Measurement of the linewidth of a home-built vacuum ultraviolet comb by frequency comb spectroscopy on NO2.

Optical frequency comb in the vacuum ultraviolet (VUV)/extreme ultraviolet (XUV) region has attracted a great deal of attention, as it provides coherent VUV/XUV radiation source with a rather narrow bandwidth, facilitating precise spectroscopic measurements in the short wavelength regime. In this study, we report on the linewidth measurement of a home-built VUV comb centered at 148 nm using direct frequency comb spectroscopy with NO2. The measurement reveals that the upper bound of our comb linewidth is less than 28 MHz. Fitting the whole trace with different repetition rates shows that the center frequency of the excitation is 2 021.25 ± 0.24 THz (∼148.32 nm). Thus, we assigned this excitation to the transition from the 6a1 orbital (ν1'=0, ν2'=0) to the 3pσu orbital (ν1'=3, ν2'=8) in NO2. Our work demonstrates that VUV combs are potentially powerful tools for precision spectroscopic measurements in the short wavelength regime.

Comparison of diclofenac with tramadol, tizanidine or placebo in the treatment of acute low back pain and sciatica: multi-center randomized controlled trial.

BACKGROUND: Low back pain (LBP) is a leading cause of disability worldwide and has posed numerous health and socioeconomic challenges. This study compared whether nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with tramadol, tizanidine or placebo would be the best treatment regime to improve the Roland Morris Disability Questionnaire (RMDQ) scores at 1 week. METHODS: This was a multi-center, double-blind, randomized, and placebo-controlled trial including adult patients with acute LBP and sciatica in three emergency departments in Hong Kong. Patients were randomized to the receive tramadol 50 mg, tizanidine 2 mg, or placebo every 6 hours for 2 weeks in a 1:1:1 ratio. The RMDQ and other secondary outcomes were measured at baseline, Day 2, 7, 14, 21, and 28. Data were analyzed on an intention to treat basis. Crude and adjusted mean differences in the changes of RMDQ and NRS scores from baseline to Day 7 between tizanidine/tramadol and placebo were determined with 95% confidence intervals. RESULTS: Two hundred and ninety-one patients were analyzed with the mean age of 47.4 years and 57.7% were male. The primary outcome of mean difference in RMDQs on Day 7 (compared with baseline) was non-significant for tizanidine compared with placebo (adjusted mean difference - 0.56, 95% CI -2.48 to 1.37) and tramadol compared with placebo (adjusted mean difference - 0.85, 95% CI -2.80 to 1.10). Only 23.7% were fully compliant to the treatment allocated. Complier Average Causal Effect analysis also showed no difference in the primary outcome for the tizanidine and tramadol versus placebo. CONCLUSION: Among patients with acute LBP and sciatica presenting to the ED, adding tramadol or tizanidine to diclofenac did not improve functional recovery.

CAG RNAs induce DNA damage and apoptosis by silencing NUDT16 expression in polyglutamine degeneration.

DNA damage plays a central role in the cellular pathogenesis of polyglutamine (polyQ) diseases, including Huntington's disease (HD). In this study, we showed that the expression of untranslatable expanded CAG RNA per se induced the cellular DNA damage response pathway. By means of RNA sequencing (RNA-seq), we found that expression of the Nudix hydrolase 16 (NUDT16) gene was down-regulated in mutant CAG RNA-expressing cells. The loss of NUDT16 function results in a misincorporation of damaging nucleotides into DNAs and leads to DNA damage. We showed that small CAG (sCAG) RNAs, species generated from expanded CAG transcripts, hybridize with CUG-containing NUDT16 mRNA and form a CAG-CUG RNA heteroduplex, resulting in gene silencing of NUDT16 and leading to the DNA damage and cellular apoptosis. These results were further validated using expanded CAG RNA-expressing mouse primary neurons and in vivo R6/2 HD transgenic mice. Moreover, we identified a bisamidinium compound, DB213, that interacts specifically with the major groove of the CAG RNA homoduplex and disfavors the CAG-CUG heteroduplex formation. This action subsequently mitigated RNA-induced silencing complex (RISC)-dependent NUDT16 silencing in both in vitro cell and in vivo mouse disease models. After DB213 treatment, DNA damage, apoptosis, and locomotor defects were rescued in HD mice. This work establishes NUDT16 deficiency by CAG repeat RNAs as a pathogenic mechanism of polyQ diseases and as a potential therapeutic direction for HD and other polyQ diseases.

Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis.

OBJECTIVE: Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic Lactobacillus gallinarum and its role in improving anti-programmed cell death protein 1 (PD1) efficacy against colorectal cancer (CRC). DESIGN: The effects of L. gallinarum in anti-PD1 response were assessed in syngeneic mouse models and azoxymethane/dextran sulfate sodium-induced CRC model. The change of immune landscape was identified by multicolour flow cytometry and validated by immunohistochemistry staining and in vitro functional assays. Liquid chromatography-mass spectrometry was performed to identify the functional metabolites. RESULTS: L. gallinarum significantly improved anti-PD1 efficacy in two syngeneic mouse models with different microsatellite instability (MSI) statuses (MSI-high for MC38, MSI-low for CT26). Such effect was confirmed in CRC tumourigenesis model. L. gallinarum synergised with anti-PD1 therapy by reducing Foxp3+ CD25+ regulatory T cell (Treg) intratumoural infiltration, and enhancing effector function of CD8+ T cells. L. gallinarum-derived indole-3-carboxylic acid (ICA) was identified as the functional metabolite. Mechanistically, ICA inhibited indoleamine 2,3-dioxygenase (IDO1) expression, therefore suppressing kynurenine (Kyn) production in tumours. ICA also competed with Kyn for binding site on aryl hydrocarbon receptor (AHR) and antagonised Kyn binding on CD4+ T cells, thereby inhibiting Treg differentiation in vitro. ICA phenocopied L. gallinarum effect and significantly improved anti-PD1 efficacy in vivo, which could be reversed by Kyn supplementation. CONCLUSION: L. gallinarum-derived ICA improved anti-PD1 efficacy in CRC through suppressing CD4+Treg differentiation and enhancing CD8+T cell function by modulating the IDO1/Kyn/AHR axis. L. gallinarum is a potential adjuvant to augment anti-PD1 efficacy against CRC.

Temperature-dependent determination of NO2 dimerization reaction based on dual-comb spectroscopy.

Dimerization reactions play a critical role in various fields of research, including cell biology, biomedicine, and chemistry. In particular, the dimerization reaction of 2NO2⇌N2O4 has been extensively applied in pollution control and raw material preparation. Spectroscopy, as a powerful tool for investigating molecular structures and reaction kinetics, has been increasingly employed to study dimerization reactions in recent years. In this study, we successfully demonstrated the application of dual-comb spectroscopy (DCS) to analyze NO2 dimerization reactions, making the first report on the application of this technique in this context. Parallel measurements of NO2 and N2O4 fingerprints spectra with high resolution at 3000 cm-1 was performed, benefiting from the unprecedented broadband and high-precision capability of DCS. The absorption cross-sections of N2O4 from 296 to 343 K was obtained from the measured spectra, which contributes to further research on the molecular spectrum of N2O4. These results demonstrate the potential of DCS for studying the dimerization reaction mechanism.

Investigation of stable pulse mode-locking regimes in a NALM figure-9 Er-doped fiber laser.

We demonstrate three typical mode-locking processes of a nonlinear amplifying loop mirror (NALM) fiber laser via a general nonlinear Schrödinger equation-based (GNLSE) simulation model. First, the pulse evolutions in the NALM cavity were separately simulated under asymmetric and weakly asymmetric conditions. We found that the splitting ratio and positions of the gain fiber can result in a suitable phase bias between clockwise and counter-clockwise beams, enabling the realization of a self-starting low-threshold operating condition. To assess the roles of the splitting ratio and gain in the mode-locking process, we simulated three pulse formation processes: in the soliton, stretched-pulse, and dissipative soliton mode-locking regimes. The simulation results show that the splitting ratio, gain, and dispersion directly influence the mode-locking condition and pulse characteristics, thereby providing effective quantified guidance for high-quality pulse generation. Finally, an experimental NALM oscillation operating under stretched pulse conditions was established to investigate the impact of the splitting ratio and pump power on the pulse characteristics. The experimental results prove that the splitting ratio, gain, and dispersion can be used to manipulate the mode-locking threshold, self-starting threshold, nonlinear effects, and pulse characteristics.

Mid-infrared dual-comb spectroscopy for rapid temperature distribution characterization.

Due to the influence of chemical reactions, phase change, and other phenomena, the combustion system is a complicated high-temperature environment. Therefore, the spatio-temporally resolved monitoring of the temperature field is crucial for gaining a comprehensive understanding of the intricate combustion environment. In this study, we proposed a fast and high-precision temperature measurement technique based on mid-infrared (MIR) dual-comb spectroscopy with a high spectral resolution and fast refresh rate. Based on this technique, the spatio-temporally resolved measurement of a non-uniform temperature field was achieved along the laser path. To verify the capability of DCS for temperature measurement, the bandhead ro-vibrational lines of the CO2 molecule were acquired, and the 1-σ uncertainty of the retrieved temperature was 3.2°C at 800°C within 100 ms. The results demonstrate the potential of our fast and high-precision laser diagnostic technique which can be further applied to combustion kinetics.

Elucidation of Carboxylesterase Mediated Pharmacokinetic Interactions between Irinotecan and Oroxylin A in Rats via Physiologically Based Pharmacokinetic Modeling.

PURPOSE: Our previous screening studies identified Oroxylin A (OXA) as a strong inhibitor on the carboxyolesterase mediated hydrolysis of irinotecan to SN-38. The current study employed a whole-body physiologically based pharmacokinetic (PBPK) modeling approach to investigate the underlying mechanisms of the carboxylesterase-mediated pharmacokinetics interactions between irinotecan and OXA in rats. METHODS: Firstly, rats received irinotecan intravenous treatment at 35 µmol/kg without or with oral OXA pretreatment (2800 µmol/kg) daily for 5 days. On day 5, blood and tissues were collected for analyses of irinotecan/SN-38 concentrations and carboxylesterase expression. In addition, effects of OXA on the enzyme kinetics of irinotecan hydrolysis and unbound fractions of irinotecan and SN-38 in rat plasma, liver and intestine were also determined. Finally, a PBPK model that integrated the physiological parameters, enzyme kinetics, and physicochemical properties of irinotecan and OXA was developed. RESULTS: Our PBPK model could accurately predict the pharmacokinetic profiles of irinotecan/SN-38, with AUC0-6h and Cmax values within ±27% of observed values. When OXA was included as a carboxylesterase inhibitor, the model could also predict the irinotecan/SN-38 plasma concentrations within twofold of those observed. In addition, the PBPK model indicated inhibition of carboxylesterase-mediated hydrolysis of irinotecan in the intestinal mucosa as the major underlying mechanism for the pharmacokinetics interactions between irinotecan and OXA. CONCLUSION: A whole-body PBPK model was successfully developed to not only predict the impact of oral OXA pretreatment on the pharmacokinetics profiles of irinotecan but also reveal its inhibition on the intestinal carboxylesterase as the major underlying mechanism.

Overview of Current Herb-Drug Interaction Databases.

An HERB-Drug Interaction (HDI) database is a structured data collection method for HDI information extracted from scattered literatures for quick retrieval. Our review summarized the ten currently available HDI databases, including those databases comprising HDI on the market. A detailed comparison on the scope of monographs, including the nature of content extracted from the original literature and user interfaces of these databases, was performed, and the number of references of fifty popular herbs in each HDI database was counted and presented in a heatmap to give users an intuitive understanding of the focuses of different HDI databases. Since it is well known that the development and maintenance of databases need continuous investment of capital and manpower, the sustainability of these databases was also reviewed and compared. Recently, artificial intelligence (AI) technologies, especially Natural Language Processing (NLP), have been applied to screen specific topics from massive articles and automatically identify the names of drugs and herbs in the literature. However, its application on the labor-intensive extraction and evaluation of HDI-related experimental conditions and results from literature remains limited due to the scarcity of these HDI data and the lack of well-established annotated datasets for these specific NLP recognition tasks. In view of the difficulties faced by current HDI databases and potential expansion of AI application in HDI database development, we propose a standardized format for data reporting and use of Concept Unique Identifier (CUI) for medical terms in the literature to accelerate the structured data collection. SIGNIFICANCE STATEMENT: The worldwide popularity of botanical and/or traditional medicine products has raised safety concerns due to potential HDI. However, the publicly available HDI databases are mostly outdated or incomplete. Through our review of the currently available HDI databases, a clear understanding of the key issues could be obtained and possible solutions to overcome the labour-intensive extraction as well as professional evaluation of information in HDI database development are proposed.

Efficacy and safety of a bridging strategy that uses intravenous platelet glycoprotein receptor inhibitors for patients undergoing surgery after coronary stent implantation: a meta-analysis.

BACKGROUND: Current guidelines indicate we can consider a bridging strategy that uses intravenous, reversible glycoprotein inhibitors for patients that required surgery following recent stent implantation. However, no strong clinical evidence exists that demonstrates the efficacy and safety of this treatment. Therefore, in this study, the efficacy and safety of a bridging strategy that uses intravenous platelet glycoprotein receptor inhibitors will be evaluated. METHODS: A meta-analysis was performed on preoperative bridging studies in patients undergoing coronary stent surgery. The primary outcome was the success rate of no major adverse cardiovascular events (MACE). The secondary outcomes were the success rate of no reoperations to stop bleeding. RESULTS: A total of 10 studies that included 382 patients were used in this meta-analysis. For the primary endpoint, the success rate was 97.7% (95% CI 94.4-98.0%) for glycoprotein IIb/IIIa inhibitors, 98.8% (95% CI 96.0-100%) for tirofiban (6 studies) and 95.8% (95% CI 90.4-99.4%) for eptifibatide (4 studies). For secondary endpoints, the success rate was 98.0% (95% CI 94.8-99.9%) for glycoprotein IIb/IIIa inhibitors, 99.7% (95% CI 97.1-100%) for tirofiban (5 studies), and 95.3% (95% CI 88.5-99.4%) for eptifibatide (4 studies). CONCLUSION: The results of this study showed that the use of intravenous platelet glycoprotein IIb/IIIa inhibitors as a bridging strategy might be safe and effective for patients undergoing coronary stent implantation that require surgery soon after.

Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model.

Furmonertinib (AST2818) is a novel third-generation irreversible EGFR TKI and recently has been approved in China for the treatment of non-small cell lung cancer (NSCLC) with EGFR-sensitizing and T790M resistance mutations. In the current study, we developed a semi-mechanistic population pharmacokinetic model to characterize the nonstationary pharmacokinetics (PK) of the furmonertinib and its active metabolite AST5902 simultaneously. The PK data of furmonertinib and AST5902 were obtained from 38 NSCLC patients and 16 healthy volunteers receiving 20-240 mg furmonertinib in three clinical trials. A nonlinear mixed-effects modeling approach was used to describe the PK data. The absorption process of furmonertinib was described by a transit compartment model. The disposition of both furmonertinib and AST5902 was described by a two-compartment model. An indirect response model accounted for the autoinduction of furmonertinib metabolism mediated by CYP3A4. The model-based simulation suggested that furmonertinib clearance was increased in one cycle of treatment (orally once daily for 21 days) compared to baseline, ranging from 1.1 to 1.8 fold corresponding to the dose range of 20-240 mg. The concentration of furmonertinib was decreased over time whereas that of AST5902 was increased. Interestingly, the concentration of the total active compounds (furmonertinib and AST5902) appeared to be stable. The food intake, serum alkaline phosphatase and body weight were identified as statistically significant covariates. The mechanism of food effect on PK was investigated, where the food intake might increase the bioavailability of furmonertinib via increasing the splanchnic blood flow. Overall, a population PK model was successfully developed to characterize the nonstationary PK of furmonertinib and AST5902 simultaneously. The concentrations of total active compounds were less affected by the autoinduction of furmonertinib metabolism.

Accumulation of the Major Components from Polygoni Multiflori Radix in Liver and Kidney after Its Long-Term Oral Administrations in Rats.

Although Polygoni Multiflori Radix (PMR) has been widely used as a tonic and an anti-aging remedy for centuries, the extensively reported hepatotoxicity and potential kidney toxicity hindered its safe use in clinical practice. To better understand its toxicokinetics, the current study was proposed, aiming to evaluate the biodistributions of the major PMR components including 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucopyranoside (TSG), emodin, emodin-8-O-ß-D-glucopyranoside (EMG) and physcion as well as their corresponding glucuronides following bolus and multiple oral administrations of PMR to rats. Male Sprague-Dawley rats received a bolus dose or 21 days of oral administrations of PMR concentrated granules at 4.12 g/kg (equivalent to 20.6 g/kg raw material). Fifteen minutes after bolus dose or the last dose on day 21, rats were sacrificed and the blood, liver, and kidney were collected for the concentration determination of both parent form and glucuronides of TSG, emodin, EMG, and physcion by HPLC-MS/MS. Among all the tested analytes, TSG, EMG, EMG glucuronides in liver and TSG, EMG, as well as all the glucuronides of these analytes in the kidney demonstrated the most significant accumulation after multiple doses. Moreover, the levels of the parent analytes were all significantly higher in liver and kidney in comparison to their plasma levels. Strong tissue binding of all four analytes and accumulation of TSG, EMG, and EMG glucuronides in the liver and TSG, EMG, as well as the glucuronides of all four analytes in the kidney after multiple dosing of PMR were considered to be associated with its toxicity.

Immune-related myocarditis in two patients receiving camrelizumab therapy and document analysis.

INTRODUCTION: Camrelizumab is an antibody against programmed death protein 1 (PD-1) and is one of immune checkpoint inhibitors (ICI). ICI may lead to autoimmune myocarditis, which has a variety of clinical manifestations and usually has a poor prognosis. This article will discuss these clinical manifestations through 2 cases of ICI-related myocarditis caused by carrelizumab. CASE REPORT: We reviewed the patients who received tumor treatment in our hospital from September 2019 to June 2020. A total of 155 patients received camrelizumab treatment. there were 2 cases of acute myocarditis, accounting for 1.29%, and 8 cases of new-onset arrhythmia. Here we present 2 cases of active myocarditis in a 69-year-old man with primary liver cancer and a 75-year-old man with non-small-cell lung cancer after treatment with camrelizumab.Management and outcome: The first patient presented with severe heart failure and died of malignant arrhythmia after being treated with glucocorticoid. The second patient presented with numbness of the extremities, weakness, and mild dyspnea. The symptoms gradually improved after treatment with glucocorticoid. The Naranjo scores of these two cases were 6 and 7, which suggested that myocarditis was probably caused by carrelizumab. DISCUSSION: ICI has been successfully used to treat a variety of malignant tumors with good results. However, blocking immune checkpoints by ICI may lead to autoimmune myocarditis with a poor prognosis. Early detection of cardiotoxicity may be possible through the patient's clinical manifestations and some commonly used cardiac examination methods.

208-µs single-shot multi-molecular sensing with spectrum-encoded dual-comb spectroscopy.

Dual-comb spectroscopy (DCS) is a powerful spectroscopic technique, which is developing for the detection of transient species in reaction kinetics on a short time scale. Conventionally, the simultaneous determination of multiple species is limited to the requirement of broadband spectral measurement at the cost of the measurement speed and spectral resolution owing to the inherent trade-off among these characteristics in DCS. In this study, a high-speed multi-molecular sensing is demonstrated and achieved through using a programmable spectrum-encoded DCS technique, where multiple narrow encoding spectral bands are reserved selectively and other comb lines are filtered out. As a dual-comb spectrometer with a repetition rate of 108 MHz is encoded spectrally over a spectral coverage range of 1520 to 1580 nm, the measurement speed is increased 6.15 times and single-shot absorption spectra of multiple molecules (C2H2, HCN, CO, CO2) at a time scale of 208 µs are obtained. Compared to conventional single-shot dual-comb spectra, encoded dual-comb spectra have improved short-term signal-to-noise ratios (SNRs) by factors of 3.65 with four encoding bands and 5.68 with two encoding bands. Furthermore, a fiber-Bragg-grating-based encoded DCS is demonstrated, which reaches 17.1 times higher average SNR than that of the unencoded DCS. This spectrum-encoded technique can largely improve the DCS measurement speed, and thus is promising for use in studies on multi-species reaction kinetics.

The 'diamond' approach to personalized drug treatment of heart failure with reduced ejection fraction.

Heart failure (HF) is a complex clinical syndrome with symptoms and signs due to cardiac dysfunction, leading to high hospitalization and morbidity. HF treatment has rapidly developed in recent decades, and breakthroughs have been made. Although conventional neurohormonal blockade therapies, including ß-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), significantly improve the prognosis of patients with heart failure with reduced ejection fraction (HFrEF), mortality and rehospitalization remain high. Therefore, new therapies are needed. Previous studies demonstrated that ivabradine, angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 (SGLT2) inhibitor, vericiguat, and omecamtiv mecarbil (OM) are beneficial for HFrEF. However, there is a lack of systematic review of the most optimal manner to use under various clinical conditions. This review summarizes the current knowledge regarding these therapies to give suggestions regarding clinical use timing, application scope, and optimal therapies under various conditions. Most importantly, we propose the HF diamond approach to express the necessity of conjunction of therapies. Different from the current guidelines, we suggest to use the diamond approach in an early and comprehensive manner at the beginning of ventricular remodeling in HFrEF to prevent further deterioration of HF and maximize the prognosis of patients.

Achieving Precise Spectral Analysis and Imaging Simultaneously with a Mode-Resolved Dual-Comb Interferometer.

In this paper, we report a scheme providing precise spectral analysis and surface imaging, simultaneously, based on a high-coherence dual-comb interferometer. With two tightly phase-locking frequency combs, we demonstrate a high-coherence dual-comb interferometer (DCI) covering 188 to 195 THz (1538.5 to 1595.7 nm) with comb-tooth resolution and a max spectral signal-to-noise ratio (SNR) of 159.7. The combination of the high-coherence dual-comb spectrometer and a reference arm simultaneously enables gas absorption spectroscopy and for the absolute distance information to be obtained in one measurement. As a demonstration, we measure the spectrum of CO2 and CO. From the same interferograms, we demonstrate that distance measurement, by time-of-flight (TOF), can be resolved with an rms precision of 0.53 µm after averaging 140 images and a measurement time of 1 s. Finally, we demonstrate that non-contact surface imaging, using 2D mechanical scanning, reaches lateral resolution of 40 µm. The longitudinal precision is 0.68 µm with a measurement time of 0.5 s. It verifies that DCS has the potential to be applied in standoff detection, environmental pollution monitors, and remote sensing.

High-repetition-rate mid-IR femtosecond pulse synthesis from two mid-IR CW QCL-seeded OPAs.

Coherent pulse synthesis in the mid-infrared (mid-IR) domain is of great interest to achieve broadband sources from parent pulses, motivated by the advantages of optical frequency properties for molecular spectroscopy and quantum dynamics. We demonstrate a simple mid-IR coherent synthesizer based on two high-repetition-rate optical parametric amplifiers (OPAs) at nJ-level pump energy. The relative carrier envelope phase between the two OPAs was passively stable for a shared continuous wave (CW) quantum cascade laser (QCL) seed. Lastly, we synthesized mid-IR pulses with a duration of 105 fs ranging from 3.4 to 4.0 µm. The scheme demonstrated the potential to obtain broader mid-IR sources by coherent synthesis from multiple CW QCL-seeded OPAs.

Reduced systemic exposure and brain uptake of donepezil in rats with scopolamine-induced cognitive impairment.

1. Donepezil (DPZ) is an acetylcholinesterase (AchE) inhibitor used in the mild to moderately severe Alzheimer's disease. Among its major metabolites, 6-O-desmethyl DPZ (6-DDPZ), 5-O-desmethyl DPZ (5-DDPZ) and DPZ N-oxide, the anti-AchE activities of 5-DDPZ and DPZ N-oxide have never been clearly identified before. Besides, there is no report on simultaneous determination of DPZ and its three metabolites in the brain, thus their uptake in hippocampus and cortex are unknown. Therefore, the current studies are proposed aiming to: (1) investigate the anti-AchE activities and brain uptake of DPZ and its three metabolites and (2) compare their pharmacokinetics and brain uptake between normal and scopolamine-induced rats.2. DPZ and its three metabolites demonstrated anti-AchE activities with the IC50 in the order of DPZ (7.20 × 10-2 µM), 6-DDPZ (1.14 × 10-1 µM), 5-DDPZ (4.03 × 10-1 µM) and DPZ N-oxide (1.61 µM). They were also evenly distributed in the brain and retained much longer in the brain than that in plasma in normal rats.3. Compared to normal rats, Cmax, AUC0→24h and AUC0→∞ of DPZ were reduced by 52.0%, 31.2% and 30.1%, respectively; Tmax of DPZ and its three metabolites were prolonged and their brain uptake were decreased in scopolamine-induced rats, suggesting the potential reduced absorption of DPZ.

High-repetition-rate femtosecond mid-infrared pulses generated by nonlinear optical modulation of continuous-wave QCLs and ICLs.

We demonstrate an effective method to obtain high-repetition-rate femtosecond mid-infrared (mid-IR) pulses by nonlinear optical modulation of mid-IR continuous-wave (CW) quantum and interband cascade lasers (ICLs and QCLs). In the experiment, a high-repetition-rate femtosecond ytterbium-doped fiber laser with nanojoule-level pulse energy was used as the pump source of optical parametric amplifiers to modulate and amplify the mid-IR CW laser. Near transform-limited 84 fs duration (7.3 cycles) mid-IR pulses were generated with above 200 mW average power and a repetition rate of 160 MHz. Moreover, the spectral tunability was demonstrated using CW QCL at different wavelengths. The scheme offered a simple method to produce high-repetition-rate ultrashort pulses and that can be flexibly adopted in other mid-IR regions.

Nusbiarylins, a new class of antimicrobial agents: Rational design of bacterial transcription inhibitors targeting the interaction between the NusB and NusE proteins.

Discovery of antibiotics of a novel mode of action is highly required in the fierce battlefield with multi-drug resistant bacterial infections. Previously we have validated the protein-protein interaction between bacterial NusB and NusE proteins as an unprecedented antimicrobial target and reported the identification of a first-in-class inhibitor of bacterial ribosomal RNA synthesis with antimicrobial activities. In this paper, derivatives of the hit compound were rationally designed based on the pharmacophore model for chemical synthesis, followed by biological evaluations. Some of the derivatives demonstrated the improved antimicrobial activity with the minimum inhibitory concentration (MIC) at 1-2 µg/mL against clinically significant bacterial pathogens. Time-kill kinetics, confocal microscope, ATP production, cytotoxicity, hemolytic property and cell permeability using Caco-2 cells of a representative compound were also measured. This series of compounds were named "nusbiarylins" based on their target protein NusB and the biaryl structure and were expected to be further developed towards novel antimicrobial drug candidates in the near future.