A multiparametric screen uncovers FDA-approved small molecules that potentiate the nuclear mechano-dysfunctions in ATR-defective cells.

Targeting nuclear mechanics is emerging as a promising therapeutic strategy for sensitizing cancer cells to immunotherapy. Inhibition of the mechano-sensory kinase ATR leads to mechanical vulnerability of cancer cells, causing nuclear envelope softness and collapse and activation of the cGAS-STING-mediated innate immune response. Finding novel compounds that interfere with the non-canonical role of ATR in controlling nuclear mechanics presents an intriguing therapeutic opportunity.

The transcription factor PREP1(PKNOX1) regulates nuclear stiffness, the expression of LINC complex proteins and mechanotransduction.

Mechanosignaling, initiated by extracellular forces and propagated through the intracellular cytoskeletal network, triggers signaling cascades employed in processes as embryogenesis, tissue maintenance and disease development. While signal transduction by transcription factors occurs downstream of cellular mechanosensing, little is known about the cell intrinsic mechanisms that can regulate mechanosignaling. Here we show that transcription factor PREP1 (PKNOX1) regulates the stiffness of the nucleus, the expression of LINC complex proteins and mechanotransduction of YAP-TAZ.

Role of the nuclear membrane protein Emerin in front-rear polarity of the nucleus.

Cell polarity refers to the intrinsic asymmetry of cells, including the orientation of the cytoskeleton. It affects cell shape and structure as well as the distribution of proteins and organelles. In migratory cells, front-rear polarity is essential and dictates movement direction.

The genetics and the molecular functions of the PREP1 homeodomain transcription factor.

Prep1 (pKnox1) is a homeodomain transcription factor of the TALE superclass whose members can act as co-factors of Hox. Prep1 is essential for embryogenesis, but in the adult it also acts as a tumor suppressor. We describe and analyze here the available mutant mice, their phenotypes and a few discordant cases.

Kinetics of IgM and IgG antibodies after scrub typhus infection and the clinical implications.

Objectives: The serological detection of IgM antibodies is the most widely used test to diagnose scrub typhus infection. However, the kinetics of IgM and IgG antibodies post-infection remain elusive, which could contribute to false positivity. The objective of this study was to document the nature of the evolution of these antibody titres after infection.

PREP1 tumor suppressor protects the late-replicating DNA by controlling its replication timing and symmetry.

The synthesis of middle-to-late-replicating DNA can be affected independently of the rest of the genome by down-regulating the tumor suppressor PREP1 (PKNOX1). Indeed, DNA combing shows that PREP1 down-regulation affects DNA replication rate, increases the number of simultaneously firing origins and the asymmetry of DNA replication, leading to DNA damage. Genome-wide analysis of replication timing by Repli-seq shows that, upon PREP1 down-regulation, 25% of the genome is replicated earlier in the S-phase.

Apoptotic programs are determined during lineage commitment of CD4+ T effectors: selective regulation of T effector-memory apoptosis by inducible nitric oxide synthase.

Lineage-committed T effectors generated in response to Ag during the inflammatory phase are destined to die during termination of the immune response. We present evidence to suggest that molecular signatures of lineage commitment are reflected in apoptotic cascades activated in CD4(+) T effectors. Exemplifying this, ablation of inducible NO synthase (iNOS) protected effector-memory T (TEM) cells, but not T(Naive) or central-memory T cells, activated in vitro, from apoptosis triggered by cytokine deprivation.

Cytokine-dependent regulation of NADPH oxidase activity and the consequences for activated T cell homeostasis.

Cellular dependence on growth factors for survival is developmentally programmed and continues in adult metazoans. Antigen-activated T cell apoptosis in the waning phase of the immune response is thought to be triggered by depletion of cytokines from the microenvironment. T cell apoptosis resulting from cytokine deprivation is mediated by reactive oxygen species (ROS), but their source and position in the apoptotic cascade is poorly understood.