Bridging the gap of storage ring light sources and linac-driven free-electron lasers

High-gain free-electron lasers (FELs) are driven by short, high-charge density electron beams as only produced at dedicated single pass or recirculating linear accelerators. We describe new conceptual, technical, and modeling solutions to produce subpicosecond, up to 100 \u3bcJ energy extreme ultra-violet and soft x-ray FEL pulses at high- and tunable repetition rates, from diffraction-limited storage ring light source. In contrast to previously proposed schemes, we show that lasing can be simultaneous to the standard multibunch radiation emission from short insertion devices, and that it can be obtained with limited impact on the storage ring infrastructure. By virtue of the high-average power but moderate pulse energy, the storage ring-driven high-gain FEL would open the door to unprecedented accuracy in time-resolved spectroscopic analysis of matter in the linear response regime, in addition to inelastic scattering experiments

Hippocampal vascularization patterns exert local and distant effects on brain structure but not vascular pathology in old age

The hippocampus within the medial temporal lobe is highly vulnerable to age-related pathology such as vascular disease. We examined hippocampal vascularization patterns by harnessing the ultra-high resolution of 7 Tesla magnetic resonance angiography. Dual-supply hemispheres with a contribution of the anterior choroidal artery to hippocampal blood supply were distinguished from single-supply ones with a sole dependence on the posterior cerebral artery. A recent study indicated that a dual vascular supply is related to preserved cognition and structural hippocampal integrity in old age and vascular disease. Here, we examined the regional specificity of these structural benefits at the level of medial temporal lobe sub-regions and hemispheres. In a cross-sectional study with an older cohort of 17 patients with cerebral small vessel disease (70.7 ±  9.0 years, 35.5% female) and 27 controls (71.1 ±  8.2 years, 44.4% female), we demonstrate that differences in grey matter volumes related to the hippocampal vascularization pattern were specifically observed in the anterior hippocampus and entorhinal cortex. These regions were especially bigger in dual-supply hemispheres, but also seemed to benefit from a contralateral dual supply. We further show that total grey matter volumes were greater in people with at least one dual-supply hemisphere, indicating that the hippocampal vascularization pattern has more far-reaching structural implications beyond the medial temporal lobe. A mediation analysis identified total grey matter as a mediator of differences in global cognition. However, our analyses on multiple neuroimaging markers for cerebral small vessel disease did not reveal any evidence that an augmented hippocampal vascularization conveys resistance nor resilience against vascular pathology. We propose that an augmented hippocampal vascularization might contribute to maintaining structural integrity in the brain and preserving cognition despite age-related degeneration. As such, the binary hippocampal vascularization pattern could have major implications for brain structure and function in ageing and dementia independent of vascular pathology, while presenting a simple framework with potential applicability to the clinical setting

Single-shot transverse coherence in seeded and unseeded free-electron lasers: A comparison

The advent of x-ray free-electron lasers (FELs) drastically enhanced the capabilities of several analytical techniques, for which the degree of transverse (spatial) coherence of the source is essential. FELs can be operated in self-amplified spontaneous emission (SASE) or seeded configurations, which rely on a qualitatively different initialization of the amplification process leading to light emission. The degree of transverse coherence of SASE and seeded FELs has been characterized in the past, both experimentally and theoretically. However, a direct experimental comparison between the two regimes in similar operating conditions is missing, as well as an accurate study of the sensitivity of transverse coherence to key working parameters. In this paper, we carry out such a comparison, focusing in particular on the evolution of coherence during the light amplification process

Carbamazepine inhibits angiotensin I-converting enzyme, linking it to the pathogenesis of temporal lobe epilepsy

We find that a common mutation that increases angiotensin I-converting enzyme activity occurs with higher frequency in male patients suffering from refractory temporal lobe epilepsy. However, in their brains, the activity of the enzyme is downregulated. As an explanation, we surprisingly find that carbamazepine, commonly used to treat epilepsy, is an inhibitor of the enzyme, thus providing a direct link between epilepsy and the renin–angiotensin and kallikrein–kinin systems

A general process for the development of peptide-based immunoassays for monoclonal antibodies

Monoclonal antibodies (mAb) are an important and growing class of cancer therapeutics, but pharmacokinetic analyses have in many cases been constrained by the lack of standard and robust pharmacologic assays. The goal of this project was to develop a general method for the production of immunoassays that can measure the levels of therapeutic monoclonal antibodies in biologic samples at relevant concentrations. Alemtuzumab and rituximab are monoclonal approved for the treatment of B-cell malignancies and were used as a model system. Phage-displayed peptide libraries were screened for peptide sequences recognized by alemtuzumab (anti-CD52) or rituximab (anti-CD20). Synthetic biotinylated peptides were used in enzyme-linked immunosorbent assays (ELISA). Peptides directly synthesized on polymer resin beads were used in an immunofluorescent-based assay. Peptide mimetope sequences were recovered for both mAb and confirmed by competitive staining and kinetic measurements. A peptide-based ELISA method was developed for each. The assay for rituximab had a limit of detection of 4 μg/ml, and the assay for alemtuzumab had a limit of detection of 1 μg/ml. Antibody-specific staining of peptide conjugated beads could be seen in a dose-dependent manner. Phage-displayed peptide libraries can be a source of highly specific mimetopes for therapeutic mAb. The biotinylated forms of those peptides are compatible with conventional ELISA methods with sensitivities comparable to other assay methods and sufficient for pharmacological studies of those mAb given at high dose. The process outlined here can be applied to any mAb to enable improved pharmacokinetic analysis during the development and clinical use of this class of therapies

Derivation and validation of four patient clusters in Still's disease, results from GIRRCS AOSD-study group and AIDA Network Still Disease Registry

Background Different patient clusters were preliminarily suggested to dissect the clinical heterogeneity in Still's disease. Thus, we aimed at deriving and validating disease clusters in a multicentre, observational, prospective study to stratify these patients. Methods Patients included in GIRRCS AOSD-study group and AIDA Network Still Disease Registry were assessed if variables for cluster analysis were available (age, systemic score, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and ferritin). K-means algorithm with Euclidean metric and Elbow plot were used to derive an adequate number of clusters. Results K-means clustering assessment provided four clusters based on means standardised according to z-scores on 349 patients. All clusters mainly presented fever, skin rash and joint involvement. Cluster 1 was composed by 115 patients distinguished by lower values of age and characterised by skin rash myalgia, sore throat and splenomegaly. Cluster 2 included 128 patients identified by lower levels of ESR, ferritin and systemic score; multiorgan manifestations were less frequently observed. Cluster 3 comprised 31 patients categorised by higher levels of CRP and ferritin, they were characterised by fever and joint involvement. Cluster 4 contained 75 patients derived by higher values of age and systemic score. Myalgia, sore throat, liver involvement and life-threatening complications, leading to a high mortality rate, were observed in these patients. Conclusions Four patient clusters in Still's disease may be recognised by a multidimensional characterisation ('Juvenile/Transitional', ' Uncomplicated', ' Hyperferritinemic' and ' Catastrophic'). Of interest, cluster 4 was burdened by an increased rate of life-threatening complications and mortality, suggesting a more severe patient group

Association of antigen processing machinery and HLA class I defects with clinicopathological outcome in cervical carcinoma

HLA class I loss is a significant mechanism of immune evasion by cervical carcinoma, interfering with the development of immunotherapies and cancer vaccines. We report the systematic investigation of HLA class I and antigen processing machinery component expression and association with clinical outcome. A tissue microarray containing carcinoma lesions from 109 cervical carcinoma patients was stained for HLA class I heavy chains, β2-microglobulin, LMP2, LMP7, LMP10, TAP1, TAP2, ERAP1, tapasin, calreticulin, calnexin and ERp57. A novel staining evaluation method was used to ensure optimal accuracy and reliability of expression data, which were correlated with known clinicopathological parameters. Partial HLA class I loss was significantly associated with decreased 5-years overall survival (61% vs. 83% for normal expression; P < 0.05) and was associated with decreased 5-years disease-free survival (DFS) (65% vs. 82% for normal expression; P = 0.05). All APM components except LMP10, calnexin and calreticulin were down-regulated in a substantial number of cases and, except ERAP1, correlated significantly with HLA class I down-regulation. LMP7, TAP1 and ERAP1 loss was significantly associated with decreased overall and (except LMP7) DFS (P < 0.05 and 0.005, respectively). ERAP1 down-regulation was an independent predictor for worse overall and DFS in multivariate analysis (HR 3.08; P < 0.05 and HR 2.84; P < 0.05, respectively). HLA class I and APM component down-regulation occur frequently in cervical carcinoma, while peptide repertoire alterations due to ERAP1 loss are a major contributing factor to tumour progression and mortality

Upgrade of Biomass-Derived Levulinic Acid via Ru/C-Catalyzed Hydrogenation to γ‑Valerolactone in Aqueous−Organic−Ionic Liquids Multiphase Systems

A liquid triphase system made by an aqueous phase, an organic phase, and an ionic liquid was designed and applied to the catalytic hydrogenation/dehydration of biomass-derived levulinic acid to γ-valerolactone. This paper demonstrates that, by operating at 100−150 °C and 35 atm of H2, both in the presence of Ru/C or of a homogeneous Ru precursor, the use of the triphase system designed to match the investigated reaction allows the following: (1) to obtain up to quantitative conversions and 100% selectivity toward the desired product; (2) to recover the product by simple phase separation; and (3) to preserve the catalyst activity for in situ recycles without loss of metal. Globally the investigated reaction proves the concept that a cradle-to-grave approach to the design of a catalytic reaction system can improve the global sustainability of a chemical transformation by improving efficiency, product isolation, and catalyst recycle