Multi-megajoule Nd: glass fusion laser design

New technologies make multi-megajoule glass lasers economically feasible. Laser architectures using harmonic switchout, target plane holographic injection, phase conjugation, continuous apodization and higher amplifier efficiencies have been devised. A plan for a multi-megajoule laser which can be built for an acceptable cost relies on manufacturing economies of scale and the demonstration of the new technologies presented here. These include continuous pour glass production, rapid harmonic crystal growth, switching of large blocks of power using larger capcaitors packed more economically and by using large identical parts counts

Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis

Defining the phospho-adhesome through the phosphoproteomic analysis of integrin signalling

Cell–extracellular matrix (ECM) adhesion is a fundamental requirement for multicellular existence due to roles in positioning, proliferation and differentiation. Phosphorylation plays a major role in adhesion signalling; however, a full understanding of the phosphorylation events that occur at sites of adhesion is lacking. Here we report a proteomic and phosphoproteomic analysis of adhesion complexes isolated from cells spread on fibronectin. We identify 1,174 proteins, 499 of which are phosphorylated (1,109 phosphorylation sites), including both well-characterized and novel adhesion-regulated phosphorylation events. Immunoblotting suggests that two classes of phosphorylated residues are found at adhesion sites—those induced by adhesion and those constitutively phosphorylated but recruited in response to adhesion. Kinase prediction analysis identifies novel kinases with putative roles in adhesion signalling including CDK1, inhibition of which reduces adhesion complex formation. This phospho-adhesome data set constitutes a valuable resource to improve our understanding of the signalling mechanisms through which cell–ECM interactions control cell behaviour

Distinct dynamical patterns that distinguish willed and forced actions

The neural pathways for generating willed actions have been increasingly investigated since the famous pioneering work by Benjamin Libet on the nature of free will. To better understand what differentiates the brain states underlying willed and forced behaviours, we performed a study of chosen and forced actions over a binary choice scenario. Magnetoencephalography recordings were obtained from six subjects during a simple task in which the subject presses a button with the left or right finger in response to a cue that either (1) specifies the finger with which the button should be pressed or (2) instructs the subject to press a button with a finger of their own choosing. Three independent analyses were performed to investigate the dynamical patterns of neural activity supporting willed and forced behaviours during the preparatory period preceding a button press. Each analysis offered similar findings in the temporal and spatial domains and in particular, a high accuracy in the classification of single trials was obtained around 200 ms after cue presentation with an overall average of 82%. During this period, the majority of the discriminatory power comes from differential neural processes observed bilaterally in the parietal lobes, as well as some differences in occipital and temporal lobes, suggesting a contribution of these regions to willed and forced behaviours