A self-referenced in-situ arrival time monitor for X-ray free-electron lasers

We present a novel, highly versatile, and self-referenced arrival time monitor for measuring the femtosecond time delay between a hard X-ray pulse from a free-electron laser and an optical laser pulse, measured directly on the same sample used for pump-probe experiments. Two chirped and picosecond long optical supercontinuum pulses traverse the sample with a mutually fixed time delay of 970 fs, while a femtosecond X-ray pulse arrives at an instant in between both pulses. Behind the sample the supercontinuum pulses are temporally overlapped to yield near-perfect destructive interference in the absence of the X-ray pulse. Stimulation of the sample with an X-ray pulse delivers non-zero contributions at certain optical wavelengths, which serve as a measure of the relative arrival time of the X-ray pulse with an accuracy of better than 25 fs. We find an excellent agreement of our monitor with the existing timing diagnostics at the SACLA XFEL with a Pearson correlation value of 0.98. We demonstrate a high sensitivity to measure X-ray pulses with pulse energies as low as 30 $\mu$J. Using a free-flowing liquid jet as interaction sample ensures the full replacement of the sample volume for each X-ray/optical event, thus enabling its utility even at MHz repetition rate XFEL sources

Optical-phonon resonances with saddle-point excitons in twisted-bilayer graphene

Twisted-bilayer graphene (tBLG) exhibits van Hove singularities in the density of states that can be tuned by changing the twisting angle $\theta$. A $\theta$-defined tBLG has been produced and characterized with optical reflectivity and resonance Raman scattering. The $\theta$-engineered optical response is shown to be consistent with persistent saddle-point excitons. Separate resonances with Stokes and anti-Stokes Raman scattering components can be achieved due to the sharpness of the two-dimensional saddle-point excitons, similar to what has been previously observed for one-dimensional carbon nanotubes. The excitation power dependence for the Stokes and anti-Stokes emissions indicate that the two processes are correlated and that they share the same phonon.Comment: 5 pages, 6 figure

Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study

Objective. To assess the efficacy of rituximab (RTX) in SSc

Aerosols implicated as a prime driver of twentieth-century North Atlantic climate variability

Systematic climate shifts have been linked to multidecadal variability in observed sea surface temperatures in the North Atlantic Ocean1. These links are extensive, influencing a range of climate processes such as hurricane activity2 and African Sahel3, 4, 5 and Amazonian5 droughts. The variability is distinct from historical global-mean temperature changes and is commonly attributed to natural ocean oscillations6, 7, 8, 9, 10. A number of studies have provided evidence that aerosols can influence long-term changes in sea surface temperatures11, 12, but climate models have so far failed to reproduce these interactions6, 9 and the role of aerosols in decadal variability remains unclear. Here we use a state-of-the-art Earth system climate model to show that aerosol emissions and periods of volcanic activity explain 76 per cent of the simulated multidecadal variance in detrended 1860–2005 North Atlantic sea surface temperatures. After 1950, simulated variability is within observational estimates; our estimates for 1910–1940 capture twice the warming of previous generation models but do not explain the entire observed trend. Other processes, such as ocean circulation, may also have contributed to variability in the early twentieth century. Mechanistically, we find that inclusion of aerosol–cloud microphysical effects, which were included in few previous multimodel ensembles, dominates the magnitude (80 per cent) and the spatial pattern of the total surface aerosol forcing in the North Atlantic. Our findings suggest that anthropogenic aerosol emissions influenced a range of societally important historical climate events such as peaks in hurricane activity and Sahel drought. Decadal-scale model predictions of regional Atlantic climate will probably be improved by incorporating aerosol–cloud microphysical interactions and estimates of future concentrations of aerosols, emissions of which are directly addressable by policy actions

Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology

BACKGROUND: The von Hippel–Lindau tumour suppressor protein–hypoxia-inducible factor (VHL–HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL–HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL–HIF pathway in systemic human cardiopulmonary physiology. METHODS AND FINDINGS: Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased. CONCLUSIONS: The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF

Anti-Interferon Autoantibodies in Autoimmune Polyendocrinopathy Syndrome Type 1

BACKGROUND: The autoimmune regulator (AIRE) gene influences thymic self-tolerance induction. In autoimmune polyendocrinopathy syndrome type 1 (APS1; OMIM 240300), recessive AIRE mutations lead to autoimmunity targetting endocrine and other epithelial tissues, although chronic candidiasis usually appears first. Autoimmunity and chronic candidiasis can associate with thymomas as well. Patients with these tumours frequently also have high titre immunoglobulin G autoantibodies neutralising type I interferon (IFN)–α and IFN-ω, which are secreted signalling proteins of the cytokine superfamily involved in both innate and adaptive immunity. METHODS AND FINDINGS: We tested for serum autoantibodies to type I IFNs and other immunoregulatory cytokines using specific binding and neutralisation assays. Unexpectedly, in 60/60 Finnish and 16/16 Norwegian APS1 patients with both AIRE alleles mutated, we found high titre neutralising immunoglobulin G autoantibodies to most IFN-α subtypes and especially IFN-ω (60% homologous to IFN-α)—mostly in the earliest samples. We found lower titres against IFN-β (30% homologous to IFN-α) in 23% of patients; two-thirds of these (from Finland only) also had low titres against the distantly related “type III IFN” (IFN-λ1; alias interleukin-29). However, autoantibodies to the unrelated type II IFN, IFN-γ, and other immunoregulatory cytokines, such as interleukin-10 and interleukin-12, were much rarer and did not neutralise. Neutralising titres against type I IFNs averaged even higher in patients with APS1 than in patients with thymomas. Anti–type I IFN autoantibodies preceded overt candidiasis (and several of the autoimmune disorders) in the informative patients, and persisted for decades thereafter. They were undetectable in unaffected heterozygous relatives of APS1 probands (except for low titres against IFN-λ1), in APS2 patients, and in isolated cases of the endocrine diseases most typical of APS1, so they appear to be APS1-specific. Looking for potentially autoimmunising cell types, we found numerous IFN-α(+) antigen-presenting cells—plus strong evidence of local IFN secretion—in the normal thymic medulla (where AIRE expression is strongest), and also in normal germinal centres, where it could perpetuate these autoantibody responses once initiated. IFN-α2 and IFN-α8 transcripts were also more abundant in antigen-presenting cells cultured from an APS1 patient's blood than from age-matched healthy controls. CONCLUSIONS: These apparently spontaneous autoantibody responses to IFNs, particularly IFN-α and IFN-ω, segregate like a recessive trait; their high “penetrance” is especially remarkable for such a variable condition. Their apparent restriction to APS1 patients implies practical value in the clinic, e.g., in diagnosing unusual or prodromal AIRE-mutant patients with only single components of APS1, and possibly in prognosis if they prove to predict its onset. These autoantibody responses also raise numerous questions, e.g., about the rarity of other infections in APS1. Moreover, there must also be clues to autoimmunising mechanisms/cell types in the hierarchy of preferences for IFN-ω, IFN-α8, IFN-α2, and IFN-β and IFN-λ1

Aberrant Function of Learning and Cognitive Control Networks Underlie Inefficient Cognitive Flexibility in Anorexia Nervosa: A Cross-Sectional fMRI Study

Objectives People with Anorexia Nervosa exhibit difficulties flexibly adjusting behaviour in response to environmental changes. This has previously been attributed to problematic behavioural shifting, characterised by a decrease in fronto-striatal activity. Additionally, alterations of instrumental learning, which relies on fronto-striatal networks, may contribute to the observation of inflexible behaviour. The authors sought to investigate the neural correlates of cognitive flexibility and learning in Anorexia Nervosa. Method Thirty-two adult females with Anorexia Nervosa and thirty-two age-matched female control participants completed the Wisconsin Card Sorting Task whilst undergoing functional magnetic resonance imaging. Event-related analysis permitted the comparison of cognitive shift trials against those requiring maintenance of rule-sets and allowed assessment of trials representing learning. Results Although both groups performed similarly, we found significant interactions in the left middle frontal gyrus, precuneus and superior parietal lobule whereby blood-oxygenated-level dependent response was higher in Anorexia Nervosa patients during shifting but lower when maintaining rule-sets, as compared to healthy controls. During learning, posterior cingulate cortex activity in healthy controls decreased whilst increasing in the Anorexia Nervosa group, whereas the right precuneus exhibited the opposite pattern. Furthermore, learning was associated with lower blood-oxygenated-level dependent response in the caudate body, as compared to healthy controls. Conclusions People with Anorexia Nervosa display widespread changes in executive function. Whilst cognitive flexibility appears to be associated with aberrant functioning of the fronto-parietal control network that mediates between internally and externally directed cognition, fronto-striatal alterations, particularly within the caudate body, were associated with instrumental learning. Together, this shows how perseverative tendencies could be a substrate of multiple high-order processes that may contribute to the maintenance of Anorexia Nervosa