DNA-PKcs is required for cGAS/STING-dependent viral DNA sensing in human cells.

To mount an efficient interferon response to virus infection, intracellular pattern recognition receptors (PRRs) sense viral nucleic acids and activate anti-viral gene transcription. The mechanisms by which intracellular DNA and DNA viruses are sensed are relevant not only to anti-viral innate immunity, but also to autoinflammation and anti-tumour immunity through the initiation of sterile inflammation by self-DNA recognition. The PRRs that directly sense and respond to viral or damaged self-DNA function by signaling to activate interferon regulatory factor (IRF)-dependent type one interferon (IFN-I) transcription. We and others have previously defined DNA-dependent protein kinase (DNA-PK) as an essential component of the DNA-dependent anti-viral innate immune system. Here, we show that DNA-PK is essential for cyclic GMP-AMP synthase (cGAS)- and stimulator of interferon genes (STING)-dependent IFN-I responses in human cells during stimulation with exogenous DNA and infection with DNA viruses.

Viral interactions with non-homologous end-joining: a game of hide-and-seek.

There are extensive interactions between viruses and the host DNA damage response (DDR) machinery. The outcome of these interactions includes not only direct effects on viral nucleic acids and genome replication, but also the activation of host stress response signalling pathways that can have further, indirect effects on viral life cycles. The non-homologous end-joining (NHEJ) pathway is responsible for the rapid and imprecise repair of DNA double-stranded breaks in the nucleus that would otherwise be highly toxic. Whilst directly repairing DNA, components of the NHEJ machinery, in particular the DNA-dependent protein kinase (DNA-PK), can activate a raft of downstream signalling events that activate antiviral, cell cycle checkpoint and apoptosis pathways. This combination of possible outcomes results in NHEJ being pro- or antiviral depending on the infection. In this review we will describe the broad range of interactions between NHEJ components and viruses and their consequences for both host and pathogen.

Notch2 pathway mediates breast cancer cellular dormancy and mobilisation in bone and contributes to haematopoietic stem cell mimicry.

BACKGROUND: Recurrence after >5-year disease-free survival affects one-fifth of breast cancer patients and is the clinical manifestation of cancer cell reactivation after persistent dormancy. METHODS: We investigated cellular dormancy in vitro and in vivo using breast cancer cell lines and cell and molecular biology techniques. RESULTS: We demonstrated cellular dormancy in breast cancer bone metastasis, associated with haematopoietic stem cell (HSC) mimicry, in vivo competition for HSC engraftment and non-random distribution of dormant cells at the endosteal niche. Notch2 signal implication was demonstrated by immunophenotyping the endosteal niche-associated cancer cells and upon co-culture with sorted endosteal niche cells, which inhibited breast cancer cell proliferation in a Notch2-dependent manner. Blocking this signal by in vivo acute administration of the γ-secretase inhibitor, dibenzazepine, induced dormant cell mobilisation from the endosteal niche and colonisation of visceral organs. Sorted Notch2HIGH breast cancer cells exhibited a unique stem phenotype similar to HSCs and in vitro tumour-initiating ability in mammosphere assay. Human samples confirmed the existence of a small Notch2HIGH cell population in primary and bone metastatic breast cancers, with a survival advantage for Notch2HIGH vs Notch2LOW patients. CONCLUSIONS: Notch2 represents a key determinant of breast cancer cellular dormancy and mobilisation in the bone microenvironment.

Sources of Embodied Creativity: Interactivity and Ideation in Contact Improvisation.

Drawing on a micro-phenomenological paradigm, we discuss Contact Improvisation (CI), where dancers explore potentials of intercorporeal weight sharing, kinesthesia, touch, and momentum. Our aim is to typologically discuss creativity related skills and the rich spectrum of creative resources CI dancers use. This spectrum begins with relatively idea-driven creation and ends with interactivity-centered, fully emergent creation: (1) Ideation internal to the mind, the focus of traditional creativity research, is either restricted to semi-independent dancing or remains schematic and thus open to dynamic specification under the partner’s influence. (2) Most frequently, CI creativity occurs in tightly coupled behavior and is radically emergent. This means that interpersonal synergies emerge without anybody’s prior design or planned coordination. The creative feat is interpersonally “distributed” over cascades of cross-scaffolding. Our micro-genetic data validate notions from dynamic systems theory such as interpersonal self-organization, although we criticize the theory for failing to explain where precisely this leaves skilled intentionality on the individuals’ part. Our answer is that dancers produce a stream of momentary micro-intentions that say “yes, and”, or “no, but” to short-lived micro-affordances, which allows both individuals to skillfully continue, elaborate, tweak, or redirect the collective movement dynamics. Both dancers can invite emergence as part of their playful exploration, while simultaneously bringing to bear global constraints, such as dance scores, and guide the collective dynamics with a set of specialized skills we shall term emergence management.

Joint Action: Mental Representations, Shared Information and General Mechanisms for Coordinating with Others.

In joint action, multiple people coordinate their actions to perform a task together. This often requires precise temporal and spatial coordination. How do co-actors achieve this? How do they coordinate their actions toward a shared task goal? Here, we provide an overview of the mental representations involved in joint action, discuss how co-actors share sensorimotor information and what general mechanisms support coordination with others. By deliberately extending the review to aspects such as the cultural context in which a joint action takes place, we pay tribute to the complex and variable nature of this social phenomenon.