly recognized as a heterogeneous disease. Preclinical in vivo model systems exist, but with the advent of precision oncology, murine models with enhanced genetic flexibility are needed to functionally annotate genetic alterations found in the human malignancy. Here, we describe the generation of focal gene disruptions and large chromosomal deletions via inducible and pancreas-specific expression of Cas9 in adult mice. Experimental mice are derived on demand directly from genetically engineered embryonic stem cells, without the need for further intercrossing. To provide initial validation of our approach, we show that disruption of the E3 ubiquitin ligase Rnf43 accelerates Kras(G12D)-dependent tumourigenesis. Moreover, we demonstrate that this system can be used to rapidly interrogate the impact of complex cancer-associated alleles through the generation of a previously unstudied 1.2 megabase deletion surrounding the CDKN2A and CDKN2B tumour suppressors. Thus, our approach is capable of reproducibly generating biallelic and precise loss of large chromosomal fragments that, in conjunction with mutant Kras, leads to development of pancreatic ductal adenocarcinoma with full penetrance

T cell shape is orchestrated by PDZ-containing proteins: Parallels with epithelial polarity

The Cre/loxP system is facilitates excision of DNA sequences located between two loxP sites by the Cre recombinase (Cre) of Bacteriophage P1. Generation of different tissue-specific Cre transgenic mice, which can be used for conditional gene inactivation in specific tissues, is an ideal tool for studying gene function in different tissues in mice. The winged-helix transcription factor, Foxa2, is essential for development of the node and notochord. In mouse, Foxa2 expression is observed in the node, notochord, floor plate and gut epithelium during development. In order to facilitate genetic studies of notochord development, we have used a 520 bp element (mNE) upstream of the Foxa2 gene, which directs specific expression in the node and notochord to generate a mouse line, mNE-Cre, in which the Cre gene was placed under the regulatory control of the mNE and linked to an IRES-lacZ reporter. Staining for b-galactocidase (b-gal) activity revealed that the Cre transgene was expressed from E7.5 to E9.5 specifically in the notochord. Moreover, crossing of the mNE-Cre transgenic mice with the loxP mouse reporter line, Z/EG, resulted in enhanced green fluorescent protein (EGFP) signal specifically in the node and notochord from E8.0 to E9.5. The mNE-Cre mice have been used to conditionally inactivate Smoothened (Smo) in the notochord, and preliminary data revealed that loss of both alleles of Smo in the notochord resulted in embryonic lethality. The mNE-Cre transgenic mice are therefore a useful resource for conditional gene manipulation in the notochord in mice.link_to_subscribed_fulltex

T cell shape and function is orchestrated by a network of T polarity proteins

Loss of polarity is one of the earliest hallmarks of epithelial neoplasia and leads to aberrant communication between the epithelial cell and its microenvironment. Understanding how deregulation of polarity occurs and how it may contribute to tumour formation is a new and unexplored area of cancer research. Genetic screens in Drosophila have identified scribble, discs large (dlg) and lethal giant larvae (lgl) as key epithelial polarity regulators with mutation in any of these genes resulting in loss of polarity, overproliferation and multilayering of epithelial cells leading to 3D-tumourous overgrowth, and in the presence of activated Ras, invasion and metastasis. We have recently described the human homologue of Scribble and demonstrated using complementation studies in Drosophila that expression of human Scribble can also regulate polarity and proliferation. Evidence from cancer patients suggests that Scribble and Dlg could act as a tumour suppressor in some epithelial cancers with, in many cases, low levels of Scribble or Dlg correlating with increased tumour invasiveness and malignancy. We have undertaken a detailed functional analysis of Scribble in mammalian epithelial cells and mice mutant for Scribble and uncovered a critical role for Scribble in the regulation of epithelial polarity required for directed migration during development and wound healing in vivo. In addition, we show that impaired human Scribble can function together with activated Ras to lead to increased invasion and tumourigenesis. Therefore, Scribble can act to promote or inhibit migration dependent on the cellular context. We propose that Scribble and other polarity regulators may be key signalling molecules involved in a new pathway regulating epithelial tumour progression in mammals