Phytochemical profiling of oak bark extract: A combined approach using near-infrared spectroscopy and liquid chromatography-mass spectrometry.

The aim of the presented study was to qualitatively and quantitatively determine the chemical composition of oak bark extracts in order to gain insights into the effectiveness as alternative medication for various diseases. The primary emphasis was on developing a near-infrared spectroscopy (NIRS) method for precise quantification of two key polyphenolic compounds, specifically gallic acid and catechin, in form of a fast and non-destructive quality control. A comprehensive dataset consisting of 48 samples from various production batches was analyzed throughout this research. Qualitative analysis was conducted using High Performance Liquid Chromatography coupled with a mass detector (LC-MS) to separate and identify individual components of the oak bark extract. Individual components were identified, confirmed and quantified using existing literature combined with appropriate standard references. Whereas the predominant nature of identified substances was of polyphenolic nature. Furthermore, a semi-quantitative assessment was additionally performed for eight identified constituents to identify their chemical stability or possible occurring transformations during storage, utilizing quantification via internal standard met in order to identify fluctuations and chemical variability within oakbark, five key components were precisely quantified using LC-MS and corresponding standard substances. For this purpose, HPLC measurements coupled to an Ultraviolet/Visible (UV/Vis) detector were utilized as reference method. NIRS measurements were performed on a FT-NIR benchtop device in transmission mode. Partial least squares regression (PLSR) was then applied for model building, after identifying the optimal spectral pretreatment. Model evaluation was performed using leave-one-out-cross validation followed by evaluation of an independent test set. The model proved promising results for the quantification of gallic acid on the benchtop device with a standard error of cross validation (SECV) of 13.41 mg/L and a standard error of prediction (SEP) of 19.33 mg/L, while the absolute concentrations of the different batches analyzed ranged from 126.49 to 332.54 mg/L. For the quantification of catechin the SECV was reported at 23.61 mg/L, the SEP at 32.35 mg/L with sample concentrations falling between 13.50 and 383.72 mg/L. In this study, we introduce various analytical methodologies for both qualitative and quantitative assessment of a complex phytochemical sample, specifically oak bark extract, aimed at identifying and confirming the presence of active compounds within the extract.

Exhausted Lag-3+ CD4+ T cells are increased in pediatric Inflammatory Bowel Disease.

T cells are one of the main drivers of inflammatory bowel diseases (IBD). Infliximab (IFX) is used in the treatment of IBD as an anti-inflammatory drug to induce remission by neutralizing TNFα. We determined the individual chemokine/homing receptor and cytokine profile in pediatric IBD patients before and during IFX therapy to identify predictive biomarkers for therapy success. Peripheral blood CD4+ cells from pediatric patients with IBD were immunomagnetically isolated and either directly analyzed by FACS for cell distribution and chemokine/homing receptor expression or evaluated for cytokine production after in-vitro-stimulation. 21 responders (RS) and 21 non-responders (NRS) were recruited. Before IFX therapy, flow cytometry revealed decreased percentages of naïve conventional T cells in pediatric IBD patients. The proportions of CD62-L+ T cells were decreased in both CD and UC therapy responders. The cytokine profile of T cells was highly altered in IBD patients compared to healthy controls (HC). During IFX therapy, the frequencies of conventional memory and regulatory memory T cells expanded in both cohorts. IFX response was marked by a decrease of α4ß7+ and IFNγ+ memory T cells in both CD and UC. In contrast, frequencies of Lag-3+ T cells proved to be significantly increased in NRS. These observations were irrespective of the underlying disease. T cells of pediatric IBD patients display an activated and rather Th1/Th17 shifted phenotype The increased expression of the checkpoint molecule Lag-3 on T cells of NRS resembles a more exhausted phenotype than in RS and HC which appeared to be a relevant predictive marker for therapy failure.

An interband cascade laser based heterodyne detector with integrated optical amplifier and local oscillator.

Heterodyne detection based on interband cascade lasers (ICL) has been demonstrated in a wide range of different applications. However, it is still often limited to bulky tabletop systems using individual components such as dual laser setups, beam shaping elements, and discrete detectors. In this work, a versatile integrated ICL platform is investigated for tackling this issue. A RF-optimized, two-section ICL approach is employed, consisting of a short section typically used for efficient modulation of the cavity field and a long gain section. Such a laser is operated in reversed mode, with the entire Fabry-Pérot waveguide utilized as a semiconductor optical amplifier (SOA) and the electrically separated short section as detector. Furthermore, a racetrack cavity is introduced as on-chip single-mode reference generator. The field of the racetrack cavity is coupled into the SOA waveguide via an 800 nm gap. By external injection of a single mode ICL operating at the appropriate wavelength, a heterodyne beating between the on-chip reference and the injected signal can be observed on the integrated detector section of the SOA-detector.

Design and performance of GaSb-based quantum cascade detectors.

InAs/AlSb quantum cascade detectors (QCDs) grown strain-balanced on GaSb substrates are presented. This material system offers intrinsic performance-improving properties, like a low effective electron mass of the well material of 0.026 m 0, enhancing the optical transition strength, and a high conduction band offset of 2.28 eV, reducing the noise and allowing for high optical transition energies. InAs and AlSb strain balance each other on GaSb with an InAs:AlSb ratio of 0.96:1. To regain the freedom of a lattice-matched material system regarding the optimization of a QCD design, submonolayer InSb layers are introduced. With strain engineering, four different active regions between 3.65 and 5.5 µm were designed with InAs:AlSb thickness ratios of up to 2.8:1, and subsequently grown and characterized. This includes an optimized QCD design at 4.3 µm, with a room-temperature peak responsivity of 26.12 mA/W and a detectivity of 1.41 × 108 Jones. Additionally, all QCD designs exhibit higher-energy interband signals in the mid- to near-infrared, stemming from the InAs/AlSb type-II alignment and the narrow InAs band gap.

Impact of higher-order dispersion on frequency-modulated combs.

Frequency-modulated (FM) combs form spontaneously in free-running semiconductor lasers and possess a vast potential for spectroscopic applications. Despite recent progress in obtaining a conclusive theoretical description, experimental FM combs often exhibit non-ideal traits, which prevents their widespread use. Here we explain this by providing a clear theoretical and experimental study of the impact of the higher-order dispersion on FM combs. We reveal that spectrally dependent dispersion is detrimental for comb performance and leads to a decreased comb bandwidth and the appearance of spectral holes. These undesirable traits can be mended by applying a radio frequency modulation of the laser bias. We show that electrical injection-locking of the laser leads to a significant increase of the comb bandwidth, a uniform-like spectral amplitudes, and the rectification of the instantaneous frequency to recover a nearly linear frequency chirp of FM combs.

Anomalous Temperature Effect in Weakly Coupled Superlattices: Carrier Transport in a THz Quantum Cascade Laser.

We present an investigation into the vertical transport through 13 different superlattice structures, where the well and barrier widths, doping concentration, dopant position, and contact layers were varied. Although superlattices have been extensively studied since 1970, there is a lack of publications on transport through superlattices similarly low doped as THz quantum cascade lasers (QCLs), for which the doping is in the 3-5×10^{10} cm^{-2} range. The superlattices presented are doped in the same range as THz QCLs, with contact layers and fabrication comparable to high-temperature THz QCLs. The temperature-dependent current-voltage characteristics were measured starting from 5 K and an anomalous temperature effect was observed at the first plateau. The measured current through the superlattice first decreases before increasing again with increasing temperature, resulting in the lowest current occurring at 75-110 K. This behavior is also observed in some THz QCLs. The effect disappears for thinner barriers, higher quantum well doping, or modified contact layers, indicating a strong dependency on band bending, due to the large difference in the doping of the contact layers and the superlattice, which is confirmed with multiscattering Büttiker simulations.

Unveiling the synergy of NIRS and enrichment technologies: A comprehensive review of in-sorbent-based detection and quantification strategies.

This comprehensive review paper aims to captivate the applicability of in-sorbent detection, where near-infrared spectroscopy (NIRS) converges with enrichment technologies. For this purpose, we collected and summarized information regarding the combination of several sophisticated analytical enrichment techniques with NIRS to further explore and develop this synergistic approach. Peer-reviewed publications, matching the criteria of in situ NIR measurements prior analyte elution, have been collected, investigated, and concluded within this review. Investigations according to used materials, commercial or self-made, composition, organic or inorganic and applied analytical methodologies have been carried out. Applications extending over a multitude of chemical fields, from environmental to medicinal applications. As this review concludes, the combination of these techniques further expands the applicability of NIRS and moreover tries to solve the long-standing issue of the comparably low sensitivity regarding this vibrational technique.

Nozaki-Bekki solitons in semiconductor lasers.

Optical frequency-comb sources, which emit perfectly periodic and coherent waveforms of light1, have recently rapidly progressed towards chip-scale integrated solutions. Among them, two classes are particularly significant-semiconductor Fabry-Perót lasers2-6 and passive ring Kerr microresonators7-9. Here we merge the two technologies in a ring semiconductor laser10,11 and demonstrate a paradigm for the formation of free-running solitons, called Nozaki-Bekki solitons. These dissipative waveforms emerge in a family of travelling localized dark pulses, known within the complex Ginzburg-Landau equation12-14. We show that Nozaki-Bekki solitons are structurally stable in a ring laser and form spontaneously with tuning of the laser bias, eliminating the need for an external optical pump. By combining conclusive experimental findings and a complementary elaborate theoretical model, we reveal the salient characteristics of these solitons and provide guidelines for their generation. Beyond the fundamental soliton circulating inside the ring laser, we demonstrate multisoliton states as well, verifying their localized nature and offering an insight into formation of soliton crystals15. Our results consolidate a monolithic electrically driven platform for direct soliton generation and open the door for a research field at the junction of laser multimode dynamics and Kerr parametric processes.

Active mid-infrared ring resonators.

High-quality optical ring resonators can confine light in a small volume and store it for millions of roundtrips. They have enabled the dramatic size reduction from laboratory scale to chip level of optical filters, modulators, frequency converters, and frequency comb generators in the visible and the near-infrared. The mid-infrared spectral region (3-12 µm), as important as it is for molecular gas sensing and spectroscopy, lags behind in development of integrated photonic components. Here we demonstrate the integration of mid-infrared ring resonators and directional couplers, incorporating a quantum cascade active region in the waveguide core. It enables electrical control of the resonant frequency, its quality factor, the coupling regime and the coupling coefficient. We show that one device, depending on its operating point, can act as a tunable filter, a nonlinear frequency converter, or a frequency comb generator. These concepts extend to the integration of multiple active resonators and waveguides in arbitrary configurations, thus allowing the implementation of purpose-specific mid-infrared active photonic integrated circuits for spectroscopy, communication, and microwave generation.

Beyond Karl Fischer titration: a monolithic quantum cascade sensor for monitoring residual water concentration in solvents.

Quality control of liquids is an important part of analytical chemistry. The gold standard for measuring residual water in organic solvents and pharmaceutical applications is Karl Fischer titration. It has a high sensitivity, selectivity and accuracy. The downsides are a time-consuming offline analysis, together with the need for toxic reagents producing waste, and it suffers from poor inter-laboratory reproducibility. In this work, we present a high-performance lab-on-a-chip sensor exploiting mid-IR spectroscopy for liquid sensing. It is operating at 6.1 µm wavelength and is suitable for robust and flexible real-time in situ analysis of the residual water concentration in isopropyl alcohol. This is demonstrated in two experiments. A custom-made 60 µL flow cell is employed to measure only minute amounts of analyte in an inline configuration. In a second approach, the whole sensor is immersed into the analyte to demonstrate sensitive and rapid in situ operation on the millisecond time scale. This is confirmed by the ability for time resolved single water-droplet monitoring, while they are mixed into the liquid sample. We obtain a limit of detection between 120 ppm and 150 ppm with a concentration coverage spanning three orders of magnitude from 1.2 × 10-2%vol to 25%vol for the flow cell and 1.5 × 10-2%vol to 19%vol in the in situ configuration, respectively.

Synchronization of frequency combs by optical injection.

Optical frequency combs based on semiconductor lasers are a promising technology for monolithic integration of dual-comb spectrometers. However, the stabilization of offset frequency fceo remains a challenging feat due the lack of octave-spanning spectra. In a dual-comb configuration, the uncorrelated jitter of the offset frequencies leads to a non-periodic signal resulting in broadened beatnotes with a limited signal-to-noise ratio (SNR). Hence, expensive data acquisition schemes and complex signal processing are currently required. Here, we show that the offset frequencies of two frequency combs can be synchronized by optical injection locking, which allows full phase-stabilization when combined with electrical injection locking of both repetition frequencies frep. A single comb line isolated via an optical Vernier filter serves as Master oscillator for injection locking. The resulting dual-comb signal is periodic and stable over thousands of periods. This enables coherent averaging using analog electronics, which increases the SNR and reduces the data size by one and three orders of magnitude, respectively. The presented method will enable fully phase-stabilized dual-comb spectrometers by leveraging on integrated optical filters and provides access for comparing and stabilizing fceo to narrow-linewidth optical references.

A mid-infrared lab-on-a-chip for dynamic reaction monitoring.

Mid-infrared spectroscopy is a sensitive and selective technique for probing molecules in the gas or liquid phase. Investigating chemical reactions in bio-medical applications such as drug production is recently gaining particular interest. However, monitoring dynamic processes in liquids is commonly limited to bulky systems and thus requires time-consuming offline analytics. In this work, we show a next-generation, fully-integrated and robust chip-scale sensor for online measurements of molecule dynamics in a liquid solution. Our fingertip-sized device utilizes quantum cascade technology, combining the emitter, sensing section and detector on a single chip. This enables real-time measurements probing only microliter amounts of analyte in an in situ configuration. We demonstrate time-resolved device operation by analyzing temperature-induced conformational changes of the model protein bovine serum albumin in heavy water. Quantitative measurements reveal excellent performance characteristics in terms of sensor linearity, wide coverage of concentrations, extending from 0.075 mg ml-1 to 92 mg ml-1 and a 55-times higher absorbance than state-of-the-art bulky and offline reference systems.

Frequency Comb Generation by Bloch Gain Induced Giant Kerr Nonlinearity.

Optical nonlinearities are known to coherently couple amplitude and phase of light, which can result in the formation of periodic waveforms. Such waveforms are referred to as optical frequency combs. Here we show that Bloch gain-a nonclassical phenomenon that was first predicted in the 1930s-can play an essential role in comb formation. We develop a self-consistent theoretical model that considers all aspects of comb dynamics: band structure, electron transport, and cavity dynamics. In quantum cascade lasers, Bloch gain gives rise to a giant Kerr nonlinearity, which enables frequency modulated combs and serves as the physical origin of the linewidth enhancement factor. Bloch gain also triggers the formation of solitonlike structures in ring resonators, paving the way toward electrically driven Kerr combs.

Engineering the spectral bandwidth of quantum cascade laser frequency combs.

Quantum cascade lasers (QCLs) facilitate compact optical frequency comb sources that operate in the mid-infrared and terahertz spectral regions, where many molecules have their fundamental absorption lines. Enhancing the optical bandwidth of these chip-sized lasers is of paramount importance to address their application in broadband high-precision spectroscopy. In this work, we provide a numerical and experimental investigation of the comb spectral width and show how it can be optimized to obtain its maximum value defined by the laser gain bandwidth. The interplay of nonoptimal values of the resonant Kerr nonlinearity and cavity dispersion can lead to significant narrowing of the comb spectrum and reveals the best approach for dispersion compensation. The implementation of high mirror losses is shown to be favorable and results in proliferation of the comb sidemodes. Ultimately, injection locking of QCLs by modulating the laser bias around the round trip frequency provides a stable external knob to control the frequency-modulated comb state and recover the maximum spectral width of the unlocked laser state.

High-speed quantum cascade detector characterized with a mid-infrared femtosecond oscillator.

Quantum cascade detectors (QCD) are photovoltaic mid-infrared detectors based on intersubband transitions. Owing to the sub-picosecond carrier transport between subbands and the absence of a bias voltage, QCDs are ideally suited for high-speed and room temperature operation. Here, we demonstrate the design, fabrication, and characterization of 4.3 µm wavelength QCDs optimized for large electrical bandwidth. The detector signal is extracted via a tapered coplanar waveguide (CPW), which was impedance-matched to 50 Ω. Using femtosecond pulses generated by a mid-infrared optical parametric oscillator (OPO), we show that the impulse response of the fully packaged QCDs has a full-width at half-maximum of only 13.4 ps corresponding to a 3-dB bandwidth of more than 20 GHz. Considerable detection capability beyond the 3-dB bandwidth is reported up to at least 50 GHz, which allows us to measure more than 600 harmonics of the OPO repetition frequency reaching 38 dB signal-to-noise ratio without the need of electronic amplification.

Distribution and Cytokine Profile of Peripheral B Cell Subsets Is Perturbed in Pediatric IBD and Partially Restored During a Successful IFX Therapy.

BACKGROUND: The role of B cells in inflammatory bowel disease (IBD) is ambiguous, as B cells may have both pathogenic and protective functions in IBD. We studied B cell subsets before and after initiation of an anti-tumor necrosis factor alpha (anti-TNFα) therapy in pediatric IBD. The aim of the study was to examine the behavior of B cells in pediatric IBD patients undergoing an anti-TNFα therapy and, more specifically, to clarify their association with a successful or an unsuccessful infliximab (IFX) treatment. METHODS: A total of N = 42 pediatric IBD patients (Crohn disease, n = 30; ulcerative colitis, n = 12) for whom an anti-TNFα therapy with and without a concomitant azathioprine (AZA) medication was administered were recruited. Fourteen healthy age-matched children served as control patients. Blood samples were collected before initiation of the anti-TNFα therapy, before the fourth infusion at the end of the induction phase, and after 6 and 12 months under therapy maintenance. Flow cytometry (CD20, CD27, CD38, CD138) and intracellular staining (interleukin 10 [IL10], TNFα, granzyme B) were performed. Responders to successful IFX therapy were classified exhibiting a fecal calprotectin level of below 100 µg/g or achieving levels of <10% of the baseline value at initiation than at the end of the 12-month follow-up period. RESULTS: Before initiation of anti-TNFα therapy, flow cytometry revealed increased percentages of naïve B cells whereas transitional B cells were reduced compared with those in the healthy control patients. The IL10-producing B cells of both ulcerative colitis and Crohn disease patients were reduced at the initiation of IFX therapy, whereas TNFα-producing transitional CD24hiCD38hi B cells in ulcerative colitis patients were increased compared with those in healthy control patients. After 12 months of therapy, we detected a significant increase of IL10-producing transitional B cells in responding patients.The IFX trough levels in the responding patients showed a significant increase until 6 months after IFX initiation, attaining mean values of 9.9 µg/mL, whereas the IFX dosage was significantly lower than that in the nonresponding patients. The IFX trough levels in AZA-treated patients reached earlier therapeutic levels than in patients without AZA comedication, whereas during the course of the IFX therapy, comedication with AZA had no significant effect on the outcome. CONCLUSIONS: Attaining a normalization of IL10 production among CD24hiCD38hi B cells after 12 months of therapy may represent additional information about the reconstitution of a patient's immune system in responding patients. The achievement of an IFX trough level of ~10 µg/mL at 6 months of treatment is associated with a successful anti-TNFα therapy. In addition, AZA comedication supports an earlier achievement of therapeutic IFX trough levels.

Mode-locked short pulses from an 8 µm wavelength semiconductor laser.

Quantum cascade lasers (QCL) have revolutionized the generation of mid-infrared light. Yet, the ultrafast carrier transport in mid-infrared QCLs has so far constituted a seemingly insurmountable obstacle for the formation of ultrashort light pulses. Here, we demonstrate that careful quantum design of the gain medium and control over the intermode beat synchronization enable transform-limited picosecond pulses from QCL frequency combs. Both an interferometric radio-frequency technique and second-order autocorrelation shed light on the pulse dynamics and confirm that mode-locked operation is achieved from threshold to rollover current. Furthermore, we show that both anti-phase and in-phase synchronized states exist in QCLs. Being electrically pumped and compact, mode-locked QCLs pave the way towards monolithically integrated non-linear photonics in the molecular fingerprint region beyond 6 µm wavelength.

Frequency combs induced by phase turbulence.

Wave instability-the process that gives rise to turbulence in hydrodynamics1-represents the mechanism by which a small disturbance in a wave grows in amplitude owing to nonlinear interactions. In photonics, wave instabilities result in modulated light waveforms that can become periodic in the presence of coherent locking mechanisms. These periodic optical waveforms are known as optical frequency combs2-4. In ring microresonator combs5,6, an injected monochromatic wave becomes destabilized by the interplay between the resonator dispersion and the Kerr nonlinearity of the constituent crystal. By contrast, in ring lasers instabilities are considered to occur only under extreme pumping conditions7,8. Here we show that, despite this notion, semiconductor ring lasers with ultrafast gain recovery9,10 can enter frequency comb regimes at low pumping levels owing to phase turbulence11-an instability known to occur in hydrodynamics, superconductors and Bose-Einstein condensates. This instability arises from the phase-amplitude coupling of the laser field provided by linewidth enhancement12, which produces the needed interplay of dispersive and nonlinear effects. We formulate the instability condition in the framework of the Ginzburg-Landau formalism11. The localized structures that we observe share several properties with dissipative Kerr solitons, providing a first step towards connecting semiconductor ring lasers and microresonator frequency combs13.

In-Phase and Anti-Phase Synchronization in a Laser Frequency Comb.

Coupled clocks are a classic example of a synchronization system leading to periodic collective oscillations. Already in 1665, Christiaan Huygens described this phenomenon as a kind of "sympathy" among oscillators. In this work, we describe the formation of two types of laser frequency combs as a system of oscillators coupled through the beating of the lasing modes. We experimentally show two completely different types of synchronization in a quantum dot laser-in-phase and splay-phase states. Both states can be generated in the same device, just by varying the damping losses of the system. This modifies the coupling among the oscillators. The temporal laser output is characterized using both linear and quadratic autocorrelation techniques. Our results show that both pulses and frequency-modulated states can be generated on demand within the same device. These findings allow us to connect laser frequency combs produced by amplitude-modulated and frequency-modulated lasers and link these to pattern formation in coupled systems such as Josephson-junction arrays.