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The study is focused on luxury brands and their marketing strategy inclusive of SOPs and Social media marketing. Luxury brand s are famous for its uniqueness and exclusiveness. What makes them demanding and irresistible to customers is their strategy of scarcity of products, creating an image of them being extremely luxurious and status centric. The study shows how the luxury brands market themselves with the help of S EO and Social Media marketing. The products being very exclusive in nature it is very difficult for the brand to find a customer base and sell customized pr oducts.At the end of this study we will be able to know how various luxury brands market their products and make them visible to th eir prospective customers through Search Engine Optimization and Social Media Marketing.

Gas attenuators are important devices providing accurate variation of photon intensity for soft X-ray beamlines. In the SwissFEL ATHOS beamline front-end the space is very limited and an innovative approach has been taken to provide attenuation of three orders of magnitude up to an energy of 1200 eV. Additive manufacturing of a differential pumping system vacuum manifold allowed a triple pumping stage to be realized in a space of less than half a meter. Measurements have shown that the response of the device is as expected from theoretical calculations.

Legends for sup figures 1-5

Supplementary Figures 1-5

Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell–produced protein that was deposited into the ECM of PDAC tumors and detected high-circulating levels of gal 4 in patients with PDAC. In orthotopic transplantation experiments, we observed increased infiltration of T cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1−/− mice, demonstrating that the effect was mediated by the adaptive immune system. By performing single-cell RNA-sequencing, we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression associated with a higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T cells, and antigen-presenting dendritic cells in tumors with reduced gal 4 expression. Using a coculture system, we observed that extracellular gal 4 induced apoptosis in T cells by binding N-glycosylation residues on CD3ε/δ. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC.

Lists of genes used to calculate signature scores for cytolytic activity, T cell activation and M1 vs M2 macrophage polarization in single cell data analysis

Top 30 markers of clusters in Immune subset of single cell data

Supplementary Tables

Raw read count, normalized expression values (TPM) and sample metadata for bulk RNA sequencing data

Top 30 markers of clusters in CAF subset of single cell data

Metadata and single cell annotation for all 7677 cells in single cell dataset

Interactions between the different degrees of freedom form the basis of many manifestations of intriguing physics in condensed matter. In this respect, quantifying the dynamics of normal modes that themselves arise from these interactions and how they interact with other excitations is of central importance. Of the different types of coupling that are often important, spin-lattice coupling is relevant to several sub-fields of condensed matter physics; examples include spintronics, high-TC superconductivity, and topological materials. While theories of materials where spin-lattice coupling is relevant can sometimes be used to infer the magnitude and character of this interaction, experimental approaches that can directly measure it are rare and incomplete. Here we use time-resolved X-ray diffraction to directly access the spin-lattice coupling by measuring both ultrafast atomic motion and the associated spin dynamics following the excitation of a coherent electromagnon by an intense THz pulse in a multiferroic hexaferrite. Comparing the dynamics of the two different components, one striking outcome is the different phase shifts relative to the driving field. This phase shift provides insight into the excitation process of such a coupled mode. This direct observation of combined lattice and magnetization dynamics paves the way to access the mode-selective spin-lattice coupling strength, which remains a missing fundamental parameter for ultrafast control of magnetism and is relevant to a wide variety of correlated electron physics., Comment: 4 figures

INTRODUCTION: Endometrioid endometrial carcinoma is a cancer type with generally excellent prognosis when diagnosed at an early stage, but there is a subset of patients with relapsing disease in spite of early diagnosis and surgical treatment. There is a need to find prognostic markers to identify these patients with increased risk of relapse. Depth of myometrial invasion, histological grade, and presence of lymphovascular invasion are known risk factors. DNA content (ploidy) and proliferation measured as S-phase fraction (SPF) have been discussed as prognostic markers but need additional evaluation. MATERIAL AND METHODS: We evaluated relapse-free survival (RFS) with respect to ploidy and SPF, which was analyzed by flow cytometry on fresh tumor tissue, in a cohort of 1001 women treated for stage I endometrioid endometrial carcinoma in northern Sweden during the period of 1993-2010, with a median follow up time of 12.0 years. Data were obtained from historical records. RESULTS: In simple analysis, both aneuploidy and high SPF were associated to increased risk of relapse with hazard ratios (HR) 2.37 (95% CI 1.52-3.70) and 1.94 (95% CI 1.24-3.02), respectively. Our data also confirmed stage, tumor grade, and ploidy as independent prognostic markers in an age adjusted cox regression multivariable analysis but we did not find SPF to contribute to prognosis. However, the combination of aneuploidy and high SPF identified a group of patients with increased risk of relapse, HR 2.02 (95% CI 1.19-3.44). CONCLUSION: In this study, which is the largest study of ploidy and SPF in stage I endometrioid endometrial carcinoma using fresh frozen tissue, aneuploidy was shown to be an independent prognostic marker. Furthermore, the combination of aneuploidy and high SPF could be used to identify patients with increased risk of relapse.

We present the first lasing results of SwissFEL, a hard X-ray free-electron laser (FEL) that recently came into operation at the Paul Scherrer Institute in Switzerland. SwissFEL is a very stable, compact and cost-effective X-ray FEL facility driven by a low-energy and ultra-low-emittance electron beam travelling through short-period undulators. It delivers stable hard X-ray FEL radiation at 1-A wavelength with pulse energies of more than 500 μJ, pulse durations of ~30 fs (root mean square) and spectral bandwidth below the per-mil level. Using special configurations, we have produced pulses shorter than 1 fs and, in a different set-up, broadband radiation with an unprecedented bandwidth of ~2%. The extremely small emittance demonstrated at SwissFEL paves the way for even more compact and affordable hard X-ray FELs, potentially boosting the number of facilities worldwide and thereby expanding the population of the scientific community that has access to X-ray FEL radiation. The first lasing results at SwissFEL, an X-ray free-electron laser, are presented, highlighting the facility’s unique capabilities. A general comparison to other major facilities is also provided.

Long-wavelength pulses from the Swiss X-ray free-electron laser (XFEL) have been used for de novo protein structure determination by native single-wavelength anomalous diffraction (native-SAD) phasing of serial femtosecond crystallography (SFX) data. In this work, sensitive anomalous data-quality indicators and model proteins were used to quantify improvements in native-SAD at XFELs such as utilization of longer wavelengths, careful experimental geometry optimization, and better post-refinement and partiality correction. Compared with studies using shorter wavelengths at other XFELs and older software versions, up to one order of magnitude reduction in the required number of indexed images for native-SAD was achieved, hence lowering sample consumption and beam-time requirements significantly. Improved data quality and higher anomalous signal facilitate so-far underutilized de novo structure determination of challenging proteins at XFELs. Improvements presented in this work can be used in other types of SFX experiments that require accurate measurements of weak signals, for example time-resolved studies., IUCrJ, 7 (6), ISSN:2052-2525

A high resolution (∆E < 100 meV) single shot spectrometer for the soft X-ray at SwissFEL is reported. Use of this high fidelity single shot data to develop new modes of operations of operation is described.

In this paper, we present a soft x-ray variable line-spacing spherical grating monochromator, which is shared between the three ATHOS beamlines at SwissFEL. The instrument uses grazing incidence angles of less than 3° to withstand the peak-fluence of femtosecond FEL pulses with energies up to 8 mJ. The upward facing monochromator grating facilitates endstations with different beam heights. We explain the integration of the monochromator into the beamlines; discuss its mechanical design, its control system and its optical components. We conclude with showing an initial calibration spectrum and detail the currently achieved performance.

The transmission of the optical components of the Bernina branch of the Aramis beamline at SwissFEL has been measured with an X-ray gas monitor from DESY and compared with a PSI gas detector upstream of the optical components. The transmission efficiencies of the mirrors and the various other in-beam components were evaluated and compared with theoretical calculations., The transmission of the optical components of the Bernina branch of the Aramis beamline at SwissFEL has been measured with an X-ray gas monitor from DESY and compared with a PSI gas detector upstream of the optical components. The transmission efficiencies of the Mo, Si and SiC mirror coatings of the Aramis beamline and the various other in-beam components were evaluated and compared with theoretical calculations, showing an agreement of 6% or better in all cases. The experiment has also shown the efficacy of the high-harmonic rejection mirrors at the Bernina branch of the Aramis beamline at SwissFEL, and characterized the transmission efficiency of the on-line spectrometer in the Aramis beamline. The theoretical transmission of the mirror coatings match the experimental data to within 7%. The accuracy of these measurements was checked against a radiative bolometer from a Japanese collaboration and found to agree to a level of 4% or better. Further comparisons with a diamond detector from a US-based inter-institute collaboration demonstrated a good agreement for the attenuator settings of the beamline.

International audience; The Bernina instrument at the SwissFEL Aramis hard X-ray free-electron laser is designed for studying ultrafast phenomena in condensed matter and material science. Ultrashort pulses from an optical laser system covering a large wavelength range can be used to generate specific non-equilibrium states, whose subsequent temporal evolution can be probed by selective X-ray scattering techniques in the range 2–12 keV. For that purpose, the X-ray beamline is equipped with optical elements which tailor the X-ray beam size and energy, as well as with pulse-to-pulse diagnostics that monitor the X-ray pulse intensity, position, as well as its spectral and temporal properties. The experiments can be performed using multiple interchangeable endstations differing in specialization, diffractometer and X-ray analyser configuration and load capacity for specialized sample environment. After testing the instrument in a series of pilot experiments in 2018, regular user operation begins in 2019.

Understanding the vulnerability of trees to drought-induced mortality is key to predicting the fate of forests in a future climate with more frequent and intense droughts, although the underlying mechanisms are difficult to study in adult trees. Here, we explored the dynamic changes of water relations and limits of hydraulic function in dying adults of Norway spruce (Picea abies L.) during the progression of the record-breaking 2018 Central European drought. In trees on the trajectory to drought-induced mortality, we observed rapid, nonlinear declines of xylem pressure that commenced at the early onset of xylem cavitation and caused a complete loss of xylem hydraulic conductance within a very short time. We also observed severe depletions of nonstructural carbohydrates, though carbon starvation could be ruled out as the cause of the observed tree death, as both dying and surviving trees showed these metabolic limitations. Our observations provide striking field-based evidence for fast dehydration and hydraulic collapse as the cause of drought-induced mortality in adult Norway spruce. The nonlinear decline of tree water relations suggests that considering the temporal dynamics of dehydration is critical for predicting tree death. The collapse of the hydraulic system within a short time demonstrates that trees can rapidly be pushed out of the zone of hydraulic safety during the progression of a severe drought. In summary, our findings point toward a higher mortality risk for Norway spruce than previously assumed, which is in line with current reports of unprecedented levels of drought-induced mortality in this major European tree species.

Optical-domain Transient Grating (TG) spectroscopy is a versatile background-free four-wave-mixing technique used to probe vibrational, magnetic and electronic degrees of freedom in the time domain. The newly developed coherent X-ray Free Electron Laser sources allow its extension to the X-ray regime. Xrays offer multiple advantages for TG: their large penetration depth allows probing the bulk properties of materials, their element-specificity can address core-excited states, and their short wavelengths create excitation gratings with unprecedented momentum transfer and spatial resolution. We demonstrate for the first time TG excitation in the hard X-ray range at 7.1 keV. In Bismuth Germanate (BGO), the nonresonant TG excitation generates coherent optical phonons detected as a function of time by diffraction of an optical probe pulse. This experiment demonstrates the ability to probe bulk properties of materials and paves the way for ultrafast coherent four-wave-mixing techniques using X-ray probes and involving nanoscale TG spatial periods., Comment: 11 pages, 4 figures

The characterization and commissioning of the X-ray photon single-shot spectrometer (PSSS) at the Aramis beamline of SwissFEL is presented. The device delivers online, non-invasive, high-resolution single-shot measurements of spectral profiles between 4 and 13 keV., The performance and parameters of the online photon single-shot spectrometer (PSSS) at the Aramis beamline of the SwissFEL free-electron laser are presented. The device operates between the photon energies 4 and 13 keV and uses diamond transmission gratings and bent Si crystals for spectral measurements on the first diffraction order of the beam. The device has an energy window of 0.7% of the median photon energy of the free-electron laser pulses and a spectral resolution (full width at half-maximum) ΔE/E on the order of 10−5. The device was characterized by comparing its performance with reference data from synchrotron sources, and a parametric study investigated other effects that could affect the reliability of the spectral information.

The evolutionary origin of vertebrates included innovations in sensory processing associated with the acquisition of a predatory lifestyle1. Vertebrates perceive external stimuli through sensory systems serviced by cranial sensory ganglia (CSG) which develop from cranial placodes; however understanding the evolutionary origin of placodes and CSGs is hampered by the gulf between living lineages and difficulty in assigning homology between cell types and structures. Here we use the Hmx gene family to address this question. We show Hmx is a constitutive component of vertebrate CSG development and thatHmxin the tunicateCionais able to drive the differentiation program of Bipolar Tail Neurons (BTNs), cells previously thought neural crest homologs2,3. UsingCionaand lamprey transgenesis we demonstrate that a unique, tandemly duplicated enhancer pair regulated Hmx in the stem-vertebrate lineage. Strikingly, we also show robust vertebrate Hmx enhancer function inCiona, demonstrating that deep conservation of the upstream regulatory network spans the evolutionary origin of vertebrates. These experiments demonstrate regulatory and functional conservation betweenCionaand vertebrateHmx, and confirm BTNs as CSG homologs. Our analysis also identifies derived evolutionary changes, including a genetic basis for secondary simplicity inCionaand unique regulatory complexity in vertebrates.

Thanks to the remarkable developments of ultrafast science, one of today's challenges is to modify material state by controlling with a light pulse the coherent motions that connect two different phases. Here we show how strain waves, launched by electronic and structural precursor phenomena, determine a macroscopic transformation pathway for the semiconducting-to-metal transition with large volume change in bistable Ti$_3$O$_5$ nanocrystals. Femtosecond powder X-ray diffraction allowed us to quantify the structural deformations associated with the photoinduced phase transition on relevant time scales. We monitored the early intra-cell distortions around absorbing metal dimers, but also long range crystalline deformations dynamically governed by acoustic waves launched at the laser-exposed Ti$_3$O$_5$ surface. We rationalize these observations with a simplified elastic model, demonstrating that a macroscopic transformation occurs concomitantly with the propagating acoustic wavefront on the picosecond timescale, several decades earlier than the subsequent thermal processes governed by heat diffusion., 30 pages (including supplementary text), 5 main figures, 9 supplementary figures; corrected author list

Several studies have documented the importance of optimal work situation and the general well-being of early-career researchers (ECRs) for enhancing the academic performance of universities. Yet, m ...

Assessment of programmed cell death ligand 1 (PD-L1) immunohistochemical staining is used for decision on treatment with programmed cell death 1 and PD-L1 checkpoint inhibitors in lung adenocarcinomas and squamous cell carcinomas. This study aimed to compare the staining properties of tumor cells between the antibody clones 28-8, 22C3, SP142, and SP263 and investigate interrater variation between pathologists to see if these stainings can be safely evaluated in the clinical setting. Using consecutive sections from a tissue microarray with tumor tissue from 55 resected lung cancer cases, staining with five PD-L1 assays (28-8 from two different vendors, 22C3, SP142, and SP263) was performed. Seven pathologists individually evaluated the percentage of positive tumor cells, scoring each sample applying cutoff levels used in clinical studies:1% positive tumor cells (score 0), 1-4% (score 1), 5-9% (score 2), 10-24% (score 3), 25-49% (score 4), and50% positive tumor cells (score 5). Pairwise analysis of antibody clones showed weighted kappa values in the range of 0.45-0.91 with the highest values for comparisons with 22C3 and 28-8 and the lowest involving SP142. Excluding SP142 resulted in kappa 0.75-0.91. Weighted kappa for interobserver variation between pathologists was 0.71-0.96. Up to 20% of the cases were differently classified as positive or negative by any pathologist compared with consensus score using ≥1% positive tumor cells as cutoff. A significantly better agreement between pathologists was seen using ≥50% as cutoff (0-5% of cases). In conclusion, the concordance between the PD-L1 antibodies 22C3, 28-8 and SP263 is relatively good when evaluating lung cancers and suggests that any one of these assays may be sufficient as basis for decision on treatment with nivolumab, pembrolizumab, and durvalumab. The scoring of the pathologist presents an intrinsic source of error that should be considered especially at low PD-L1 scores.

Research on the link between Machiavellianism and depression has yielded equivocal results. In this study, we examined the possible moderating role of ability emotional intelligence (a-EI) on the Machiavellianism-depression relationship. a-EI was approached as a factor influencing the effectiveness of Machiavellians' manipulative strategies. A total of 469 participants were recruited (34% male; mean age: 42.37). Machiavellian dispositions were assessed with the Machiavellianism subscale of the Dirty Dozen. a-EI was measured with the 10-scenario version of the Geneva EMOtion Knowledge-Blends—a performance-based test. Depressive symptoms were evaluated with the PHQ-9, a scale covering both cognitive-affective and somatic aspects of depression. Correlational analyses revealed no raw association between Machiavellianism, a-EI, and depression. In men, a-EI was found to moderate the effect of Machiavellianism on depression in such a way that Machiavellianism was protective against depressive symptoms when coupled with high a-EI. Component-level analyses indicated that the observed interaction was essentially underpinned by somatic depression. Machiavellianism predicted somatic depression negatively in males with high a-EI and positively in males with low a-EI. No association was identified in females. This study suggests that Machiavellianism is not depressogenic in itself. Remarkably, Machiavellianism might have antidepressant virtues in men exhibiting high a-EI.

The magnetic quantum states of holmium single atom magnets on MgO(100) have proven extremely robust when exposed to high magnetic fields and temperatures up to 35 K. Here we address the stability of Ho at small magnetic fields, where the hyperfine interaction creates several avoided level crossings. Using spin-polarized scanning tunneling microscopy, we demonstrate quantum state control via Landau-Zener tunneling and stable magnetization at zero field. Our observations indicate a total spin ground state of ${J}_{z}=\ifmmode\pm\else\textpm\fi{}8$. Combined quantum and classical control render Ho a promising qubit candidate.

The two Aramis beamlines at SwissFEL are currently under commissioning, first pilot experiments have already been carried out. In total we have 10 mirror systems, 6 offset mirrors and 4 mirrors in KB [1] configuration. We use bilayer mirror coatings to handle the single shot damage challenge at FELs. The optics has to keep the coherence of the FEL pulses. We use flat mirrors with figure errors on the single nm level in two-actuator mechanical bender systems. The vertically deflecting KB mirrors have a polished-in gravity sag compensation. The performance of the mirror systems has been verified with X-rays.

The three essential pillars of magnetic data storage devices are readability, writeability, and stability. However, these requirements compete as magnetic domain sizes reach the fundamental limit of single atoms and molecules. The proven magnetic bistability of individual holmium atoms on magnesium oxide appeared to operate within this magnetic trilemma, sacrificing writeability for unprecedented stability. Using the magnetic stray field created by the tip of a spin-polarized scanning tunneling microscope (SP-STM), we controllably move the Ho state into the quantum regime, allowing us to write its state via the quantum tunneling of magnetization (QTM). We find that the hyperfine interaction causes both the excellent magnetic bistability, even at zero applied magnetic field, and the avoided level crossings which we use to control the magnetic state via QTM. We explore how to use such a system to realize a high-fidelity single atom NOT gate (inverter). Our approach reveals the prospect of combining the best traits of the classical and quantum worlds for next generation data storage.

The Paul Scherrer Institut is currently constructing Athos, its second Free Electron Laser with a photon energy range from 250 eV to 1900 eV and pulse energies up to 8 mJ. A single soft X-ray beamline is attached to the undulator section and distributes the radiation into three branches. The beamline design is based on a variable line space spherical grating monochromator with a grating chamber and two retractable distribution mirrors. An achromatic focusing with individual KB-mirror systems downstream of the exit slits focus the beam to the endstations. The stations can operate alternatively without interfering with each other.

Vertebrates have evolved the most sophisticated nervous systems we know. These differ from the nervous systems of invertebrates in several ways, including the evolution of new cell types, and the emergence and elaboration of patterning mechanisms to organise cells in time and space. Vertebrates also generally have many more cells in their central nervous systems than invertebrates, and an increase in neural cell number may have contributed to the sophisticated anatomy of the brain and spinal cord. Here we study how increased cell number evolved in the vertebrate central nervous system, investigating the regulation of cell proliferation in lampreys as basally-diverging vertebrate, and focusing on the spinal cord because of its relatively simple anatomy. Markers of proliferating cells show that a medial proliferative progenitor zone is found throughout the lamprey spinal cord. We show that inhibition of Notch signalling disrupts the maintenance of this proliferative zone. When Notch signalling is blocked progenitor cells differentiate precociously, the proliferative medial zone is lost, and differentiation markers activate throughout the medial-lateral axis of the spinal cord. Comparison to other chordates suggests that the emergence of a persistent Notch-regulated proliferative progenitor zone in the medial spinal cord of vertebrate ancestors was a critical step for the evolution of the vertebrate spinal cord and its complexity.Summary statementVertebrates develop nervous systems with numerous cells. Study of cell proliferation in the lamprey nervous system links this to a medial proliferation zone regulated by Notch signalling, a vertebrate innovation.

The SwissFEL soft X-ray free-electron laser (FEL) beamline Athos will be ready for user operation in 2021. Its design includes a novel layout of alternating magnetic chicanes and short undulator segments. Together with the APPLE X architecture of undulators, the Athos branch can be operated in different modes producing FEL beams with unique characteristics ranging from attosecond pulse length to high-power modes. Further space has been reserved for upgrades including modulators and an external seeding laser for better timing control. All of these schemes rely on state-of-the-art technologies described in this overview. The optical transport line distributing the FEL beam to the experimental stations was designed with the whole range of beam parameters in mind. Currently two experimental stations, one for condensed matter and quantum materials research and a second one for atomic, molecular and optical physics, chemical sciences and ultrafast single-particle imaging, are being laid out such that they can profit from the unique soft X-ray pulses produced in the Athos branch in an optimal way., Journal of Synchrotron Radiation, 26 (4), ISSN:0909-0495, ISSN:1600-5775

Preserving the coherence and wavefront of a diffraction limited x-ray beam from the source to the experiment poses stringent quality requirements on the production processes for X-ray optics. In the near future this will require on-line and in-situ at-wavelength metrology for both, free electron lasers and diffraction limited storage rings. A compact and easy to move X-ray grating interferometry (XGI) setup has been implemented by the Beamline Optics Group at PSI in order to characterize x-ray optical components by determining the aberrations from reconstructing the x-ray wavefront. The XGI setup was configured for measurements in the moire mode and tested with focusing optic at Swiss Light Source, Diamond Light Source and LCLS. In this paper measurements on a bendable toroidal mirror, a zone plate, a single and a stack of beryllium compound refractive lenses (CRL) are presented. From these measurements the focal position and quality of the beam spot in terms of wavefront distortions are determined by analysing the phase-signal obtained from the XGI measurement. In addition, using a bendable toroidal mirror, we directly compare radius of curvature measurements obtained from XGI data with data from a long-trace profilometer, and compare the CRL wavefront distortions with data obtained by ptychography.

We use spin-polarized scanning tunneling microscopy to demonstrate that Ho atoms on magnesium oxide exhibit a coercive field of more than 8 T and magnetic bistability for many minutes, both at 35 K. The first spontaneous magnetization reversal events are recorded at 45 K for which the metastable state relaxes in an external field of 8 T. The transverse magnetic anisotropy energy is estimated from magnetic field and bias voltage dependent switching rates at 4.3 K. Our measurements constrain the possible ground state of Ho single atom magnets to either Jz = 7 or 8, both compatible with magnetic bistability at fields larger than 10 mT., Comment: 4 pages and supplemental information

In this report, we analyse X-ray induced damage of B4C-coated bilayer materials under various irradiation geometries, following the conditions of our experiment performed at the free-electron-laser facility SACLA. We start with the discussion of structural damage in solids and damage threshold doses for the experimental system components: B4C, SiC, Mo and Si. Later, we analyze the irradiation of the experimentally tested coated bilayer systems under two different incidence conditions of a linearly polarized X-ray pulse: (i) grazing incidence, and (ii) normal incidence, in order to compare quantitatively the effect of the pulse incidence on the radiation tolerance of both systems. For that purpose, we propose a simple theoretical model utilizing properties of hard X-ray propagation and absorption in irradiated materials and of the following electron transport. With this model, we overcome the bottleneck problem of large spatial scales, inaccessible for any existing first-principle-based simulation tools due to their computational limitations for large systems. Predictions for damage thresholds obtained with the model agree well with the available experimental data. In particular, they confirm that two coatings tested: 15 nm B4C/20 nm Mo on silicon wafer and 15 nm B4C/50 nm SiC on silicon wafer can sustain X-ray irradiation at the fluences up to ~10 μJ/μm2, when exposed to linearly polarized 10 keV X-ray pulse at a grazing incidence angle of 3 mrad. Below we present the corresponding theoretical analysis. Potential applications of our approach for design and radiation tolerance tests of multilayer components within X-ray free-electron-laser optics are indicated.

TbPc2 single-molecule magnets adsorbed on a magnesium oxide tunnel barrier exhibit record magnetic remanence, record hysteresis opening, perfect out-of-plane alignment of the magnetic easy axes, and self-assembly into a well-ordered layer.

Anthropogenic disturbance of wildlife is of growing conservation concern, but we lack comprehensive approaches of its multiple negative effects. We investigated several effects of disturbance by winter outdoor sports on free-ranging alpine Black Grouse by simultaneously measuring their physiological and behavioral responses. We experimentally flushed radio-tagged Black Grouse from their snow burrows, once a day, during several successive days, and quantified their stress hormone levels (corticosterone metabolites in feces [FCM] collected from individual snow burrows). We also measured feeding time allocation (activity budgets reconstructed from radio-emitted signals) in response to anthropogenic disturbance. Finally, we estimated the related extra energy expenditure that may be incurred: based on activity budgets, energy expenditure was modeled from measures of metabolism obtained from captive birds subjected to different ambient temperatures. The pattern of FCM excretion indicated the existence of a funneling effect as predicted by the allostatic theory of stress: initial stress hormone concentrations showed a wide inter-individual variation, which decreased during experimental flushing. Individuals with low initial pre-flushing FCM values augmented their concentration, while individuals with high initial FCM values lowered it. Experimental disturbance resulted in an extension of feeding duration during the following evening foraging bout, confirming the prediction that Black Grouse must compensate for the extra energy expenditure elicited by human disturbance. Birds with low initial baseline FCM concentrations were those that spent more time foraging. These FCM excretion and foraging patterns suggest that birds with high initial FCM concentrations might have been experiencing a situation of allostatic overload. The energetic model provides quantitative estimates of extra energy expenditure. A longer exposure to ambient temperatures outside the shelter of snow burrows, following disturbance, could increase the daily energy expenditure by >10%, depending principally on ambient temperature and duration of exposure. This study confirms the predictions of allostatic theory and, to the best of our knowledge, constitutes the first demonstration of a funneling effect. It further establishes that winter recreation activities incur costly allostatic behavioral and energetic adjustments, which call for the creation of winter refuge areas together with the implementation of visitor-steering measures for sensitive wildlife.

The causative agent of Legionnaires' disease, Legionella pneumophila, grows in environmental amoebae and mammalian macrophages within a distinct compartment, the 'Legionella-containing vacuole' (LCV). Intracellular bacteria are protected from many antibiotics, and thus are notoriously difficult to eradicate. To identify novel compounds that restrict intracellular bacterial replication, we previously developed an assay based on a coculture of amoebae and GFP-producing L. pneumophila. This assay was used to screen a pathway-based, highly diverse chemical library, referred to as the Sinergia library. In this work, we chose to focus on a group of 11 hit compounds, the majority of which originated from the query molecule CN585, a compound that targets the protein phosphatase calcineurin. Further studies on 78 related compound variants revealed crucial structural attributes, namely a triple-ring scaffold with a central triazine moiety, substituted in positions 3 and 5 by two piperidine or pyrrolidine rings, and in position 1 by an amine group bearing a single aliphatic chain moiety. The most effective compound, ZINC00615682, inhibited intracellular replication of L. pneumophila with an IC50 of approximately 20 nM in Acanthamoeba castellanii and slightly less efficiently in Dictyostelium discoideum or macrophages. Pharmacological and genetic attempts to implicate calcineurin in the intracellular replication of L. pneumophila failed. Taken together, these results show that the amoebae-based screen and structure-activity relationship analysis is suitable for the identification of novel inhibitors of the intracellular replication of L. pneumophila. The most potent compound identified in this study targets (an) as yet unidentified host factor(s).

The eye has served as a classical model to study cell specification and tissue induction for over a century. Nevertheless, the molecular mechanisms that regulate the induction and maintenance of eye-field cells, and the specification of neural retina cells are poorly understood. Moreover, within the developing anterior forebrain, how prospective eye and telencephalic cells are differentially specified is not well defined. In the present study, we have analyzed these issues by manipulating signaling pathways in intact chick embryo and explant assays. Our results provide evidence that at blastula stages, BMP signals inhibit the acquisition of eye-field character, but from neural tube/optic vesicle stages, BMP signals from the lens are crucial for the maintenance of eye-field character, inhibition of dorsal telencephalic cell identity and specification of neural retina cells. Subsequently, our results provide evidence that a Rax2-positive eye-field state is not sufficient for the progress to a neural retina identity, but requires BMP signals. In addition, our results argue against any essential role of Wnt or FGF signals during the specification of neural retina cells, but provide evidence that Wnt signals together with BMP activity are sufficient to induce cells of retinal pigment epithelial character. We conclude that BMP activity emanating from the lens ectoderm maintains eye-field identity, inhibits telencephalic character and induces neural retina cells. Our findings link the requirement of the lens ectoderm for neural retina specification with the molecular mechanism by which cells in the forebrain become specified as neural retina by BMP activity., SUMMARY: BMP signals from the lens are crucial to maintain eye-field character, inhibit dorsal telencephalic cell identity, and specificy neural retina cells in chick embryos.

Background: Neurogenins are required for the specification of neuronal precursors and regulate the expression of basic Helix-Loop-Helix genes involved in neuronal differentiation. Jawed vertebrates ...

The Photon Arrival and Length Monitor (PALM), a THz streak camera device developed by PSI for non-destructive hard x-ray measurements of photon pulse length and arrival time versus a pump laser[1], was brought to the SACLA XFEL[2] in Japan in a cross-calibration temporal diagnostics campaign after an initial experiment where only the PALM was being used[3]. The device was used with 9 keV pink beam and a 9.0 and 8.8 keV two-color mode, successfully measuring the temporal ifnromation of the pulses for several different FEL operating conditions. The most interesting achievement is the PALM’s ability to measure two arrival times of the two colorors as tey are shifted against each other by the FEL, opening up new possibilities in temporal accuracy for two-color experiments. SwissFEL will employ two such devices at the end stations for use by both operators and experimenters to improve the operation of the FEL and to better interpret experimental data. References [1]P. N. Juranic et. al, Journal of Instrumentation (2014) 9. [2]T. Ishikawa et. al., Nature Photonics (2012) 6(8). [3] P. N. Juranic et. al., Optics Express (2014) 22.