Ultrasound analysis of cervical thoracic duct for patients with constrictive pericarditis and chylothorax.

PURPOSE: To analyze ultrasound features of cervical thoracic duct for patients with constrictive pericarditis and chylothorax. METHODS: Patients were retrospectively assessed. The patients were divided into a non-pleural effusion (PE) group (n = 54), a chylothorax group (n = 23), and non-chylothorax group (n = 28). Conventional ultrasound was used to obtain the maximum inner diameter and collapse of the inferior vena cava, the inner diameter of left cervical thoracic duct, and the frequency of opening of the valve at the end of the left thoracic duct. Contrast ultrasonography was used to score the reverse flow of the thoracic tube. RESULTS: The percentage of PE was 48.5%, and the percentage of chylothorax was 21.9%. The three groups had significant differences in five parameters. The inner diameter of left cervical thoracic duct was correlated with the degree of central venous pressure. Contrast ultrasonography was effective in quantitative assessment of the degree of intravenous-thoracic cord reverse flow which correlated with all parameters of central venous pressure. CONCLUSION: Thoracic duct dilation and regurgitation secondary to central venous pressure can lead to chyloreflux disorder and may be the mechanism of chylothorax occurrence in constrictive pericarditis.

Inorganic carbon is overlooked in global soil carbon research: A bibliometric analysis.

Soils are a major player in the global carbon (C) cycle and climate change by functioning as a sink or a source of atmospheric carbon dioxide (CO2). The largest terrestrial C reservoir in soils comprises two main pools: organic (SOC) and inorganic C (SIC), each having distinct fates and functions but with a large disparity in global research attention. This study quantified global soil C research trends and the proportional focus on SOC and SIC pools based on a bibliometric analysis and raise the importance of SIC pools fully underrepresented in research, applications, and modeling. Studies on soil C pools started in 1905 and has produced over 47,000 publications (>1.7 million citations). Although the global C stocks down to 2 m depth are nearly the same for SOC and SIC, the research has dominantly examined SOC (>96 % of publications and citations) with a minimal share on SIC (<4%). Approximately 40 % of the soil C research was related to climate change. Despite poor coverage and publications, the climate change-related research impact (citations per document) of SIC studies was higher than that of SOC. Mineral associated organic carbon, machine learning, soil health, and biochar were the recent top trend topics for SOC research (2020-2023), whereas digital soil mapping, soil properties, soil acidification, and calcite were recent top trend topics for SIC. SOC research was contributed by 151 countries compared to 88 for SIC. As assessed by publications, soil C research was mainly concentrated in a few countries, with only 9 countries accounting for 70 % of the research. China and the USA were the major producers (45 %), collaborators (37 %), and funders of soil C research. SIC is a long-lived soil C pool with a turnover rate (leaching and recrystallization) of more than 1000 years in natural ecosystems, but intensive agricultural practices have accelerated SIC losses, making SIC an important player in global C cycle and climate change. The lack of attention and investment towards SIC research could jeopardize the ongoing efforts to mitigate climate change impacts to meet the 1.5-2.0 °C targets under the Paris Climate Agreement of 2015. This bibliographic study calls to expand the research focus on SIC and including SIC fluxes in C budgets and models, without which the representation of the global C cycle is incomplete.

Multi-Wavelength-Recognizable Memristive Devices via Surface Plasmon Resonance Effect for Color Visual System.

Photoelectric memristor has attracted many attentions thanks to their promising potential in optical communication chips and artificial vision systems. However, the implementation of an artificial visual system based on memristive devices remains a considerable challenge because most photoelectric memristors cannot recognize color. Herein, multi-wavelength recognizable memristive devices based on silver(Ag) nanoparticles (NPs) and porous silicon oxide (SiOx ) nanocomposites are presented. Rely on the effects of localized surface plasmon resonance (LSPR) and optical excitation of Ag NPs in SiOx , the set voltage of the device can be gradually reduced. Moreover, the current overshoot problem is alleviated to suppress conducting filament overgrowth after visible light irradiation with different wavelengths, resulting in diverse low resistance states (LRS). Taking advantage of the characteristics of controlled switching voltage and LRS resistance distribution, color image recognition is finally realized in the present work. X-ray photoelectron spectroscopy (XPS) and conductive atomic force microscopy (C-AFM) show that the light irradiation plays an important role on resistive switching (RS) process: the photo-assisted Ag ionization leads to a significant reduction of set voltage and overshoot current. This work provides an effective method toward the development of multi-wavelength-recognizable memristive devices for future artificial color vision system.

Temperature and organic carbon quality control the anaerobic carbon mineralization in peat profiles via modulating microbes: A case study of Changbai Mountain.

Peatlands account for a significant fraction of the global carbon stock. However, the complex interplay of abiotic and biotic factors governing anaerobic carbon mineralization in response to warming remains unclear. In this study, peat sediments were collected from a typical northern peatland-Changbai Mountain to investigate the behavior and mechanism of anaerobic carbon mineralization in response to depth (0-200 cm) and temperature (5 °C, 15 °C and 20 °C), by integrating geochemical and microbial analysis. Several indices including humification indexes (HI), aromaticity, and water extractable organic carbon (WEOC) components were applied to evaluate carbon quality, while 16S rRNA sequencing was used to measure microbial composition. Regardless of temperature, degradations of carbon quality and associated reduction in microbial abundance as well as diversity resulted in a decrease in anaerobic carbon mineralization (both CO2 and CH4) towards greater depth. Warming either from 5 °C to 15 °C or 20 °C significantly increased anaerobic carbon mineralization in all depth profiles by improving carbon availability. Enhanced carbon availabilities were mediated by the change in microbial composition (p < 0.01) and an increase in metabolic activities, which was particularly evident in the enhanced ß-glucosidase activity and microbial collaborations. A remarkable increase of over 10-fold in the relative abundance of the Geothrix genus was observed under warming. Overall, warming resulted in an enhanced contribution of CH4 emission and a higher ratio of hydrogenotrophic methanogenesis, as evidenced by carbon isotope fractionation factors. In addition, deep peat soils (>100 cm) with recalcitrant carbon demonstrated greater temperature sensitivity (Q10: ∼2.0) than shallow peat soils (Q10:∼1.2) when temperature increased from 15 °C to 20 °C. The findings of this study have significantly deepened our understanding for mechanisms of carbon quality and microbe-driven anaerobic carbon mineralization in peatlands under global warming.

Indexing brain state-dependent pupil dynamics with simultaneous fMRI and optical fiber calcium recording.

Pupillometry, a noninvasive measure of arousal, complements human functional MRI (fMRI) to detect periods of variable cognitive processing and identify networks that relate to particular attentional states. Even under anesthesia, pupil dynamics correlate with brain-state fluctuations, and extended dilations mark the transition to more arousable states. However, cross-scale neuronal activation patterns are seldom linked to brain state-dependent pupil dynamics. Here, we complemented resting-state fMRI in rats with cortical calcium recording (GCaMP-mediated) and pupillometry to tackle the linkage between brain-state changes and neural dynamics across different scales. This multimodal platform allowed us to identify a global brain network that covaried with pupil size, which served to generate an index indicative of the brain-state fluctuation during anesthesia. Besides, a specific correlation pattern was detected in the brainstem, at a location consistent with noradrenergic cell group 5 (A5), which appeared to be dependent on the coupling between different frequencies of cortical activity, possibly further indicating particular brain-state dynamics. The multimodal fMRI combining concurrent calcium recordings and pupillometry enables tracking brain state-dependent pupil dynamics and identifying unique cross-scale neuronal dynamic patterns under anesthesia.

Efficacy of contrast-enhanced ultrasound in detection of type II endoleak after abdominal aortic aneurysm surgery: A prospective cohort study.

PURPOSE: This study aimed to evaluate the efficacy of conventional contrast-enhanced ultrasound (CEUS) in detection of type II endoleak after endovascular abdominal aortic aneurysm repair (EVAR). METHODS: From January 2015 to April 2018, 205 patients underwent EVAR were included. CEUS and computed tomography angiography (CTA) were performed at 1-month follow-up postoperatively to detect type II endoleak. CEUS was performed at 3- and 6-month follow-up to evaluate the development of type II endoleak. The diameter extension of type II endoleak increased greater than 5 mm was defined as enlarge group, and that increased less than 5 mm was defined as stable group. The difference of arrival time (AT) of contrast agent, maximum cross-sectional area (MCSA) of contrast agent and the blood flow velocity (BFV) of the abnormal blood around the stent graft were compared. RESULTS: At 1-month after EVAR, 65 cases of endoleak were detected by CEUS, including 25 cases of type I, 30 cases of type II endoleak and 10 cases of type III endoleak. Among them, 50 cases were also detected by CTA. The diameter extension of 12 cases of type II endoleak increased greater than 5 mm, and that of eight cases increased less than 5 mm. The average AT of the enlarge group was significantly shorter than that of the stable group, while the MCSA of contrast agent and the BFV were significantly higher than that of the stable group (p < 0.05). CONCLUSION: CEUS has predictive value for the natural outcome of type II endoleak.

Zeolite-Based Memristive Synapse with Ultralow Sub-10-fJ Energy Consumption for Neuromorphic Computation.

The development of neuromorphic computation faces the appreciable challenge of implementing hardware with energy consumption on the level of a femtojoule per synaptic event to be comparable with the energy consumption of human brain. Controllable ultrathin conductive filaments are needed to achieve such extremely low energy consumption in memristive synapses but their formation is difficult to control owing to their stochastic morphology and unexpected overgrowth. Herein, a zeolite-based memristive synapse is demonstrated for the first time, in which Ag exchange in the sub-nanometer pore closely resembles synaptic Ca2+ dynamics across biomembrane channel. Particularly, the confined ultrasmall pore and low Ag ion migration barrier give the zeolite-based memristive synapse ultralow energy consumption below 10 fJ per synaptic spike, on par with the biological counterpart. Experimental results reveal that the gradual memristive effect is attributed to the dimension modulation of Ag clusters. In addition to emulating inherent cognitive functions through electrical stimulations, the experience-dependent transition of short-term plasticity to long-term plasticity using a chemical modulation method is achieved by treating the initial Ag quantity as a learning experience. The proposed memristors can be used to develop highly efficient memristive neural networks and are considered as a candidate for application in neuromorphic computation.

CDX2 and Reg IV expression and correlation in gastric cancer.

BACKGROUND: Ectopic expression of CDX2 is associated with the development and progression of gastric cancer. Previous studies showed that CDX2 may be an upstream regulator of Reg IV expression in gastric cancer, and our previous report showed that Reg IV upregulated SOX9 expression and enhanced cell migration and invasion in gastric cancer cells. However, the regulatory roles of CDX2 have not been clarified in gastric cancer, and the correlation between CDX2 and Reg IV requires further study. METHODS: CDX2 and Reg IV were examined in gastric cancer specimens and paired adjacent tissues via real-time PCR and immunohistochemistry (IHC). The association between CDX2 and Reg IV was assessed using the χ2-test and Spearman's rank correlation. To verify their relationship, knockdown and exogenous expression of CDX2 or Reg IV were performed in AGS and MKN-45 gastric cancer cells, and their expression was subsequently analyzed via a real-time PCR and western blotting. Wound-healing and Transwell assays were used to examine migration and invasion in AGS and MKN-45 cells following CDX2 silencing or overexpression. RESULTS: A positive correlation was observed between CDX2 and Reg IV expression at the mRNA and protein levels in gastric cancer tissues. CDX2 silencing significantly downregulated Reg IV expression, and CDX2 overexpression significantly upregulated Reg IV expression in AGS and MKN-45 cells. Neither Reg IV silencing nor overexpression had any effect on CDX2 protein expression in AGS or MKN-45 cells, even though both affected the expression of CDX2 mRNA. Functionally, CDX2 silencing significantly inhibited cell migration and invasion, and CDX2 overexpression significantly promoted cell migration and invasion in AGS and MKN-45 cells. CONCLUSIONS: Our findings demonstrate that CDX2 expression was positively correlated with that of Reg IV in gastric cancer, and CDX2 promoted cell migration and invasion through upregulation of Reg IV expression in AGS and MKN-45 cells.

A new phosphonium-based ionic liquid to synthesize nickel metaphosphate for hydrogen evolution reaction.

The electrochemical hydrogen evolution reaction (HER) is a promising strategy for production of hydrogen; however, it is still restricted by appropriate efficient and low-cost electrocatalysts. Herein, for the first time, the n-octylammonium hypophosphite, a kind of protic ionic liquid (IL), was used as a new phosphorus source for the manufacture of nickel metaphosphate (Ni2P4O12) electrocatalysts. In contrast to traditional multi-step fabrication processes, the n-octylammonium hypophosphite acted as both reactant and solvent to synthesize Ni2P4O12 by a one-step calcination approach. The obtained Ni2P4O12 as an alkaline HER catalyst required a low overpotential of 116 mV at -10 mA cm-2 and a small Tafel slope of 97 mV dec-1, comparable to the majority of reported Ni-based materials and other phosphate catalysts. Furthermore, this catalyst exhibited robust stability with no distinct attenuation of current density after a long-term durability test in 1 M KOH. Therefore, this task-specific IL strategy with a simple reaction system, reducing the occurrence of side reactions, provided a new perspective on design of high-efficiency metaphosphate electrocatalysts.

Biodegradable Natural Pectin-Based Flexible Multilevel Resistive Switching Memory for Transient Electronics.

Transient electronics that can physically vanish in solution can offer opportunities to address the ecological challenges for dealing with the rapidly growing electronic waste. As one important component, it is desirable that memory devices combined with the transient feature can also be developed as secrecy information storage systems besides the above advantage. Resistive switching (RS) memory is one of the most promising technologies for next-generation memory. Herein, the biocompatible pectin extracted from natural orange peel is introduced to fabricate RS memory devices (Ag/pectin/indium tin oxides (ITO)), which exhibit excellent RS characteristics, such as forming free characteristic, low operating voltages (≈1.1 V), fast switching speed (<70 ns), long retention time (>104 s), and multilevel RS behaviors. The device performance is not degraded after 104 bending cycles, which will be beneficial for flexible memory applications. Additionally, instead of using acid solution, the Ag/pectin/ITO memory device can be dissolved rapidly in deionized water within 10 min thanks to the good solubility arising from ionization of its carboxylic groups, which shows promising application for green electronics. The present biocompatible memory devices based on natural pectin suggest promising material candidates toward enabling high-density secure information storage systems applications, flexible electronics, and green electronics.

Multilevel Resistive Switching in P-N Heterostructure Memory.

High storage density is an important requirement for resistive random access memory (RRAM) devices. Multilevel resistive switching (RS) in RRAMs does not require much change to current technologies compared with device size reduction and 3D integration. Herein, five stable resistance states can be obtained in a Pt/p-NiO/n+-Si memory device by controlling the current compliance (CC). The RS mechanism can be attributed to the formation and rupture of localized conducting filaments (CFs) in an NiO film. The conductivity of the low resistance states (LRS) is determined through the combined action of the P-N junction and localized CFs. The CC can be used to effectively modulate the formation of localized CFs and junction resistance. Importantly, different LRS have large differences in resistance values, resulting in multilevel memory. A model is suggested and discussed to account for the observed multilevel memory operation.

Amphiphilic Endomorphin-1 Derivative Functions as Self-assembling Nanomedicine for Effective Brain Delivery.

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1), an endogenous µ-opioid receptor ligand with strong antinociceptive activity, is not in clinical use because of its limited metabolic stability and membrane permeability. In this study, we develop a short-peptide self-delivery system for brain targets with the capability to deliver EM-1 without vehicle. Two amphiphilic EM-1 derivatives, C18-SS-EM1 and C18-CONH-EM1, were synthesized by attaching a stearyl moiety to EM-1 via a disulfide and amide bond, respectively. The amphiphilicity of EM-1 derivatives enabled self-assembling into nanoparticles for brain delivery. The study assessed morphology, circular dichroism, and metabolic stability of the formulations, as well as their pharmacodynamics and in vivo distribution, directly monitored by near-IR fluorescence imaging in mouse brains. In aqueous solution, the C18-SS-EM1 derivative self-assembled into spherical nanostructures with a diameter of 10-20 nm. Near-IR fluorescence analysis visualized the accumulation of the peptides in the brain. Importantly, the analgesic effect of C18-SS-EM1 nanoparticles was significantly stronger as compared to that of unmodified EM-1 or C18-CONH-EM1 nanoparticles. An in vitro release study demonstrated that self-assembled C18-SS-EM1 nanoparticles possessed reduction-responsive behavior. In summary, self-assembling C18-SS-EM1 nanoparticles, which integrate the advantages of lipidization, nanoscale characteristics and, labile disulfide bonds, represent a promising strategy for brain delivery of short peptides.

Photocatalytic Reduction of Graphene Oxide-TiO2 Nanocomposites for Improving Resistive-Switching Memory Behaviors.

Graphene oxide (GO)-based resistive-switching (RS) memories offer the promise of low-temperature solution-processability and high mechanical flexibility, making them ideally suited for future flexible electronic devices. The RS of GO can be recognized as electric-field-induced connection/disconnection of nanoscale reduced graphene oxide (RGO) conducting filaments (CFs). Instead of operating an electrical FORMING process, which generally results in high randomness of RGO CFs due to current overshoot, a TiO2 -assisted photocatalytic reduction method is used to generate RGO-domains locally through controlling the UV irradiation time and TiO2 concentration. The elimination of the FORMING process successfully suppresses the RGO overgrowth and improved RS memory characteristics are achieved in graphene oxide-TiO2 (Go-TiO2 ) nanocomposites, including reduced SET voltage, improved switching variability, and increased switching speed. Furthermore, the room-temperature process of this method is compatible with flexible plastic substrates and the memory cells exhibit excellent flexibility. Experimental results evidence that the combined advantages of reducing the oxygen-migration barrier and enhancing the local-electric-field with RGO-manipulation are responsible for the improved RS behaviors. These results offer valuable insight into the role of RGO-domains in GO memory devices, and also, this mild photoreduction method can be extended to the development of carbon-based flexible electronics.

Identification of the absorbed components and metabolites of modified Huo Luo Xiao Ling Dan in rat plasma by UHPLC-Q-TOF/MS/MS.

To reveal the material basis of Huo Luo Xiao Ling Dan (HLXLD), a sensitive and selective ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) method was developed to identify the absorbed components and metabolites in rat plasma after oral administration of HLXLD. The plasma samples were pretreated by liquid-liquid extraction and separated on a Shim-pack XR-ODS C18 column (75 × 3.0 mm, 2.2 µm) using a gradient elution program. With the optimized conditions and single sample injection of each positive or negative ion mode, a total of 109 compounds, including 78 prototype compounds and 31 metabolites, were identified or tentatively characterized. The fragmentation patterns of representative compounds were illustrated as well. The results indicated that aromatization and hydration were the main metabolic pathways of lactones and tanshinone-related metabolites; demethylation and oxidation were the major metabolic pathways of alkaloid-related compounds; methylation and sulfation were the main metabolic pathways of phenolic acid-related metabolites. It is concluded the developed UHPLC-Q-TOF/MS method with high sensitivity and resolution is suitable for identifying and characterizing the absorbed components and metabolites of HLXLD, and the results will provide essential data for further studying the relationship between the chemical components and pharmacological activity of HLXLD.

Compatibility effects of herb pair Phellodendri chinensis cortex and Anemarrhenae rhizoma on benign prostatic hyperplasia using targeted metabolomics.

Phellodendri chinensis cortex (P. C. cortex) and Anemarrhenae rhizoma (A. rhizoma) herb pair is a core component of traditional Chinese medicines used to treat inflammation and benign prostatic hyperplasia (BPH). The present study was designed to profile the arachidonic acid (AA) metabolomic characteristics in rat plasma and prostate after being treated with P. C. cortex and A. rhizoma as well as their combination. Plasma and prostate samples from sham group, BPH model group, herb pair group and two single herb groups were collected on days 7, 14, 21 and 28. Then, a systemic metabolomic analysis based on UFLC-MS/MS was employed to quantify AA and its cyclooxygenase and lipoxygenase pathway metabolites (15-HETE, 12-HETE, 5-HETE, AA, PGI2 , PGF2α , 8-HETE, PGD2 , PGE2 and LTB4 ). The results demonstrated that BPH led a significant increase of 10 biomarkers in plasma and tissue (p < 0.05). The clusters of herb pair group and single herb groups showed a tendency to return to the initial space, and the AA and its metabolites from those groups were differently downregulated to a healthier level, with the combination of single herbs most obvious. The present study demonstrated that P. C. cortex-A. rhizoma herb pair might produce synergistic or complementary compatibility effects on suppressing inflammatory processes occurring in BPH.

Highly Chemiluminescent Magnetic Beads for Label-Free Sensing of 2,4,6-Trinitrotoluene.

Until now, despite the great success acquired in scientific research and commercial applications, magnetic beads (MBs) have been used for nothing more than a carrier in most cases in bioassays. In this work, highly chemiluminescent magnetic beads containing N-(4-aminobutyl)-N-ethyl isoluminol (ABEI) and Co2+ (Co2+/ABEI/MBs) were first synthesized via a facile strategy. ABEI and Co2+ were grafted onto the surface of carboxylated MBs by virtue of a carboxyl group and electrostatic interaction. The as-prepared Co2+/ABEI/MBs exhibited good paramagnetic properties, satisfactory stability, and intense chemiluminescence (CL) emission when reacted with H2O2, which was more than 150 times that of ABEI functionalized MBs. Furthermore, it was found that 2,4,6-trinitrotoluene (TNT) aptamer could attach to the surface of Co2+/ABEI/MBs via electrostatic interaction and coordination interaction between TNT aptamer and Co2+, leading to a decrease in CL intensity due to the catalytic site Co2+ being blocked by the aptamer. In the presence of TNT, TNT would bind strongly with TNT aptamer and detach from the surface of Co2+/ABEI/MBs, resulting in partial restoration of the CL signal. Accordingly, label-free aptasensor was developed for the determination of TNT in the range of 0.05-25 ng/mL with a detection limit of 17 pg/mL. This work demonstrates that Co2+/ABEI/MBs are easily connected with recognition biomolecules, which are not only magnetic carriers but also direct sensing interfaces with excellent CL activity. It provides a novel CL interface with a magnetic property which easily separates analytes from the sample matrix to construct label-free bioassays.

Ultralight Fe@C Nanocapsules/Sponge Composite with Reversibly Tunable Microwave Absorption Performances.

Microwave absorbers are usually designed to solve electromagnetic interferences at a specific frequency, while the requirements may be dynamic during service life. Therefore, a recoverable tuning for microwave absorption properties in response to an external stimulus would be highly desirable. We herein present a micro/nano-scale hybrid absorber, in which high-performance Fe@C nanocapsule absorbents are integrated with a porous melamine sponge skeleton, exhibiting multiple merits of light weight, strong absorption and high elasticity. By mechanically compressing and decompressing the absorber, microwave absorption performances can be effectively shifted between 18 GHz and 26.5 GHz. The present study thus provides a new strategy for the design of a 'dynamic' microwave absorber.

Pharmacokinetics, tissue distribution, and excretion studies of l-isocorypalmine using ultra high performance liquid chromatography with tandem mass spectrometry.

l-Isocorypalmine is a newly identified metabolite of l-tetrahydropalmatine with a unique dual pharmacological profile as a partial dopamine receptor 1 agonist and dopamine receptor 2 antagonist properties for treating cocaine use disorder. The purpose of this study was to explore the pharmacokinetic profiles, tissue distribution, and excretion of l-isocorypalmine in Sprague-Dawley rats. A sensitive and reliable ultra high performance liquid chromatography with tandem mass spectrometry method was developed and validated for determination of l-isocorypalmine in biological samples. The biological samples were extracted by liquid-liquid extraction and separated on a Bonshell ASB C18 column (2.1 × 100 mm, 2.7 µm, Agela) with gradient mobile phase at the flow rate of 0.2 mL/min. The detection was performed by positive electrospray ionization with multiple reaction monitoring mode. Satisfactory linearity, precision, accuracy, extraction recovery, and acceptable matrix effect were achieved. The quantitative method was successfully applied to the pharmacokinetics, tissue distribution, and excretion study of l-isocorypalmine. The results showed that l-isocorypalmine was rapidly distributed, and eliminated from rat plasma and manifested linear dynamics in a dose range of 7.5-15 mg/kg. In addition, the results would be helpful for further clinical reference of l-isocorypalmine as a potential candidate drug for the treatment of cocaine addiction.

Simultaneous determination of l-tetrahydropalmatine and its active metabolites in rat plasma by a sensitive ultra-high-performance liquid chromatography with tandem mass spectrometry method and its application in a pharmacokinetic study.

A sensitive and reliable ultra-high-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for simultaneous determination of l-tetrahydropalmatine (l-THP) and its active metabolites l-isocorypalmine (l-ICP) and L-corydalmine (l-CD) in rat plasma. The analytes were extracted by liquid-liquid extraction and separated on a Bonshell ASB C18 column (2.1 × 100 mm; 2.7 µm; Agela) using acetonitrile-formic acid aqueous as mobile phase at a flow rate of 0.2 mL/min in gradient mode. The method was validated over the concentration range of 4.00-2500 ng/mL for l-THP, 0.400-250 ng/mL for l-ICP and 1.00-625 ng/mL for l-CD. Intra- and inter-day accuracy and precision were within the acceptable limits of <15% at all concentrations. Correlation coefficients (r) for the calibration curves were >0.99 for all analytes. The quantitative method was successfully applied for simultaneous determination of l-THP and its active metabolites in a pharmacokinetic study after oral administration with l-THP at a dose of 15 mg/kg to rats.

AMG 580: a novel small molecule phosphodiesterase 10A (PDE10A) positron emission tomography tracer.

Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [(3)H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [(18)F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.