Field-resolved infrared spectroscopy of biological systems.

The proper functioning of living systems and physiological phenotypes depends on molecular composition. Yet simultaneous quantitative detection of a wide variety of molecules remains a challenge1-8. Here we show how broadband optical coherence opens up opportunities for fingerprinting complex molecular ensembles in their natural environment. Vibrationally excited molecules emit a coherent electric field following few-cycle infrared laser excitation9-12, and this field is specific to the sample's molecular composition. Employing electro-optic sampling10,12-15, we directly measure this global molecular fingerprint down to field strengths 107 times weaker than that of the excitation. This enables transillumination of intact living systems with thicknesses of the order of 0.1 millimetres, permitting broadband infrared spectroscopic probing of human cells and plant leaves. In a proof-of-concept analysis of human blood serum, temporal isolation of the infrared electric-field fingerprint from its excitation along with its sampling with attosecond timing precision results in detection sensitivity of submicrograms per millilitre of blood serum and a detectable dynamic range of molecular concentration exceeding 105. This technique promises improved molecular sensitivity and molecular coverage for probing complex, real-world biological and medical settings.

In-line synthesis of multi-octave phase-stable infrared light.

Parametric downconversion driven by modern, high-power sources of 10-fs-scale near-infrared pulses, in particular intrapulse difference-frequency generation (IPDFG), affords combinations of properties desirable for molecular vibrational spectroscopy in the mid-infrared range: broad spectral coverage, high brilliance, and spatial and temporal coherence. Yet, unifying these in a robust and compact radiation source has remained a key challenge. Here, we address this need by employing IPDFG in a multi-crystal in-line geometry, driven by the 100-W-level, 10.6-fs pulses of a 10.6-MHz-repetition-rate, nonlinearly post-compressed Yb:YAG thin-disk oscillator. Polarization tailoring of the driving pulses using a bichromatic waveplate is followed by a sequence of two crystals, LiIO3 and LiGaS2, resulting in the simultaneous coverage of the 800-cm-1-to-3000-cm-1 spectral range (at -30-dB intensity) with 130 mW of average power. We demonstrate that optical-phase coherence is maintained in this in-line geometry, in theory and experiment, the latter employing ultra-broadband electro-optic sampling. These results pave the way toward coherent spectroscopy schemes like field-resolved and frequency-comb spectroscopy, as well as nonlinear, ultrafast spectroscopy and optical-waveform synthesis across the entire infrared molecular fingerprint region.

Optimum Sample Thickness for Trace Analyte Detection with Field-Resolved Infrared Spectroscopy.

The strong absorption of liquid water in the infrared (IR) molecular fingerprint region constitutes a challenge for applications of vibrational spectroscopy in chemistry, biology, and medicine. While high-power IR laser sources enable the penetration of ever thicker aqueous samples, thereby mitigating the detrimental effects of strong attenuation on detection sensitivity, a basic advantage of heterodyne-measurement-based methods has-to the best of our knowledge-not been harnessed in broadband IR measurements to date. Here, employing field-resolved spectroscopy (FRS), we demonstrate in theory and experiment fundamental advantages of techniques whose signal-to-noise ratio (SNR) scales linearly with the electric field over those whose SNR scales linearly with radiation intensity, including conventional Fourier-transform infrared (FTIR) and direct absorption spectroscopy. Field-scaling brings about two major improvements. First, it squares the measurement dynamic range. Second, we show that the optimum interaction length with samples for SNR-maximized measurements is twice the value usually considered to be optimum for FTIR devices. In order to take full advantage of these properties, the measurement must not be significantly affected by technical noise, such as intensity fluctuations, which are common for high-power sources. Recently, it has been shown that subcycle, nonlinear gating of the molecular fingerprint signal renders FRS robust against intensity noise. Here, we quantitatively demonstrate this advantage of FRS for thick aqueous samples. We report sub-µg/mL detection sensitivities for transmission path lengths up to 80 µm and a limit of detection in the lower µg/mL range for transmission paths as long as 200 µm.

Second-harmonic generation and self-phase modulation of few-cycle mid-infrared pulses.

Near-single-cycle mid-infrared pulses with a spectrum covering 5.4-11 µm are efficiently frequency-doubled in different GaSe crystals. The second-harmonic spectrum spans 3-4.3 µm at a power conversion efficiency of >20%. We measure an effective nonlinear coefficient of deff≈35 pm/V. We also report on self-phase modulation and spectral broadening of the mid-infrared pulses in various bulk materials and find an increase of 45% of spectral width for 5 mm of Ge. These results demonstrate that nonlinear optical conversions can efficiently be driven by few-cycle mid-infrared radiation.

Sub-attosecond-precision optical-waveform stability measurements using electro-optic sampling.

The generation of laser pulses with controlled optical waveforms, and their measurement, lie at the heart of both time-domain and frequency-domain precision metrology. Here, we obtain mid-infrared waves via intra-pulse difference-frequency generation (IPDFG) driven by 16-femtosecond near-infrared pulses, and characterise the jitter of sub-cycle fractions of these waves relative to the gate pulses using electro-optic sampling (EOS). We demonstrate sub-attosecond temporal jitter at individual zero-crossings and sub-0.1%-level relative amplitude fluctuations in the 10-kHz-0.625-MHz band. Chirping the nearly-octave-spanning mid-infrared pulses uncovers wavelength-dependent attosecond-scale waveform jitter. Our study validates EOS as a broadband (both in the radio-frequency and the optical domains), highly sensitive measurement technique for the jitter dynamics of optical waveforms. This sensitivity reveals outstanding stability of the waveforms obtained via IPDFG and EOS, directly benefiting precision measurements including linear and nonlinear (infrared) field-resolved spectroscopy. Furthermore, these results form the basis toward EOS-based active waveform stabilisation and sub-attosecond multi-oscillator synchronisation/delay tracking.

Microstructure and Local Mechanical Properties of the Heat-Affected Zone of a Resistance Spot Welded Medium-Mn Steel.

The properties of the heat-affected zone (HAZ) are reported to have a great influence on the mechanical performance of resistance spot welded advanced high strength steels. Therefore, in the present work, the HAZ of a medium-Mn steel is characterized regarding its microstructure and its mechanical properties depending on the distance to the fusion zone (FZ). In order to obtain the local mechanical properties of the HAZ, samples were heat-treated in a joule-heating thermal simulator using different peak temperatures to physically simulate the microstructure of the HAZ. By comparing the microstructure and the hardness of these heat-treated samples and the HAZ, the local peak temperatures within the HAZ could be determined. Subsequently, tensile tests were conducted, and the austenite phase fraction was measured magnetically on the physically simulated HAZ samples in order to determine the local mechanical properties of the HAZ. As verified by energy-dispersive X-ray spectroscopy, peak temperatures above 1200 °C led to a uniform distribution of manganese, resulting in a predominantly martensitic microstructure with high strength and low total elongation after quenching. Below 1100 °C, the diffusion of manganese is restricted, and considerable fractions of austenite remain stable. The austenite fraction increases almost linearly with decreasing peak temperature, which leads to an increase of the total elongation and to a slight decrease in the strength, depending on the distance to the FZ. Temperatures below 700 °C exhibit hardly any effect on the initial microstructure and mechanical properties.

Post-transplant multimorbidity index and quality of life in patients with chronic graft-versus-host disease-results from a joint evaluation of a prospective German multicenter validation trial and a cohort from the National Institutes of Health.

Comorbidity after allogeneic hematopoietic stem cell transplantation (alloHSCT) impairs quality of life (QoL), physical functioning, and survival. We developed a new standardized measure to capture comorbidity after transplantation, the Post-transplant Multimorbidity Index (PTMI) in a cohort of 50 long term survivors. We subsequently evaluated the content validity and impact on survival and QoL within a multicenter trial, including 208 patients (pts) after alloHSCT, who were prospectively evaluated applying the FACT-BMT, the Human Activity Profile (HAP), the SF-36 v.2, PTMI and the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). The most prevalent comorbidities were compensated arterial hypertension (28.4%), ambulatory infections (25.5%), iron overload (23%), mild renal function impairment (20%), and osteoporosis (13%). Applying the PTMI 13% of patients had no comorbidity, while 37.1% had 1-3 comorbidities, 27.4% had 4-6 comorbidities, and 13.5% had > 6 comorbidities. Chronic graft-versus-host disease (cGvHD) was significantly associated with the PTMI, while age and prior acute GvHD were not. In contrast, the HCT-CI was not associated with the presence of cGvHD. cGvHD was significantly associated with depression (r = 0.16), neurological disease (r = 0.21), osteoporosis (r = 0.18) and nonmelanoma skin cancer (r = 0.26). The PTMI demonstrated strong measurement properties and compared to the HCT-CI captured a wider range of comorbidities associated with cGvHD.

Correlative microscopy of a carbide-free bainitic steel.

In this work a carbide-free bainitic steel was examined by a novel correlative microscopy approach using transmission Kikuchi diffraction (TKD) and transmission electron microscopy (TEM). The individual microstructural constituents could be identified by TKD based on their different crystal structure for bainitic ferrite and retained austenite and by image quality for the martensite-austenite (M-A) constituent. Subsequently, the same area was investigated in the TEM and a good match of these two techniques regarding the identification of the area position and crystal orientation could be proven. Additionally, the M-A constituent was examined in the TEM for the first time after preceded unambiguous identification using a correlative microscopy approach. The selected area diffraction pattern showed satellites around the main reflexes which might indicate a structural modulation.