Nano-film functionalized exposed core fibers enabling resonance-driven dispersive wave tailoring

Light sources with specific optical properties are the backbone of optical technologies such as spectroscopy or hyperspectral imaging. Yet, the creation of broadband, stable, and spectrally flat light sources, especially at low pump energies, remains a particular challenge. Supercontinuum generation (SCG) is a well-established method for broadband light generation in optical fibers. For tailorable SCG spectra, it is essential to accurately design and precisely control the dispersion of fibers with new methods. This thesis aims to explore nonlinear frequency conversion in resonance-enhanced fibers to create tunable broadband light sources with tailored properties at low pump energies. By depositing high refractive index nano-films with different thicknesses on the surface of the exposed fiber core, the dispersion of the fibers and thus the output spectrum of SCG can be tuned. Different nano-film geometries are investigated, featuring TiO2 nano-films with a uniform thickness, Ta2O5 nano-films with a gradually increasing thickness along the fiber length, and periodically structured Ta2O5 nano-films. Experiments and simulations reveal the advantages of a longitudinally varying dispersion over uniformly coated fibers concerning an enhanced spectral flatness and an enlarged bandwidth. Furthermore, periodically structured nano-films lead to multi-color tailorable higher-order dispersive waves via quasi phase-matching, which are outside of the wavelength range of classical soliton-based SCG. Resonance-based modifications of the fiber dispersion by using nano-films are a powerful new tool to efficiently shape nonlinear frequency conversion in SCG even at low pump energies. It has high technological potential for the realization of novel, ultrafast, broadband, and stable nonlinear light sources for biophotonics, environmental, life sciences, medical diagnostics, and metrology

Evaluation of the therapeutic potential of ant-TLR4-antibody MTS510 in experimental stroke and significa of different routes of application

Toll-like receptors (TLRs) are central sensors for the inflammatory response in ischemia-reperfusion injury. We therefore investigated whether TLR4 inhibition could be used to treat stroke in a standard model of focal cerebral ischemia. Anti-TLR4/MD2-antibody (mAb clone MTS510) blocked TLR4-induced cell activation in vitro, as reported previously. Here, different routes of MTS510 application in vivo were used to study the effects on stroke outcome up to 2d after occlusion of the middle cerebral artery (MCAO) for 45 min in adult male C57Bl/6 wild-type mice. Improved neurological performance, reduced infarct volumes, and reduced brain swelling showed that intravascular application of MTS510 had a protective effect in the model of 45 min MCAO. Evaluation of potential long-term adverse effects of anti-TLR4-mAb-treament revealed no significant deleterious effect on infarct volumes nor neurological deficit after 14d of reperfusion in a mild model of stroke (15 min MCAO). Interestingly, inhibition of TLR4 resulted in an altered adaptive immune response at 48 hours after reperfusion. We conclude that blocking TLR4 by the use of specific mAb is a promising strategy for stroke therapy. However, long-term studies with increased functional sensitivity, larger sampling sizes and use of other species are required before a clinical use could be envisaged

Electric current-driven spectral tunability of surface plasmon polaritons in gold coated tapered fibers

Here we introduce the concept of electrically tuning surface plasmon polaritons using current-driven heat dissipation, allowing controlling plasmonic properties via a straightforward-to-access quantity. The key idea is based on an electrical current flowing through the plasmonic layer, changing plasmon dispersion and phase-matching condition via a temperature-imposed modification of the refractive index of one of the dielectric media involved. This scheme was experimentally demonstrated on the example of an electrically connected plasmonic fiber taper that has sensitivities >50000 nm/RIU. By applying a current, dissipative heat generated inside metal film heats the surrounding liquid, reducing its refractive index correspondingly and thus modifying the phase-matching condition to the fundamental taper mode. We observed spectral shifts of the plasmonic resonance up to 300 nm towards shorter wavelength by an electrical power of ≤ 80 mW, clearly showing that our concept is important for applications that demand precise real-time and external control on plasmonic dispersion and resonance wavelengths

Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Regulates the Unfolding of Autoimmune Diabetes

Evidence has been accumulating that shows that insulin-dependent diabetes is subject to immunoregulation. To determine whether cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is involved, we injected anti–CTLA-4 mAb into a TCR transgenic model of diabetes at different stages of disease. When injected into young mice, months before they would normally become diabetic, anti–CTLA-4 induced diabetes rapidly and essentially universally; this was not the result of a global activation of T lymphocytes, but did reflect a much more aggressive T cell infiltrate in the pancreatic islets. These effects were only observed if anti–CTLA-4 was injected during a narrow time window, before the initiation of insulitis. Thus, engagement of CTLA-4 at the time when potentially diabetogenic T cells are first activated is a pivotal event; if engagement is permitted, invasion of the islets occurs, but remains quite innocuous for months, if not, insulitis is much more aggressive, and diabetes quickly ensues

Understanding Nonlinear Pulse Propagation in Liquid Strand-Based Photonic Bandgap Fibers

Ultrafast supercontinuum generation crucially depends on the dispersive properties of the underlying waveguide. This strong dependency allows for tailoring nonlinear frequency conversion and is particularly relevant in the context of waveguides that include geometry-induced resonances. Here, we experimentally uncovered the impact of the relative spectral distance between the pump and the bandgap edge on the supercontinuum generation and in particular on the dispersive wave formation on the example of a liquid strand-based photonic bandgap fiber. In contrast to its air-hole-based counterpart, a bandgap fiber shows a dispersion landscape that varies greatly with wavelength. Particularly due to the strong dispersion variation close to the bandgap edges, nanometer adjustments of the pump wavelength result in a dramatic change of the dispersive wave generation (wavelength and threshold). Phase-matching considerations confirm these observations, additionally revealing the relevance of third order dispersion for interband energy transfer. The present study provides additional insights into the nonlinear frequency conversion of resonance-enhanced waveguide systems which will be relevant for both understanding nonlinear processes as well as for tailoring the spectral output of nonlinear fiber sources

Topological Requirements and Signaling Properties of T Cell–activating, Anti-CD28 Antibody Superagonists

Full activation of naive T cells requires both engagement of the T cell antigen receptor (TCR; signal 1) and costimulatory signaling by CD28 (signal 2). We previously identified two types of rat CD28-specific monoclonal antibodies (mAbs): “conventional,” TCR signaling–dependent costimulatory mAbs and “superagonistic” mAbs capable of inducing the full activation of primary resting T cells in the absence of TCR ligation both in vitro and in vivo. Using chimeric rat/mouse CD28 molecules, we show that the superagonists bind exclusively to the laterally exposed C′′D loop of the immunoglobulin-like domain of CD28 whereas conventional, costimulatory mAbs recognize an epitope close to the binding site for the natural CD80/CD86 ligands. Unexpectedly, the C′′D loop reactivity of a panel of new antibodies raised against human CD28 could be predicted solely on the basis of their superagonistic properties. Moreover, mouse CD28 molecules engineered to express the rat or human C′′D loop sequences activated T cell hybridomas without TCR ligation when cross-linked by superagonistic mAbs. Finally, biochemical analysis revealed that superagonistic CD28 signaling activates the nuclear factor κB pathway without inducing phosphorylation of either TCRζ or ZAP70. Our findings indicate that the topologically constrained interactions of anti-CD28 superagonists bypass the requirement for signal 1 in T cell activation. Antibodies with this property may prove useful for the development of T cell stimulatory drugs

Therapeutic and Adverse Effects of a Non-Steroidal Glucocorticoid Receptor Ligand in a Mouse Model of Multiple Sclerosis

-methyl-ethylammonium chloride (CpdA), a dissociating non-steroidal GR ligand, in the context of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).. Administration of high-dose CpdA to mice was lethal while treatment of EAE with low to intermediate amounts of CpdA dissolved in water significantly ameliorated the disease. The beneficial effect of CpdA required expression of the GR in T cells and was achieved by down regulating LFA-1 and CD44 on peripheral Th cells and by repressing IL-17 production.. Hence, non-steroidal GR ligands require careful analysis prior to their translation into new therapeutic concepts

Tailored multi-color dispersive wave formation in quasi-phase-matched exposed core fibers

Published online: January 17, 2022Widely wavelength-tunable femtosecond light sources in a compact, robust footprint play a central role in many prolific research fields and technologies, including medical diagnostics, biophotonics, and metrology. Fiber lasers are on the verge in the development of such sources, yet widespan spectral tunability of femtosecond pulses remains a pivotal challenge. Dispersive wave generation, also known as Cherenkov radiation, offers untapped potentials to serve these demands. In this work, the concept of quasi-phase matching for multi-order dispersive wave formation with record-high spectral fidelity and femtosecond durations is exploited in selected, partially conventionally unreachable spectral regions. Versatile patterned sputtering is utilized to realize height-modulated high-index nano-films on exposed fiber cores to alter fiber dispersion to an unprecedented degree through spatially localized, induced resonances. Nonlinear optical experiments and simulations, as well as phase-mismatching considerations based on an effective dispersion, confirm the conversion process and reveal unique emission features, such as almost power-independent wavelength stability and femtosecond duration. This resonance-empowered approach is applicable to both fiber and on-chip photonic systems and paves the way to instrumentalize dispersive wave generation as a unique tool for efficient, coherent femtosecond multi-frequency conversion for applications in areas such as bioanalytics, life science, quantum technology, or metrology.Tilman A.K. Lühder, Mario Chemnitz, Henrik Schneidewind, Erik P. Schartner, Heike Ebendorff-Heidepriem, and Markus A. Schmid

Factors predisposing to humoral autoimmunity against brain-antigens in health and disease Analysis of 49 autoantibodies in over 7000 subjects

Background:Circulating autoantibodies (AB) against brain-antigens, often deemed pathological, receive increasing attention. We assessed predispositions and seroprevalence/characteristics of 49 AB in >7000 individuals.Methods:Exploratory cross-sectional cohort study, investigating deeply phenotyped neuropsychiatric patients and healthy individuals of GRAS Data Collection for presence/characteristics of 49 brain-directed serum-AB. Predispositions were evaluated through GWAS of NMDAR1-AB carriers, analyses of immune check-point genotypes, APOE4 status, neurotrauma. Chi-square, Fisher’s exact tests and logistic regression analyses were used.Results:Study of N=7025 subjects (55.8% male; 41±16 years) revealed N=1133 (16.13%) carriers of any AB against 49 defined brain-antigens. Overall, age dependence of seroprevalence (OR=1.018/year; 95% CI [1.015-1.022]) emerged, but no disease association, neither general nor with neuropsychiatric subgroups. Males had higher AB seroprevalence (OR=1.303; 95% CI [1.144-1.486]). Immunoglobulin class (N for IgM:462; IgA:487; IgG:477) and titers were similar. Abundant were NMDAR1-AB (7.7%). Low seroprevalence (1.25%-0.02%) was seen for most AB (e.g. amphiphysin, KCNA2, ARHGAP26, GFAP, CASPR2, MOG, Homer-3, KCNA1, GLRA1b, GAD65). Non-detectable were others. GWAS of NMDAR1-AB carriers revealed three genome-wide significant SNPs, two intergenic, one in TENM3, previously autoimmune disease-associated. Targeted analysis of immune check-point genotypes (CTLA4, PD1, PD-L1) uncovered effects on humoral anti-brain autoimmunity (OR=1.55; 95% CI [1.058-2.271]) and disease likelihood (OR=1.43; 95% CI [1.032-1.985]). APOE4 carriers (∼19%) had lower seropositivity (OR=0.766; 95% CI [0.625-0.933]). Neurotrauma predisposed to NMDAR1-AB seroprevalence (IgM: OR=1.599; 95% CI [1.022-2.468]).Conclusions:Humoral autoimmunity against brain-antigens, frequent across health and disease, is predicted by age, gender, genetic predisposition, and brain injury. Seroprevalence, immunoglobulin class, or titers do not predict disease