Epithelial-mesenchymal transition: an organizing principle of mammalian regeneration.

Introduction: The MRL mouse strain is one of the few examples of a mammal capable of healing appendage wounds by regeneration, a process that begins with the formation of a blastema, a structure containing de-differentiating mesenchymal cells. HIF-1α expression in the nascent MRL wound site blastema is one of the earliest identified events and is sufficient to initiate the complete regenerative program. However, HIF-1α regulates many cellular processes modulating the expression of hundreds of genes. A later signal event is the absence of a functional G1 checkpoint, leading to G2 cell cycle arrest with increased cellular DNA but little cell division observed in the blastema. This lack of mitosis in MRL blastema cells is also a hallmark of regeneration in classical invertebrate and vertebrate regenerators such as planaria, hydra, and newt. Results and discussion: Here, we explore the cellular events occurring between HIF-1α upregulation and its regulation of the genes involved in G2 arrest (EVI-5, γH3, Wnt5a, and ROR2), and identify epithelial-mesenchymal transition (EMT) (Twist and Slug) and chromatin remodeling (EZH-2 and H3K27me3) as key intermediary processes. The locus of these cellular events is highly regionalized within the blastema, occurring in the same cells as determined by double staining by immunohistochemistry and FACS analysis, and appears as EMT and chromatin remodeling, followed by G2 arrest determined by kinetic expression studies.

Control of CD4+ T Cell Differentiation and Function by PI3K Isoforms.

The phosphoinositide-3-kinase (PI3K) pathway is a highly conserved intracellular signaling pathway involving numerous key effectors which, in response to diverse extracellular stimuli, modulate the phenotype and function of most mammalian cell types in a pleiotropic manner. PI3K signaling plays a critical role in the development, activation, and differentiation of lymphocytes. In particular, the PI3Kδ and PI3Kγ isoforms have been shown to carry out essential, non-redundant roles in T cells, and therefore, tight regulation of the PI3K pathway is important to maintain the balance between immune tolerance and inflammation. Recent and ongoing efforts to manipulate the biology of T helper cell subsets in the treatment of autoimmune conditions, inflammatory disorders, as well as cancer have shown promising results, and targeting the PI3K pathway may be beneficial in these contexts. However, more insight as to the precise function of individual PI3K isoforms in pathogenic and protective immune cell subsets is still required, and how exactly PI3K signaling is regulated and integrated with classical immune pathways. This chapter provides an overview of the role of PI3K isoforms in the differentiation and function of T helper cell subsets, within the broader context of targeting this pathway to potentially alleviate immunopathology.

Origin of micrometer-scale dislocation motion during hydrogen desorption.

Hydrogen, while being a potential energy solution, creates arguably the most important embrittlement problem in high-strength metals. However, the underlying hydrogen-defect interactions leading to embrittlement are challenging to unravel. Here, we investigate an intriguing hydrogen effect to shed more light on these interactions. By designing an in situ electron channeling contrast imaging experiment of samples under no external stresses, we show that dislocations (atomic-scale line defects) can move distances reaching 1.5 µm during hydrogen desorption. Combining molecular dynamics and grand canonical Monte Carlo simulations, we reveal that grain boundary hydrogen segregation can cause the required long-range resolved shear stresses, as well as short-range atomic stress fluctuations. Thus, such segregation effects should be considered widely in hydrogen research.