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Coherent diffractive imaging of individual free nanoparticles has opened routes for the in situ analysis of their transient structural, optical, and electronic properties. So far, single-shot single-particle diffraction was assumed to be feasible only at extreme ultraviolet and X-ray free-electron lasers, restricting this research field to large-scale facilities. Here we demonstrate single-shot imaging of isolated helium nanodroplets using extreme ultraviolet pulses from a femtosecond-laser-driven high harmonic source. We obtain bright wide-angle scattering patterns, that allow us to uniquely identify hitherto unresolved prolate shapes of superfluid helium droplets. Our results mark the advent of single-shot gas-phase nanoscopy with lab-based short-wavelength pulses and pave the way to ultrafast coherent diffractive imaging with phase-controlled multicolor fields and attosecond pulses. Diffraction imaging studies of free individual nanoparticles have so far been restricted to XUV and X-ray free - electron laser facilities. Here the authors demonstrate the possibility of using table-top XUV laser sources to image prolate shapes of superfluid helium droplets.

The diversity of nanoparticle shapes generated by condensation from gaseous matter reflects the fundamental competition between thermodynamic equilibration and the persistence of metastable configurations during growth. In the kinetically limited regime, intermediate geometries that are favoured only in early formation stages can be imprinted in the finally observed ensemble of differently structured specimens. Here we demonstrate that single-shot wide-angle scattering of femtosecond soft X-ray free-electron laser pulses allows three-dimensional characterization of the resulting metastable nanoparticle structures. For individual free silver particles, which can be considered frozen in space for the duration of photon exposure, both shape and orientation are uncovered from measured scattering images. We identify regular shapes, including species with fivefold symmetry and surprisingly large aspect ratio up to particle radii of the order of 100 nm. Our approach includes scattering effects beyond Born’s approximation and is remarkably efficient—opening up new routes in ultrafast nanophysics and free-electron laser science. The occurrence of thermodynamically metastable nanoparticles determines the particle growth in nature, but capturing them is experimentally challenging. Barke et al . identify the three-dimensional shape of metastable silver nanoparticles in gas phase, characterized by X-ray free-electron laser.

Introduction Microglia are tissue macrophages of the central nervous system that monitor brain homeostasis and react upon neuronal damage and stress. Aging and neurodegeneration induce a hypersensitive, pro-inflammatory phenotype, referred to as primed microglia. To determine the gene expression signature of priming, the transcriptomes of microglia in aging, Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS) mouse models were compared using Weighted Gene Co-expression Network Analysis (WGCNA). Results A highly consistent consensus transcriptional profile of up-regulated genes was identified, which prominently differed from the acute inflammatory gene network induced by lipopolysaccharide (LPS). Where the acute inflammatory network was significantly enriched for NF-κB signaling, the primed microglia profile contained key features related to phagosome, lysosome, antigen presentation, and AD signaling. In addition, specific signatures for aging, AD, and ALS were identified. Conclusion Microglia priming induces a highly conserved transcriptional signature with aging- and disease-specific aspects.

In our studies of ovarian cancer cells we have identified subpopulations of cells that are in a transitory E/M hybrid stage, i.e. cells that simultaneously express epithelial and mesenchymal markers. E/M cells are not homogenous but, in vitro and in vivo, contain subsets that can be distinguished based on a number of phenotypic features, including the subcellular localization of E-cadherin, and the expression levels of Tie2, CD133, and CD44. A cellular subset (E/M-MP) (membrane E-cadherin(low)/cytoplasmic E-cadherin(high)/CD133(high), CD44(high), Tie2(low)) is highly enriched for tumor-forming cells and displays features which are generally associated with cancer stem cells. Our data suggest that E/M-MP cells are able to differentiate into different lineages under certain conditions, and have the capacity for self-renewal, i.e. to maintain a subset of undifferentiated E/M-MP cells during differentiation. Trans-differentiation of E/M-MP cells into mesenchymal or epithelial cells is associated with a loss of stem cell markers and tumorigenicity. In vivo xenograft tumor growth is driven by E/M-MP cells, which give rise to epithelial ovarian cancer cells. In contrast, in vitro, we found that E/M-MP cells differentiate into mesenchymal cells, in a process that involves pathways associated with an epithelial-to-mesenchymal transition. We also detected phenotypic plasticity that was dependent on external factors such as stress created by starvation or contact with either epithelial or mesenchymal cells in co-cultures. Our study provides a better understanding of the phenotypic complexity of ovarian cancer and has implications for ovarian cancer therapy.

The regioselectivity of the Claisen rearrangement with different meta-substituted and meta- and para-substituted allyl phenyl ethers was investigated. The main results were that in meta-substituted Claisen rearrangements the regioselectivity depends roughly on the electronic nature of the substituent, with electron-donating groups favoring migration further from the meta-substituent while electron-withdrawing groups favor migration towards the meta-substituent. Different para-substituents were tested with two meta-substituents, Me, and Cl. Most of the para-substituent tested had a clear effect on the product ratio, in all but one case enhancing the proportion of the major product favored by the meta-substituent. Population analysis was performed with Mulliken, Löwdin, Hirshfeld, and natural population analysis to analyze the influence of the substituents on the atomic charges on the reaction sites. It was observed that the atomic charge on the carbon that forms the major isomer is of higher negativity than the atomic charge on the carbon that forms the minor isomer.

Stroke is the leading cause of serious long-term disability and the fifth leading cause of death in the United States. Treatment options for stroke are few in number and limited in efficacy. Neuroinflammation mediated by microglia and infiltrating peripheral immune cells is a major component of stroke pathophysiology. Interfering with the inflammation cascade after stroke holds the promise to modulate stroke outcome. The calcium activated potassium channel K Ca 3.1 is expressed selectively in the injured CNS by microglia. K Ca 3.1 function has been implicated in pro-inflammatory activation of microglia and there is recent literature suggesting that this channel is important in the pathophysiology of ischemia/reperfusion (stroke) related brain injury. Here we describe the potential of repurposing Senicapoc, a K Ca 3.1 inhibitor, to intervene in the inflammation cascade that follows ischemia/reperfusion.

Microglia are the macrophages of the CNS, with innate neuroimmune function, and play important roles in tissue homeostasis, CNS development and neurodegeneration. Here human microglial gene expression profiles were generated. Human and mouse microglia were highly similar, except for aging-regulated genes, indicating that microglial aging differs between humans and mice. Microglia are essential for CNS homeostasis and innate neuroimmune function, and play important roles in neurodegeneration and brain aging. Here we present gene expression profiles of purified microglia isolated at autopsy from the parietal cortex of 39 human subjects with intact cognition. Overall, genes expressed by human microglia were similar to those in mouse, including established microglial genes CX3CR1 , P2RY12 and ITGAM ( CD11B ). However, a number of immune genes, not identified as part of the mouse microglial signature, were abundantly expressed in human microglia, including TLR , Fcγ and SIGLEC receptors, as well as TAL1 and IFI16 , regulators of proliferation and cell cycle. Age-associated changes in human microglia were enriched for genes involved in cell adhesion, axonal guidance, cell surface receptor expression and actin (dis)assembly. Limited overlap was observed in microglial genes regulated during aging between mice and humans, indicating that human and mouse microglia age differently.

Key Points Brain myeloid cells are a diverse group of mononuclear cells that mediate the local immune response during development, health and brain diseases. They consist of endogenous microglia, CNS-resident macrophages and monocytes that infiltrate the diseased CNS, each of them having specific disease-related functions. Mutations in microglial-related genes can have a significant impact on the functions of these cells and are linked to various disorders. Primary microgliopathies are usually caused by a single gene mutation, whereby the lack of a distinct microglial-associated gene results in microglia dysfunction accompanied by neural damage. In secondary myeloid cell brain disorders, myeloid cells undergo a shift towards a disease-specific phenotype that potentially contributes to the chronicity of these diseases. There are various lines of evidence showing significant differences in myeloid cell function between mice and humans. From a drug discovery perspective, it is crucial to understand whether findings in mice also apply to brain myeloid cells in humans. Brain myeloid cells are increasingly being recognized as promising potential targets for the treatment of CNS disorders. Several pharmaceutical drug development programmes targeting brain myeloid cells have been initiated, with more anticipated in the near future. CNS myeloid cells mediate the local immune response during development, health and brain diseases and are emerging as potential therapeutic targets for the treatment of neurological and psychiatric disorders. Here, Biber and colleagues assess strategies for targeting CNS myeloid cells and consider key issues associated with their clinical translation. Myeloid cells of the central nervous system (CNS), which include parenchymal microglia, macrophages at CNS interfaces and monocytes recruited from the circulation during disease, are increasingly being recognized as targets for therapeutic intervention in neurological and psychiatric diseases. The origin of these cells in the immune system distinguishes them from ectodermal neurons and other glia and endows them with potential drug targets distinct from classical CNS target groups. However, despite the identification of several promising therapeutic approaches and molecular targets, no agents directly targeting these cells are currently available. Here, we assess strategies for targeting CNS myeloid cells and address key issues associated with their translation into the clinic.

Current magnetic memories are based on writing and reading out the domains with opposite orientation of the magnetization vector. Alternatively, information can be encoded in regions with a different value of the saturation magnetization. The latter approach can be realized in principle with chemical order-disorder transitions in intermetallic alloys. Here, we study such transformations in a thin-film (35 nm) Fe60Al40alloy and demonstrate the formation of periodic magnetic nanostructures (PMNS) on its surface by direct laser interference patterning (DLIP). These PMNS are nonvolatile and detectable by magnetic force microscopy (MFM) at room temperature after DLIP with a single nanosecond pulse. We provide different arguments that the PMNS we observe originate from increasing magnetization in maxima of the interference pattern because of chemical disordering in the atomic lattice of the alloy at temperatures T higher than the critical temperature Tc for the order (B2)-disorder (A2) transition. Theoretically, our simulations of the temporal evolution of a partially ordered state at T > Tc reveal that the disordering rate is significant even below the melting threshold. Experimentally, we find that the PMNS are erasable with standard thermal annealing at T < Tc.

Presenilin 1 (PS1) and Presenilin 2 (PS2) are the enzymatic component of the γ-secretase complex that cleaves amyloid precursor protein (APP) to release amyloid beta (Aβ) peptide. PS deficiency in mice results in neuroinflammation and neurodegeneration in the absence of accumulated Aβ. We hypothesize that PS influences neuroinflammation through its γ-secretase action in CNS innate immune cells. We exposed primary murine microglia to a pharmacological γ-secretase inhibitor which resulted in exaggerated release of TNFα and IL-6 in response to lipopolysaccharide. To determine if this response was mediated by PS1, PS2 or both we used shRNA to knockdown each PS in a murine microglia cell line. Knockdown of PS1 did not lead to decreased γ-secretase activity while PS2 knockdown caused markedly decreased γ-secretase activity. Augmented proinflammatory cytokine release was observed after knockdown of PS2 but not PS1. Proinflammatory stimuli increased microglial PS2 gene transcription and protein in vitro. This is the first demonstration that PS2 regulates CNS innate immunity. Taken together, our findings suggest that PS2 is the predominant γ-secretase in microglia and modulates release of proinflammatory cytokines. We propose PS2 may participate in a negative feedback loop regulating inflammatory behavior in microglia.