Efficient intra-cavity frequency doubled, diode-pumped, Q-switched alexandrite laser directly emitting in the UV.

We present an intra-cavity frequency doubled Q-switched diode-pumped alexandrite ring-laser directly emitting in the UV at 386 nm. Using LBO as nonlinear crystal, the laser yields a pulse energy up to 3 mJ at 500 Hz with an excellent beam quality of M2 = 1.1. The pulse length is about 920 ns, allowing for very narrow bandwidth in single longitudinal mode operation. The optical-to-optical efficiency for the UV laser is > 9% and almost unchanged compared to the fundamental laser. First injection-seeding experiments show single longitudinal mode operation. The parameters of the laser are suitable for the use as an emitter in a multi-purpose atmospheric Doppler lidar system.

Energy-scaling of a diode-pumped Alexandrite laser and prototype development for a compact general-purpose Doppler lidar.

We present design and performance data of an energy-scaled diode-pumped Alexandrite laser in single longitudinal mode operation developed as a beam source in a mobile general-purpose Doppler lidar. A maximum pulse energy in Q-switched operation of 4.6 mJ and a maximum average power of 2.7 W were achieved for a repetition rate range from 500 to 750 Hz with excellent beam quality of M 2=1.1. Two rugged and compact demonstrator lasers were built and integrated into mobile lidar systems, where a bandwidth of approximately 3 MHz is measured. Measurements of atmospheric winds and temperatures were conducted during several field campaigns from summer 2022 to spring 2023.

Circulating miRNAs associated with nonalcoholic fatty liver disease.

MicroRNAs (miRNAs) are secreted from cells as either protein-bound or enclosed in extracellular vesicles. Circulating liver-derived miRNAs are modifiable by weight-loss or insulin-sensitizing treatments, indicating that they could be important biomarker candidates for diagnosis, monitoring, and prognosis in nonalcoholic liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Unfortunately, the noninvasive diagnosis of NASH and fibrosis remains a key challenge, which limits case finding. Current diagnostic guidelines, therefore, recommend liver biopsies, with risks of pain and bleeding for the patient and substantial healthcare costs. Here, we summarize mechanisms of RNA secretion and review circulating RNAs associated with NAFLD and NASH for their biomarker potential. Few circulating miRNAs are consistently associated with NAFLD/NASH: miR-122, miR-21, miR-34a, miR-192, miR-193, and the miR-17-92 miRNA-cluster. The hepatocyte-enriched miRNA-122 is consistently increased in NAFLD and NASH but decreased in liver cirrhosis. Circulating miR-34a, part of an existing diagnostic algorithm for NAFLD, and miR-21 are consistently increased in NAFLD and NASH. MiR-192 appears to be prominently upregulated in NASH compared with NAFDL, whereas miR-193 was reported to distinguish NASH from fibrosis. Various members of miRNA cluster miR-17-92 are reported to be associated with NAFLD and NASH, although with less consistency. Several other circulating miRNAs have been reported to be associated with fatty liver in a few studies, indicating the existence of more circulating miRNAs with relevant as diagnostic markers for NAFLD or NASH. Thus, circulating miRNAs show potential as biomarkers of fatty liver disease, but more information about phenotype specificity and longitudinal regulation is needed.

Rugged diode-pumped Alexandrite laser as an emitter in a compact mobile lidar system for atmospheric measurements.

We present design and performance data of two diode-pumped Alexandrite lasers developed explicitly as laser emitters in mobile potassium resonance lidar systems. The lasers yield an output power of up to 1.75 mJ at a repetition rate of 500 Hz with a beam quality of $M{{^2}} \lt {1.1}$ in both spatial directions. Reliable single longitudinal mode operation with a unrivaled narrow linewidth of 3.3 MHz at a potassium resonance line at 769.898 nm is achieved. The wavelength can be switched from pulse to pulse in a range of several gigahertz so the potassium line can be scanned. The lasers are finally integrated in highly efficient lidar systems with a power consumption of 500 W for the whole lidar system. The extremely high spectral requirements are investigated and the performance for different working points regarding repetition rates and pump durations is investigated. Several weeks of remotely controlled operation of the prototype in a field campaign were conducted without changes of the output parameters. Approximately 1000 h of reliable single longitudinal mode operation was achieved during the campaign and measurements of Doppler-Mie wind observations in the stratosphere and of the potassium layer in the mesopause were conducted simultaneously even at daytime.

Dissociation of Muscle Insulin Resistance from Alterations in Mitochondrial Substrate Preference.

Alterations in muscle mitochondrial substrate preference have been postulated to play a major role in the pathogenesis of muscle insulin resistance. In order to examine this hypothesis, we assessed the ratio of mitochondrial pyruvate oxidation (VPDH) to rates of mitochondrial citrate synthase flux (VCS) in muscle. Contrary to this hypothesis, we found that high-fat-diet (HFD)-fed insulin-resistant rats did not manifest altered muscle substrate preference (VPDH/VCS) in soleus or quadriceps muscles in the fasting state. Furthermore, hyperinsulinemic-euglycemic (HE) clamps increased VPDH/VCS in both muscles in normal and insulin-resistant rats. We then examined the muscle VPDH/VCS flux in insulin-sensitive and insulin-resistant humans and found similar relative rates of VPDH/VCS, following an overnight fast (∼20%), and similar increases in VPDH/VCS fluxes during a HE clamp. Altogether, these findings demonstrate that alterations in mitochondrial substrate preference are not an essential step in the pathogenesis of muscle insulin resistance.

OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance.

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensing O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase in O-GlcNAc signaling in macrophages. O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. Suppressing O-GlcNAc signaling by O-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1) O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage O-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.

Diode-pumped cw Alexandrite laser with temporally stable 6.5 W in TEM00 operation with prospect of power scaling.

We present the design of a longitudinally diode-pumped Alexandrite laser in continuous-wave operation and resulting performance data. A laser power of 6.5 W in fundamental mode operation was measured, which is, to the best of our knowledge, the highest laser power in fundamental mode operation yet reported. The laser crystal was pumped by two diode modules emitting at 637 nm. The pump radiation was polarization-combined and spatially symmetrized. The laser operates at an output power of 6.5 W with an optical-to-optical efficiency of 26%, temporally stable output with stability of 8% on ms timescale, a beam quality of M2 = 1.1 in both spatial directions and emission of an output wavelength of 752 nm. Measurements of the thermal dioptric power at pumping intensities up to 9.5 kW/cm2 support the appropriate approach of the design. Based on our results, we estimate the potential and show our concept for future scaling of the output power.

The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones.

OBJECTIVES: GPR142, which is highly expressed in pancreatic islets, has recently been deorphanized as a receptor for aromatic amino acids; however, its physiological role and pharmacological potential is unclear. METHODS AND RESULTS: We find that GPR142 is expressed not only in ß- but also in α-cells of the islets as well as in enteroendocrine cells, and we confirm that GPR142 is a highly selective sensor of essential aromatic amino acids, in particular Trp and oligopeptides with N-terminal Trp. GPR142 knock-out mice displayed a very limited metabolic phenotype but demonstrated that L-Trp induced secretion of pancreatic and gut hormones is mediated through GPR142 but that the receptor is not required for protein-induced hormone secretion. A synthetic GPR142 agonist stimulated insulin and glucagon as well as GIP, CCK, and GLP-1 secretion. In particular, GIP secretion was sensitive to oral administration of the GPR142 agonist an effect which in contrast to the other hormones was blocked by protein load. Oral administration of the GPR142 agonist increased [3H]-2-deoxyglucose uptake in muscle and fat depots mediated through insulin action while it lowered liver glycogen conceivably mediated through glucagon, and, consequently, it did not lower total blood glucose. Nevertheless, acute administration of the GPR142 agonist strongly improved oral glucose tolerance in both lean and obese mice as well as Zucker fatty rat. Six weeks in-feed chronic treatment with the GPR142 agonist did not affect body weight in DIO mice, but increased energy expenditure and carbohydrate utilization, lowered basal glucose, and improved insulin sensitivity. CONCLUSIONS: GPR142 functions as a sensor of aromatic amino acids, controlling GIP but also CCK and GLP-1 as well as insulin and glucagon in the pancreas. GPR142 agonists could have novel interesting potential in modifying metabolism through a balanced action of gut hormones as well as both insulin and glucagon.

Diode-pumped Q-switched Alexandrite laser in single longitudinal mode operation with Watt-level output power.

We present significantly improved performance data of a diode-pumped Q-switched Alexandrite laser in single longitudinal mode operation developed as a beam source for resonance lidar systems. The average output power of the laser-operating at the potassium resonance at 770 nm with a linewidth below 10 MHz-could be increased by a factor of five to the Watt-level by means of an optimized resonator design and pump scheme. The pulse energy is 1.7 mJ with a beam quality of M2≤1.1 in both spatial directions at a repetition rate of 500 Hz.

Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity.

OBJECTIVE: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle. METHODS: We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated. Tissues were used for histology, qPCR, Western blot, co-immunoprecipitation, and chromatin immunoprecipitation analyses. RESULTS: We found elevated levels of O-GlcNAc-modified proteins in obese, type 2 diabetic people compared with well-matched obese and lean controls. Muscle-specific OGT knockout mice were lean, and whole body energy expenditure and insulin sensitivity were increased in these mice, consistent with enhanced glucose uptake and elevated glycolytic enzyme activities in skeletal muscle. Moreover, enhanced glucose uptake was also observed in white adipose tissue that was browner than that of WT mice. Interestingly, mKO mice had elevated mRNA levels of Il15 in skeletal muscle and increased circulating IL-15 levels. We found that OGT in muscle mediates transcriptional repression of Il15 by O-GlcNAcylating Enhancer of Zeste Homolog 2 (EZH2). CONCLUSIONS: Elevated muscle O-GlcNAc levels paralleled insulin resistance and type 2 diabetes in humans. Moreover, OGT-mediated signaling is necessary for proper skeletal muscle metabolism and whole-body energy homeostasis, and our data highlight O-GlcNAcylation as a potential target for ameliorating metabolic disorders.