Coherent terabit communications with microresonator Kerr frequency combs

Optical frequency combs enable coherent data transmission on hundreds of wavelength channels and have the potential to revolutionize terabit communications. Generation of Kerr combs in nonlinear integrated microcavities represents a particularly promising option enabling line spacings of tens of GHz, compliant with wavelength-division multiplexing (WDM) grids. However, Kerr combs may exhibit strong phase noise and multiplet spectral lines, and this has made high-speed data transmission impossible up to now. Recent work has shown that systematic adjustment of pump conditions enables low phase-noise Kerr combs with singlet spectral lines. Here we demonstrate that Kerr combs are suited for coherent data transmission with advanced modulation formats that pose stringent requirements on the spectral purity of the optical source. In a first experiment, we encode a data stream of 392 Gbit/s on subsequent lines of a Kerr comb using quadrature phase shift keying (QPSK) and 16-state quadrature amplitude modulation (16QAM). A second experiment shows feedback-stabilization of a Kerr comb and transmission of a 1.44 Tbit/s data stream over a distance of up to 300 km. The results demonstrate that Kerr combs can meet the highly demanding requirements of multi-terabit/s coherent communications and thus offer a solution towards chip-scale terabit/s transceivers

Analyse der Rolle der IL-23/Th17 Achse während B-Zell vermittelter Autoimmunität

Rheumatoid arthritis (RA) is a common autoimmune disease. Early RA is characterized by an initial break in immunological tolerance, the appearance of specific autoantibodies and a phase of “asymptomatic autoimmunity”. Finally, RA shifts into a state of active disease and manifests itself in autoantibody-mediated chronic synovitis which leads to cartilage and bone destruction. Apart from autoantibodies, the IL-23/Th17 axis has been identified as a major driving force during RA pathogenesis. The exact contribution of the IL-23/Th17 axis, however, has remained incompletely understood. Multiple “hits” through infectious agents and other environmental factors are suggested to be responsible for the transition from asymptomatic autoimmunity into active RA. However, checkpoints and mechanisms regulating this transition still remain obscure. In this work, we aimed to elucidate the role of the IL-23/Th17 axis during the pathogenesis of autoimmune arthritis. Therefore, we dissected the role of IL-23 during the initial break of tolerance and during the autoantibody mediated joint inflammation. Here we report, that the IL-23/Th17 axis does not directly contribute to antibody induced joint inflammation. Instead, IL-23 was found to be decisively involved in orchestrating the transition from asymptomatic autoimmunity into chronic autoimmune disease. Prior to the onset of experimental arthritis Th17 cells accumulated inside germinal centers of secondary lymphatic organs. There, IL-23 activated Th17 cells increased the pro-inflammatory activity of autoreactive antibodies by suppressing the expression of-galactoside 2,6 sialyltransferase (st6gal1) in developing plasma cells in a IL-21 and IL-22 dependent manner. Subsequently, autoantigen specific IgG glycosylation shifted towards a pro-inflammatory status which triggers the onset of arthritis. Similarly, plasmablasts from RA patients show a decreased st6gal1 activity compared to healthy control. IgG from these individuals showed corresponding changes in its glycosylation profile and inflammatory activity. The work presented in this thesis identifies a so far unrecognized mechanism by which Th17 cells unmask a preexisting breach in humoral tolerance and initiate the transition from a stage of asymptomatic autoimmunity into inflammatory autoimmune disease. The key findings of the work presented here have previously been published in Nature Immunology (Pfeifle et al. 20171).Rheumatoide Arthritis (RA) ist eine der häufigsten Autoimmunerkrankungen. Sie äußert sich typischerweise in der Form einer symmetrischen Polyarthritis und befällt zumeist die kleinen diarthrodialen Gelenke an Hand und Fuß. Dort verursachen Antikörper gegen körpereigene Proteine chronische Entzündungen des Synoviums und führen letztendlich zu irreversibler Schädigung der betroffenen Gelenke. Diese Autoantikörper markieren den Beginn einer „asymptomatischen Phase“, welche bis zu 10 Jahre andauern kann. Aus bisher ungeklärten Gründen kommt es im Verlauf der Erkrankung zum Ausbruch einer chronischen Synovitis. Bemerkenswerterweise lassen sich vor dem Auftreten erster klinischer Symptome Veränderungen in der Glycanstruktur der funktionsvermittelnden Fc Teile der Autoantikörper feststellen. Die endständige Sialylierung dieser Fc Glycane nimmt ab, wodurch den betreffenden Antikörpern die Fähigkeit abhandenkommt an anti-inflammatorische Rezeptoren zu binden. Stattdessen werden verstärkt pro-inflammatorische Rezeptoren aktiviert und das Krankheitsbild verschiebt sich von befundloser Autoimmunität zur rheumatoiden Arthritis. Warum und aufgrund welcher Mechanismen sich diese Glycanstrukturen auf den Autoantikörpern ändern, war jedoch bisher unverstanden. In dieser Arbeit zeigen wir, dass die IL-23/Th17 Achse, während der entzündlichen Phase der Arthritis nicht direkt involviert ist. Stattdessen war IL-23 unverzichtbar für die Entwicklung pathogener Antikörper. Während der prodromalen Phase der Arthritis wurde beobachtet, dass Th17 Zellen in den Keimzentren sekundär lymphatischer Organe akkumulieren. Diese durch das Zytokin IL-23 aktivierten Th17 Zellen waren in der Lage mittels IL-21 und IL-22 die Expression der -galactoside 2,6 sialyltransferase (st6gal1) in sich entwickelnden Plasmazellen zu hemmen. Dies führte zu einer verminderten Sialylierung an den Fc Teilen von Autoantikörpern. Diese „desialylierten“ Autoantikörper hatten in vitro eine höhere inflammatorische Aktivität und lösten in vivo eine Arthritis aus. Durch die Neutralisierung von IL-23 während der prodromalen Phase der Arthritis, oder durch enzymatische Sialylierung der betreffenden Autoantikörper konnte dies verhindert werden. Im Rahmen dieser Arbeit konnte eine bisher unbekannte Funktion der IL-23/Th17 Achse aufgezeigt werden, welche Autoantikörper eine pro-inflammatorische, arthritogene Funktion verleiht. Hierdurch nun kann ein bereits existierender Bruch der immunologischen Toleranz zu Tage treten und den Übergang von asymptomatischer Autoimmunität zur inflammatorischen Autoimmun-erkrankung bewirken. Ähnlich der Situation im Tiermodell, konnte in dieser Arbeit auch bei RA Patienten eine verminderte Aktivität des Enzyms St6gal1 nachgewiesen werden. Gleichsam wurden bei RA Patienten eine verminderte Fc-Sialylierung und eine erhöhte inflammatorische Aktivität festgestellt. Darüber hinaus konnte bei Personen unmittelbar vor dem Auftreten erster Symptome eine Desialierung spezifischer Autoantikörper beobachtet werden. Dies legt nahe, dass es im humanen System einen ähnlichen Mechanismus gibt, welcher die Aktivität der Autoantikörper kurz vor dem Ausbruch einer aktiven RA reguliert. Dieser Arbeit bietet eine molekulare Erklärung für den Übergang von asymptomatischer Autoimmunität zur aktiven RA. Darüber hinaus liefert sie Hinweise auf neue therapeutische Möglichkeiten bei der Behandlung dieser Erkrankung. Ausgehend von den hier vorliegenden Daten ist eine Neutralisation von IL-23 während einer aktiven Arthritis wenig erfolgversprechend, da hiermit der Antikörper vermittelten Entzündung nicht mehr Einhalt geboten werden kann. Da die IL-23/Th17 Achse jedoch den Übergang von beschwerdefreier Autoimmunität zu aktiven Arthritis vermittelt, könnte die Neutralisation präventiv eingesetzt werden. Darüber könnte der Erhalt der Remission nach Rituximab Behandlung durch IL-23 Depletion unterstützt werden. Teile dieser Arbeit wurden 2016 in Nature Immunology veröffentlicht 1

Novel mechanism mediated by the IL-23/Th17 axis contributing to auto-immune arthritis

Background Checkpoints and mechanisms regulating the onset of rheumatoid arthritis (RA) remain largely elusive. Apart from B cells and auto-antibodies, Th17 cells were shown to critically contribute to disease development. Mice lacking IL-23, a cytokine controlling the pathogenicity of Th17 cells, are completely protected against arthritis. Yet, the exact role of the IL-23/Th17 axis during this autoantibody-driven disease remain incompletely understood. Material and methods IL23A-/- mice and mice receiving an IL23 blocking antibody were analysed during active and passive arthritis models including collagen-induced arthritis (CIA), the K/BxN arthritis model, collagen-antibody induced arthritis (CAIA) and K/BxN-serum transfer arthritis. Both clinical, histological and immunological parameters of arthritis were assessed. IgG glycosylation was analysed using the MALDI-TOF technique. IgG activity was determined by measuring the cytokine release of immune-complex-stimulated myeloid cells. To study the crosstalk between B cells and Th17 cells, co-culture experiments were performed. Results Here we report, that the IL-23/Th17 axis did not directly contribute to auto-antibody induced inflammation within inflamed joints, but controlled the glycosylation profile and inflammatory activity of auto-antibodies during the prodromal phase of disease. Th17 cells were found to accumulate in germinal centres auf secondary lymphatic organs prior to onset of experimental arthritis, where they suppressed the expression of β-glactoside α2,6-sialyltransferase 1 (St6gal1) in differentiating plasmablasts. The consecutive change in the immunoglobulin G (IgG) glycosylation profile provoked a shift towards a pro-inflammatory autoantibody repertoire and triggered the inflammatory phase of arthritis. Plasmablasts of RA patients similarly displayed a decreased St6gal1 activity, while IgG from these individuals showed corresponding changes in its glycosylation profile as well as an increased inflammatory activity, suggesting that related pathways might contribute to onset and progression of autoantibody-mediated diseases in humans. Conclusion Our current findings identify a novel IL-23/Th17-dependent checkpoint that controls autoantibody activity, unmasks a preexisting breach in humoral tolerance, and initiates the transition from a stage of asymptomatic autoimmunity into inflammatory autoimmune disease

Novel mechanism mediated by the IL23/TH17 axis contributing to auto-immune arthritis

Background Checkpoints and mechanisms regulating the onset of rheumatoid arthritis (RA) remain largely elusive. Apart from B cells and auto-antibodies, Th17 cells were shown to critically contribute to disease development. Mice lacking IL-23, a cytokine controlling the pathogenicity of Th17 cells, are completely protected against arthritis. Yet, the exact role of the IL-23/Th17 axis during this autoantibody-driven disease remain incompletely understood. Material and methods IL23A-/- mice and mice receiving an IL23 blocking antibody were analysed during active and passive arthritis models including collagen-induced arthritis (CIA), the K/BxN arthritis model, collagen-antibody induced arthritis (CAIA) and K/BxN-serum transfer arthritis. Both clinical, histological and immunological parameters of arthritis were assessed. IgG glycosylation was analysed using the MALDI-TOF technique. IgG activity was determined by measuring the cytokine release of immune-complex-stimulated myeloid cells. To study the crosstalk between B cells and Th17 cells, co-culture experiments were performed. Results Here we report, that the IL-23/Th17 axis did not directly contribute to auto-antibody induced inflammation within inflamed joints, but controlled the glycosylation profile and inflammatory activity of auto-antibodies during the prodromal phase of disease. Th17 cells were found to accumulate in germinal centres auf secondary lymphatic organs prior to onset of experimental arthritis, where they suppressed the expression of β-glactoside α2,6-sialyltransferase 1 (St6gal1) in differentiating plasmablasts. The consecutive change in the immunoglobulin G (IgG) glycosylation profile provoked a shift towards a pro-inflammatory autoantibody repertoire and triggered the inflammatory phase of arthritis. Plasmablasts of RA patients similarly displayed a decreased St6gal1 activity, while IgG from these individuals showed corresponding changes in its glycosylation profile as well as an increased inflammatory activity, suggesting that related pathways might contribute to onset and progression of autoantibody-mediated diseases in humans. Conclusion Our current findings identify a novel IL-23/Th17-dependent checkpoint that controls autoantibody activity, unmasks a preexisting breach in humoral tolerance, and initiates the transition from a stage of asymptomatic autoimmunity into inflammatory autoimmune disease

Performance of a proposed event-type based analysis for the Cherenkov Telescope Array

The Cherenkov Telescope Array (CTA) will be the next-generation observatory in the field of very-high-energy (20 GeV to 300 TeV) gamma-ray astroparticle physics. Classically, data analysis in the field maximizes sensitivity by applying quality cuts on the data acquired. These cuts, optimized using Monte Carlo simulations, select higher quality events from the initial dataset. Subsequent steps of the analysis typically use the surviving events to calculate one set of instrument response functions (IRFs). An alternative approach is the use of event types, as implemented in experiments such as the Fermi-LAT. In this approach, events are divided into sub-samples based on their reconstruction quality, and a set of IRFs is calculated for each sub-sample. The sub-samples are then combined in a joint analysis, treating them as independent observations. This leads to an improvement in performance parameters such as sensitivity, angular and energy resolution. Data loss is reduced since lower quality events are included in the analysis as well, rather than discarded. In this study, machine learning methods will be used to classify events according to their expected angular reconstruction quality. We will report the impact on CTA high-level performance when applying such an event-type classification, compared to the classical procedure

Chasing Gravitational Waves with the Chereknov Telescope Array

Presented at the 38th International Cosmic Ray Conference (ICRC 2023), 2023 (arXiv:2309.08219)2310.07413International audienceThe detection of gravitational waves from a binary neutron star merger by Advanced LIGO and Advanced Virgo (GW170817), along with the discovery of the electromagnetic counterparts of this gravitational wave event, ushered in a new era of multimessenger astronomy, providing the first direct evidence that BNS mergers are progenitors of short gamma-ray bursts (GRBs). Such events may also produce very-high-energy (VHE, > 100GeV) photons which have yet to be detected in coincidence with a gravitational wave signal. The Cherenkov Telescope Array (CTA) is a next-generation VHE observatory which aims to be indispensable in this search, with an unparalleled sensitivity and ability to slew anywhere on the sky within a few tens of seconds. New observing modes and follow-up strategies are being developed for CTA to rapidly cover localization areas of gravitational wave events that are typically larger than the CTA field of view. This work will evaluate and provide estimations on the expected number of of gravitational wave events that will be observable with CTA, considering both on- and off-axis emission. In addition, we will present and discuss the prospects of potential follow-up strategies with CTA