The European strategy for accelerator-based photon science.

The League of European Accelerator-based Photon Sources (LEAPS), comprising 19 large-scale user facilities in 10 member and associated states, has put forward for the first time a European strategy for a transformative way of cooperation, thereby mobilizing the members' substantial expertise in photon science and technology, in infrastructure management and service to users and stakeholders. This European Strategy for Accelerator-based Photon Sources-ESAPS 2022-is a coherent pan-European plan addressing the future challenges and needs of the new era in research and innovation, designed to put Europe in a global leadership position in important future key technologies. In ESAPS2022, ambitious facility upgrades and technology development plans as well as a new strategic challenge-driven use of these facilities are discussed.

2-Chloroacetamidine, a novel immunomodulator, suppresses antigen-induced mouse airway inflammation.

BACKGROUND: Citrullination is a presently under-recognized posttranslational protein modification catalyzed by PAD enzymes. Immune responses to citrullinated neo-epitopes are identified in a growing number of inflammatory and autoimmune diseases. However, the involvement of hypercitrullination in the pathogenesis of bronchial asthma is still unknown. METHODS: As main experimental tool, we examined the effect of 2-chloroacetamidine (2CA), a PAD enzyme inhibitor, on OVA-immunized and airway-challenged BALB/c mice; a commonly used model of allergic airway inflammation. We also measured the effect of 2CA on ex vivo lymphocytes and cell lines. RESULTS: In vivo, 2CA dramatically suppressed lung tissue hypercitrullination, inflammatory cell recruitment, and airway-Th2 cytokine secretion. 2CA also suppressed systemic OVA-specific and total IgE production dramatically, effectively preventing de novo and diminishing established disease without measurably impacting general immunocompetence. In vitro, 2CA markedly inhibited the proliferation of mouse and human T cells with cell cycle block and apoptosis during a limited, postactivation phase. CONCLUSIONS: 2CA acts as narrow-spectrum immunosuppressant that selectively targets lymphocyte populations involved in active inflammatory tissue lesions. If hypercitrullination is generated in patients with asthma, 2CA may represent a novel disease modulator for human asthmatics/allergic diseases.

Neuronal T-cell autoreactivity is amplified in overweight children with new-onset insulin-requiring diabetes.

OBJECTIVE: Disease-associated T-cell autoreactivities are seen in most type 1 diabetic patients and are thought to emerge before islet autoantibodies, but host factors that impact autoimmune elements remain uncertain. We assessed if adiposity and measures of insulin sensitivity impact T- and B-cell autoimmunity in children with insulin-requiring diabetes. RESEARCH DESIGN AND METHODS: Insulin-requiring children and adolescents diagnosed between January 2004 and June 2008 were studied (n = 261): age 9.7 ± 4 years, 92% white, and 60% male. T-cell responses to 10 diabetes-associated antigens, ß-cell autoantibodies (GADA, IA-2A, IAA, and ICA), BMI z score (BMIz), and waist percentile were measured at onset and 3 months later. RESULTS: All but one subject had either T- or B-cell autoimmunity. Diabetes-associated T-cell autoreactivities were found in 92% of subjects. Higher amplitude T-cell autoreactivities to neuronal diabetes-associated autoantigens were seen in those with the highest BMIz quintile, BMI ≥85th percentile (P < 0.05), and waist circumference ≥85th percentile (P < 0.05). There were no relationships between the number of T-cell reactivities or T-cell diversity with adiposity measures or autoantibody number or type. Patients with positive T-cell reactivities but without autoantibodies had the highest BMIz (P = 0.006). CONCLUSIONS: Our observations link obesity and diabetes-related autoimmunity, suggesting an amplification of neuronal T-cell autoimmunity associated with adiposity and/or insulin resistance, with obesity-related inflammation possibly enhancing islet autoimmunity.

TRPV1 gates tissue access and sustains pathogenicity in autoimmune encephalitis.

Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1-/- B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1+ neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P. In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy.

'Sensing' the link between type 1 and type 2 diabetes.

Obesity-associated insulin resistance is a core element of metabolic syndrome and type 2 diabetes (T2D). Notably, insulin resistance is also a feature of type 1 diabetes (T1D), where findings in the non-obese diabetic mouse model have implicated transient receptor potential vanilloid-1 (TRPV1+) sensory neurons in local islet inflammation and glucose metabolism. Here, we briefly review the role of TRPV1 in non-obese diabetic (NOD) T1D pathogenesis, highlighting commonalities that suggest TRPV1 may contribute to obesity and T2D as well. With the recently discovered importance of adipose infiltrating lymphocytes in the metabolic disturbances of obesity and T2D, sensory innervation of fat may thus play an analogous role to sensory neurons in the islet--modulating neuroendocrine homeostasis and inflammation. In such a scenario, TRPV1+ sensory nerves would provide the pathoaetiological link connecting the shared metabolic and immunologic features of type 1 diabetes and T2D.

Increased T cell proliferative responses to islet antigens identify clinical responders to anti-CD20 monoclonal antibody (rituximab) therapy in type 1 diabetes.

Type 1 diabetes mellitus is believed to be due to the autoimmune destruction of ß-cells by T lymphocytes, but a single course of rituximab, a monoclonal anti-CD20 B lymphocyte Ab, can attenuate C-peptide loss over the first year of disease. The effects of B cell depletion on disease-associated T cell responses have not been studied. We compare changes in lymphocyte subsets, T cell proliferative responses to disease-associated target Ags, and C-peptide levels of participants who did (responders) or did not (nonresponders) show signs of ß-cell preservation 1 y after rituximab therapy in a placebo-controlled TrialNet trial. Rituximab decreased B lymphocyte levels after four weekly doses of mAb. T cell proliferative responses to diabetes-associated Ags were present at baseline in 75% of anti-CD20- and 82% of placebo-treated subjects and were not different over time. However, in rituximab-treated subjects with significant C-peptide preservation at 6 mo (58%), the proliferative responses to diabetes-associated total (p = 0.032), islet-specific (p = 0.048), and neuronal autoantigens (p = 0.005) increased over the 12-mo observation period. This relationship was not seen in placebo-treated patients. We conclude that in patients with type 1 diabetes mellitus, anti-B cell mAb causes increased proliferative responses to diabetes Ags and attenuated ß-cell loss. The way in which these responses affect the disease course remains unknown.

Phase and microphase separation of polymer thin films dewetted from silicon--a spin-echo resolved grazing incidence neutron scattering study.

An understanding of the structure of ultrathin polymer films on solid substrates has scientific importance in applications as well as in fundamental studies of polymer diffusion or adsorption. We present studies of the organization of dewetted droplets of polymers on a silicon surface using a new neutron scattering technique, spin-echo resolved grazing incidence scattering (SERGIS), that has the potential to address at the same time the droplet-droplet correlations and the chemical configuration inside each droplet. For the seminal experiments, the polarized neutron reflectometer EVA at the Institut Laue-Langevin, Grenoble, France, was equipped with a spin-echo setup, and measurements were taken on surface structures previously characterized by different techniques. The dewetted polymers used in our studies were pure polystyrene, a mixture of polystyrene and polyparamethylstyrene, and a diblock copolymer of the two homopolymers. Even with a provisional setup SERGIS, we were able to determine the correlation between the droplets, providing results in excellent agreement with those obtained by atomic force microscopy and grazing incidence small-angle X-ray and neutron scattering. In addition, it was confirmed that the correlation function for diblock copolymer droplets is more complex than for polymer mixtures, exhibiting partial ordering of the copolymer within each droplet.

B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies.

Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.

Copper-phthalocyanine based metal-organic interfaces: the effect of fluorination, the substrate, and its symmetry.

Metal-organic interfaces based on copper-phthalocyanine monolayers are studied in dependence of the metal substrate (Au versus Cu), of its symmetry [hexagonal (111) surfaces versus fourfold (100) surfaces], as well as of the donor or acceptor semiconducting character associated with the nonfluorinated or perfluorinated molecules, respectively. Comparison of the properties of these systematically varied metal-organic interfaces provides new insight into the effect of each of the previously mentioned parameters on the molecule-substrate interactions.

Molecular heterojunction morphology on rough substrate surfaces: component separation by Fourier subtraction.

The study of molecular heterojunction morphology is often complicated by the presence of a topographically complex substrate. On such substrates, it is difficult to definitively assign a topographic feature to a specific component. We propose a technique, based on the separation of features in reciprocal space (Fourier subtraction), to deconvolute a heterojunction surface into two real space images. The technique has been successfully applied to three classes of systems: (1) where the overlayer features are smaller than those of the substrate, such as with small molecule growth on polymer substrates (DIP/PEDOT:PSS); (2) where the overlayer features are larger than the substrate, such as with a polymer film in contact with a corrugated metal surface (P3HT/Al), and (3) where both the overlayer and substrate features are of the same size. The Fourier subtraction method extends the study of morphology to heterojunctions with realistic substrates, where the complex topography may previously have prevented a basic description of the specific features of each component in a heterojunction film.

Unexpected acceleration of type 1 diabetes by transgenic expression of B7-H1 in NOD mouse peri-islet glia.

OBJECTIVE: Autoimmune target tissues in type 1 diabetes include pancreatic ß-cells and peri-islet Schwann cells (pSC)--the latter active participants or passive bystanders in pre-diabetic autoimmune progression. To distinguish between these alternatives, we sought to suppress pSC autoimmunity by transgenic expression of the negative costimulatory molecule B7-H1 in NOD pSC. RESEARCH DESIGN AND METHODS: A B7-H1 transgene was placed under control of the glial fibrillary acidic protein (GFAP) promoter. Transgenic and wild-type NOD mice were compared for transgene PD-1 affinities, diabetes development, insulitis, and pSC survival. Mechanistic studies included adoptive type 1 diabetes transfer, B7-H1 blockade, and T-cell autoreactivity and sublineage distribution. RESULTS: Transgenic and endogenous B7-H1 bound PD-1 with equal affinities. Unexpectedly, the transgene generated islet-selective CD8(+) bias with accelerated rather than suppressed diabetes progression. T-cells of diabetic transgenics transferred type 1 diabetes faster. There were no earlier pSC losses due to conceivable transgene toxicity, but transgenic pSC loss was enhanced by 8 weeks, preceded by elevated GFAP autoreactivity, with high-affinity T-cells targeting the major NOD K(d)-GFAP epitope, p253-261. FoxP3(+) regulatory T- and CD11c(+) dendritic cell pools were unaffected. CONCLUSIONS: In contrast with transgenic B7-H1 in NOD mouse ß-cells, transgenic B7-H1 in pSC promotes rather than protects from type 1 diabetes. Here, ectopic B7-H1 enhanced the pathogenicity of effector T-cells, demonstrating that pSC can actively impact diabetes progression-likely through modification of intraislet T-cell selection. Although pSC cells emerge as a new candidate for therapeutic targets, caution is warranted with regard to the B7-H1-PD1 axis, where B7-H1 overexpression can lead to accelerated autoimmune disease.

A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis.

OBJECTIVE: Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk, but the therapeutic potential of vitamin D in established MS has not been explored. Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical, immunologic, and clinical outcomes in patients with MS prospectively. METHODS: An open-label randomized prospective controlled 52-week trial matched patients with MS for demographic and disease characteristics, with randomization to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks), and further downtitrated to 0 IU/day. Calcium (1,200 mg/day) was given throughout the trial. Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups. Secondary endpoints included 25(OH)D and other biochemical measures, immunologic biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score. RESULTS: Forty-nine patients (25 treatment, 24 control) were enrolled [mean age 40.5 years, EDSS 1.34, and 25(OH)D 78 nmol/L]. All calcium-related measures within and between groups were normal. Despite a mean peak 25(OH)D of 413 nmol/L, no significant adverse events occurred. Although there may have been confounding variables in clinical outcomes, treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls. CONCLUSIONS: High-dose vitamin D (approximately 10,000 IU/day) in multiple sclerosis is safe, with evidence of immunomodulatory effects. CLASSIFICATION OF EVIDENCE: This trial provides Class II evidence that high-dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high-dose supplementation. The trial, however, lacked statistical precision and the design requirements to adequately assess changes in clinical disease measures (relapses and Expanded Disability Status Scale scores), providing only Class level IV evidence for these outcomes.

Radiation-induced premelting of ice at silica interfaces.

The existence of surface and interfacial melting of ice below 0 degrees C has been confirmed by many different experimental techniques. Here we present a high-energy x-ray reflectivity study of the interfacial melting of ice as a function of both temperature and x-ray irradiation dose. We found a clear increase of the thickness of the quasiliquid layer with the irradiation dose. By a systematic x-ray study, we have been able to unambiguously disentangle thermal and radiation-induced premelting phenomena. We also confirm the previously announced very high water density (1.25 g/cm(3)) within the emerging quasiliquid layer.

Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes.

OBJECTIVE: In patients with long-standing type 1 diabetes, we investigated whether improved beta-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote beta-cell growth and/or limit beta-cell apoptosis and 2) weaken the anti-beta-cell autoimmunity. RESEARCH DESIGN AND METHODS: For this study, 20 individuals (mean age 39.5 +/- 11.1 years) with long-standing type 1 diabetes (21.3 +/- 10.7 years) were enrolled in this prospective open-label crossover trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide. RESULTS: In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels >or=0.05 ng/ml (0.02 nmol/l) were found. Residual beta-cells responded to physiological (mixed-meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 +/- 2.9 kg body wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 +/- 0.11 vs. 0.55 +/- 0.13 units x kg(-1) x day(-1) without exenatide; P = 0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion. CONCLUSIONS: In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving beta-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining beta-cells.

Validity and reproducibility of measurement of islet autoreactivity by T-cell assays in subjects with early type 1 diabetes.

OBJECTIVE: Type 1 diabetes results from an immunemediated destruction of beta-cells, likely to be mediated by T lymphocytes, but the sensitivity, specificity, and other measures of validity of existing assays for islet autoreactive T-cells are not well established. Such assays are vital for monitoring responses to interventions that may modulate disease progression. RESEARCH DESIGN AND METHODS: We studied the ability of cellular assays to discriminate responses in patients with type 1 diabetes and normal control subjects in a randomized blinded study in the U.S. and U.K. We evaluated the reproducibility of these measurements overall and to individual analytes from repeat collections. RESULTS: Responses in the cellular immunoblot, U.K.-ELISPOT, and T-cell proliferation assays could differentiate patients from control subjects with odds ratios of 21.7, 3.44, and 3.36, respectively, with sensitivity and specificity as high as 74 and 88%. The class II tetramer and U.S. ELISPOT assays performed less well. Despite the significant association of the responses with type 1 diabetes, the reproducibility of the measured responses, both overall and individual analytes, was relatively low. Positive samples from normal control subjects (i.e., false positives) were generally isolated to single assays. CONCLUSIONS: The cellular immunoblot, U.K.-ELISPOT, and T-cell proliferation assays can distinguish responses from patients with type 1 diabetes and healthy control subjects. The limited reproducibility of the measurements overall and of responses to individual analytes may reflect the difficulty in detection of low frequency of antigen-specific T-cells or variability in their appearance in peripheral blood.

Obesity predisposes to Th17 bias.

Obesity is associated with numerous inflammatory conditions including atherosclerosis, autoimmune disease and cancer. Although the precise mechanisms are unknown, obesity-associated rises in TNF-alpha, IL-6 and TGF-beta are believed to contribute. Here we demonstrate that obesity selectively promotes an expansion of the Th17 T-cell sublineage, a subset with prominent pro-inflammatory roles. T-cells from diet-induced obese mice expand Th17 cell pools and produce progressively more IL-17 than lean littermates in an IL-6-dependent process. The increased Th17 bias was associated with more pronounced autoimmune disease as confirmed in two disease models, EAE and trinitrobenzene sulfonic acid colitis. In both, diet-induced obese mice developed more severe early disease and histopathology with increased IL-17(+) T-cell pools in target tissues. The well-described association of obesity with inflammatory and autoimmune disease is mechanistically linked to a Th17 bias.

Normalization of obesity-associated insulin resistance through immunotherapy.

Obesity and its associated metabolic syndromes represent a growing global challenge, yet mechanistic understanding of this pathology and current therapeutics are unsatisfactory. We discovered that CD4(+) T lymphocytes, resident in visceral adipose tissue (VAT), control insulin resistance in mice with diet-induced obesity (DIO). Analyses of human tissue suggest that a similar process may also occur in humans. DIO VAT-associated T cells show severely biased T cell receptor V(alpha) repertoires, suggesting antigen-specific expansion. CD4(+) T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon-gamma (IFN-gamma)-secreting T helper type 1 (T(H)1) cells, overwhelming static numbers of T(H)2 (CD4(+)GATA-binding protein-3 (GATA-3)(+)) and regulatory forkhead box P3 (Foxp3)(+) T cells. CD4(+) (but not CD8(+)) T cell transfer into lymphocyte-free Rag1-null DIO mice reversed weight gain and insulin resistance, predominantly through T(H)2 cells. In obese WT and ob/ob (leptin-deficient) mice, brief treatment with CD3-specific antibody or its F(ab')(2) fragment, reduces the predominance of T(H)1 cells over Foxp3(+) cells, reversing insulin resistance for months, despite continuation of a high-fat diet. Our data suggest that the progression of obesity-associated metabolic abnormalities is under the pathophysiological control of CD4(+) T cells. The eventual failure of this control, with expanding adiposity and pathogenic VAT T cells, can successfully be reversed by immunotherapy.

Shape changes of supported Rh nanoparticles during oxidation and reduction cycles.

The microscopic insight into how and why catalytically active nanoparticles change their shape during oxidation and reduction reactions is a pivotal challenge in the fundamental understanding of heterogeneous catalysis. We report an oxygen-induced shape transformation of rhodium nanoparticles on magnesium oxide (001) substrates that is lifted upon carbon monoxide exposure at 600 kelvin. A Wulff analysis of high-resolution in situ x-ray diffraction, combined with transmission electron microscopy, shows that this phenomenon is driven by the formation of a oxygen-rhodium-oxygen surface oxide at the rhodium nanofacets. This experimental access into the behavior of such nanoparticles during a catalytic cycle is useful for the development of improved heterogeneous catalysts.

Incommensurate strain-induced ordering of interstitial oxygen in Nb.

We present a semi-phenomenological theory of the strain-induced interaction between interstitial oxygen dissolved in Nb and predict an incommensurate oxygen ordering wave which is mediated by the intrinsic bcc instability at k = 2/3(111). We discuss the stability range of this ordering phenomenon, which may play a role in the performance of Nb radio frequency (RF) cavities for high energy particle accelerators.

'Sensing' autoimmunity in type 1 diabetes.

Type 1 diabetes (T1D) results from autoimmune-mediated loss of insulin-producing beta-cells. Recent findings suggest that the events controlling T1D development are not only immunological, but also neuronal in nature. In the non-obese diabetic (NOD) mouse model of T1D, a mutant sensory neuron channel, TRPV1, initiates chronic, progressive beta-cell stress, inducing islet cell inflammation. This novel mechanism of organ-specific damage requires a permissive, autoimmune-prone host, but ascribes tissue specificity to the local secretory dysfunction of sensory afferent neurons. In NOD mice, normalizing this neuronal function by administration of the neurotransmitter substance P clears islet cell inflammation, reduces insulin resistance and restores normoglycemia. Here, we discuss this neuro-immuno-endocrine model, its implications and the involvement of sensory neurons in other autoimmune disorders. These developments might provide novel neuronal-based therapeutic interventions, particularly in diabetes.