A mini-resonant photoacoustic sensor based on a sphere-cylinder coupled acoustic resonator for high-sensitivity trace gas sensing.

This paper reports a mini-resonant photoacoustic sensor for high-sensitivity trace gas sensing. The sensor primarily contains a sphere-cylinder coupled acoustic resonator, a cylindrical buffer chamber, and a fiber-optic acoustic sensor. The acoustic field distributions of this mini-resonant photoacoustic sensor and the conventional T-type resonant photoacoustic sensor have been carefully evaluated, showing that the first-order resonance frequency of the present mini-resonant photoacoustic sensor is reduced by nearly a half compared to that of the T-type resonant photoacoustic sensor. The volume of the developed photoacoustic cavity is only about 0.8 cm3. Trace methane is selected as the target analytical gas and a detection limit of 101 parts-per-billion at 100-s integration time has been achieved, corresponding to a normalized noise equivalent absorption (NNEA) coefficient of 1.04 × 10-8 W·cm-1·Hz-1/2. The developed mini-resonant photoacoustic sensor provides potential for high-sensitivity trace gas sensing in narrow spaces.

Proteoform-Resolved Profiling of Plasminogen Activation Reveals Novel Abundant Phosphorylation Site and Primary N-Terminal Cleavage Site.

Plasminogen (Plg), the zymogen of plasmin (Plm), is a glycoprotein involved in fibrinolysis and a wide variety of other physiological processes. Plg dysregulation has been implicated in a range of diseases. Classically, human Plg is categorized into two types, supposedly having different functional features, based on the presence (type I) or absence (type II) of a single N-linked glycan. Using high-resolution native mass spectrometry, we uncovered that the proteoform profiles of human Plg (and Plm) are substantially more extensive than this simple binary classification. In samples derived from human plasma, we identified up to 14 distinct proteoforms of Plg, including a novel highly stoichiometric phosphorylation site at Ser339. To elucidate the potential functional effects of these post-translational modifications, we performed proteoform-resolved kinetic analyses of the Plg-to-Plm conversion using several canonical activators. This conversion is thought to involve at least two independent cleavage events: one to remove the N-terminal peptide and another to release the active catalytic site. Our analyses reveal that these processes are not independent but are instead tightly regulated and occur in a step-wise manner. Notably, N-terminal cleavage at the canonical site (Lys77) does not occur directly from intact Plg. Instead, an activation intermediate corresponding to cleavage at Arg68 is initially produced, which only then is further processed to the canonical Lys77 product. Based on our results, we propose a refined categorization for human Plg proteoforms. In addition, we reveal that the proteoform profile of human Plg is more extensive than that of rat Plg, which lacks, for instance, the here-described phosphorylation at Ser339.

Effects of Metabolites, Sex, Sire, and Muscle Type on Chilled Lamb Meat Colour.

Meat is an important source of high-value protein providing sustainable nutrition for human health. The discolouration of meat results in significant waste, which threatens the sustainability of meat production in terms of availability, affordability, and utilisation. Advancing the knowledge of factors and underlying mechanisms for meat discolouration supports the sustainability transformation of meat production practices. Previous studies found that colour stability may be associated with signature changes in certain metabolites, including NADH, glutamate, methionine, and testosterone. This study aimed to confirm the effect of these metabolites and sex, sire, and muscle type on lamb meat colour. NADH and glutamate improved colour stability as evidenced by the increased metmyoglobin reductase activity, while methionine and testosterone had detrimental effects. Overall, lamb meat was discoloured with retail display for up to 10 days at 4 °C. The semitendinosus muscle had higher L*, b*, and hue angle and lower a* (p < 0.05) than other muscles, especially in ewes. Lamb meat from rams had a higher L* and hue angle and lower a* than the ewes (p < 0.05), especially in the colour-labile group, suggesting an interaction between sex and sire. The outcomes of this study will help make the production of meat more sustainable by assisting the meat industry in improving the selection of animals for meat production and processing practices to reduce meat waste due to discolouration.

Highly sensitive trace gas detection based on a miniaturized 3D-printed Y-type resonant photoacoustic cell.

We report, what we believe to be, a novel miniaturized 3D-printed Y-type resonant photoacoustic cell (YRPAC) consisting of a frustum of cone-type buffer chamber and a cylindrical resonant chamber. The volume of the designed YRPAC is about 7.0 cm3, which is only about a half of the T-resonant photoacoustic cell (TRPAC). The finite element simulation of the sound field distribution of the TRPAC and YRPAC based on COMSOL shows that the photoacoustic signal is enhanced with the shape of the buffer chamber changing from the traditional cylinder to a frustum of cone. The photoacoustic spectroscopy (PAS) system, utilizing the YRPAC and TRPAC as the photoacoustic reaction units, a 1653.7 nm distributed feedback (DFB) laser as the excitation light source, a cantilever beam acoustic sensor as the acoustic sensing unit, and a high-speed spectrometer as the demodulation unit, has been successfully developed for high-sensitivity trace CH4 sensing. When the CH4 concentration is 1000 ppm, the 2f signal of YRPAC in the first-order resonance mode is 2.3 nm, which is 1.7 times higher than the 2f signal amplitude of TRPAC. The detection sensitivity and minimum detection limit for the PAS system are 2.29 pm/ppm and 52.8 parts per billion (ppb) at 100 s of averaging time. The reported YRPAC has higher sensitivity, smaller size, and faster response time compared to the conventional TRPAC, which can provide a new solution for PAS development.

Synthesis and Structural Characterization of Macrocyclic Plasmin Inhibitors.

Two series of macrocyclic plasmin inhibitors with a C-terminal benzylamine group were synthesized. The substitution of the N-terminal phenylsulfonyl group of a previously described inhibitor provided two analogues with sub-nanomolar inhibition constants. Both compounds possess a high selectivity against all other tested trypsin-like serine proteases. Furthermore, a new approach was used to selectively introduce asymmetric linker segments. Two of these compounds inhibit plasmin with Ki values close to 2 nM. For the first time, four crystal structures of these macrocyclic inhibitors could be determined in complex with a Ser195Ala microplasmin mutant. The macrocyclic core segment of the inhibitors binds to the open active site of plasmin without any steric hindrance. This binding mode is incompatible with other trypsin-like serine proteases containing a sterically demanding 99-hairpin loop. The crystal structures obtained experimentally explain the excellent selectivity of this inhibitor type as previously hypothesized.

High-sensitivity miniature dual-resonance photoacoustic sensor based on silicon cantilever beam for trace gas sensing.

We report a miniature dual-resonance photoacoustic (PA) sensor, mainly consisting of a small resonant T-type PA cell and an integrated sensor probe based on a silicon cantilever beam. The resonance frequency of the miniature T-type PA cell is matched with the first-order natural frequency of the cantilever beam to achieve double resonance of the acoustic signal. The volume of the designed T-type PA cell is only about 2.26 cubic centimeters. A PA spectroscopy (PAS) system, employing the dual-resonance photoacoustic (PA) sensor as the prober and a high-speed spectrometer as the demodulator, has been implemented for high-sensitivity methane sensing. The sensitivity and the minimum detection limit can reach up to 2.0 pm/ppm and 35.6 parts-per-billion, respectively, with an averaging time of 100 s. The promising performance demonstrated a great potential of employing the reported sensor for high-sensitivity gas sensing in sub cubic centimeter-level spaces.

Ultra-High-Sensitivity, Miniaturized Fabry-Perot Interferometric Fiber-Optic Microphone for Weak Acoustic Signals Detection.

An ultra-high-sensitivity, miniaturized Fabry-Perot interferometric (FPI) fiber-optic microphone (FOM) has been developed, utilizing a silicon cantilever as an acoustic transducer. The volumes of the cavity and the FOM are determined to be 60 microliters and 102 cubic millimeters, respectively. The FOM has acoustic pressure sensitivities of 1506 nm/Pa at 2500 Hz and 26,773 nm/Pa at 3233 Hz. The minimum detectable pressure (MDP) and signal-to-noise ratio (SNR) of the designed FOM are 0.93 µPa/Hz1/2 and 70.14 dB, respectively, at an acoustic pressure of 0.003 Pa. The designed FOM has the characteristics of ultra-high sensitivity, low MDP, and small size, which makes it suitable for the detection of weak acoustic signals, especially in the field of miniaturized all-optical photoacoustic spectroscopy.

High-Sensitivity Multitrace Gas Simultaneous Detection Based on an All-Optical Miniaturized Photoacoustic Sensor.

We propose an all-optical miniaturized multigas simultaneous detection photoacoustic (PA) sensor, which is primarily composed of a copper tube, a silica cantilever, and four single-mode fibers. Three single-mode fibers are used as excitation fibers to transmit lasers of different wavelengths, and the remaining one is used as a probe fiber. The volumes of the PA cell (PAC) and the sensor are 36 µL and 71 cubic millimeters, respectively. A laser photoacoustic spectroscopy (PAS) system, using the all-optical miniaturized PA sensor as a detector, 1532.8, 1576.3, and 1653.7 nm distributed feedback (DFB) lasers as the excitation sources for acetylene (C2H2), hydrogen sulfide (H2S), and methane (CH4) gases, and a high-speed spectrometer as a demodulator, has been developed for multigas simultaneous measurements. The minimum detection limits of 4.8, 162, and 16.6 parts per billion (ppb) have been achieved for C2H2, H2S, and CH4, respectively, with an integration time of 100 s. The reported sensor shows a potential for high-sensitivity multigas simultaneous measurements in cubic millimeter-scale space.

Synthetic Studies on the Synthesis of Toxicodenane A and 8,11-epi-Toxicodenane A.

The diverse synthesis of oxatricyclotridecanes and oxatricyclododecanes, which are the core structures of toxicodenane A and its skeletal analogues, via a unified manner is presented. The stereochemistry at the bridgehead position of the oxa-bridged bicycle could be efficiently controlled through a diastereoselective anti- and syn-Grignard allylation reaction by appropriately tuning the reaction conditions such as the solvent, the counterion of the Grignard reagent, the substrate, or a combination of these. The ring size could be precisely elaborated via a Lewis acid-mediated intramolecular transacetalation and Prins cyclization cascade reaction by varying the steric hindrance of olefin moiety. Namely, substrates bearing a terminally unsubstituted olefinic functionality afforded oxatricyclotridecanes with an overwhelming preference, while those bearing a dimethyl-substituted olefinic group produced exclusively oxatricyclododecanes. The wide utility and generality of the above key transformations are highlighted by the applications in the unified synthesis of (±)-toxicodenance A, (+)-toxicodenane A, (+)-8,11-epi-toxicodenane A, and other oxatricyclic cores with different stereochemistries and ring sizes.

The Phosphinamide-Based Catalysts: Discovery, Methodology Development, and Applications in Natural Product Synthesis.

In the total synthesis of natural products, synthetic efficiency has been an important driver for designing and developing new synthetic strategies and methodologies. To this end, the step, atom, and time economy and the overall yield are major factors to be considered. On the other hand, developing unified routes that can be used for synthesizing multiple molecules, specifically skeletally different classes of molecules, are also important aspects with which to be concerned. In the efforts toward efficient and flexible synthesis of structurally unique terpenoid and indole alkaloid natural products, we have designed and developed several phosphinamide-based new catalysts and reaction methodologies that have been compellingly demonstrated to be widely useful as strategic protocols for the diverse synthesis of various complex terpenoids and indole alkaloids. The important progress of these results will be summarized in this Account.In the first part, we present the stories of successful design and establishment of a novel method for the synthesis of P-stereogenic phosphinamides (P-SPhos) via a Pd-catalyzed C-H desymmetric enantioselective arylation, as well as the flexible derivatization of the P-stereogenic phosphinamides into various types of skeletally unique tricyclic and N,P-bidentate P-stereogenic compounds. Subsequently, the discovery of P-stereogenic phosphinamides as chiral organocatalysts for the desymmetric enantioselective reduction of cyclic 1,3-diketones and of phosphinamide-based cyclopalladium complex (C-Pd) as precatalysts for highly efficient Suzuki-Miyaura cross-coupling reaction of sterically congested nonactivated enolates is introduced. The notable features of the P-stereogenic phosphinamide-catalyzed desymmetric enantioselective reduction are highlighted by the broad substrate compatibility and excellent stereoselectivity, as well as most significantly, the good recoverability and reusability of catalysts. With regard to the sterically congested nonactivated enolates, such substrates are challenging for Suzuki cross-coupling reactions. We demonstrate that the phosphinamide-based cyclopalladium is a type of highly active precatalyst that allows the reaction to proceed under mild conditions and to be easily scaled up. Following the methodology development, the practical applications of these methods serving as strategic transformations are highlighted by the unified synthesis of four cyathane-type and two hamigeran-type terpenoids.In the second part, we describe the development of a robust method for oxidative Heck cross-coupling of indolyl amides by using the phosphinamide-based cyclopalladium as catalyst or phosphinamide as coligand. The method provides a general and straightforward method for diverse synthesis of indolyl δ-lactam derivatives, which present as a common core in a variety of Aspidosperma-derived indole alkaloids. The successful demonstration of this protocol for a concise and divergent synthesis of leuconodine-type indole alkaloids is also presented. We believe the results presented in this Account would have significant implications beyond our results and would find further applications in the field of synthetic methodology and natural product synthesis.

Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)-Toxicodenane A.

We present the first enantioselective total synthesis and absolute configuration assignment of (+)-toxicodenane A via a nine-step sequence from the readily available material. The synthesis features a desymmetric enantioselective reduction of 2,2-disubstituted 1,3-cyclohexanedione for the synthesis of a chiral 2,2-disubstituted 3-hydroxy cyclohexanone building block, a highly diastereoselective Grignard reaction for the incorporation of an allyl group, and a Lewis acid-mediated intramolecular transacetalation and Prins cascade reaction for the construction of oxa-bridged bicyclic rings.

All-optical high-sensitivity resonant photoacoustic sensor for remote CH4 gas detection.

This paper presents an all-optical high-sensitivity resonant photoacoustic (PA) sensor to realize remote, long-distance and space-limited trace gas detection. The sensor is an integration of a T-type resonant PA cell and a particular cantilever-based fiber-optic acoustic sensor. The finite element simulations about the cantilever vibration mode and the PA field distributions are carried out based on COMSOL. The all-optical high-sensitivity resonant PA sensor, together with a high-speed spectrometer and a DFB laser source, makes up of a photoacoustic spectroscopy (PAS) system which is employed for CH4 detection. The measured sensitivity is 0.6 pm/ppm in the case of 1000 s average time, and the minimum detection limit (MDL) reaches 15.9 parts per billion (ppb). The detective light source and the excitation light source are all transmitted by optical fibers, therefore remote and long-distance measurement of trace gas can be realized. Furthermore, the excitation light source and the acoustic sensor are designed at the same side of the PA cell, the sensor may be used for space-limited trace gas detection.

Synthesis and Biological Evaluation of Diversified Hamigeran B Analogs as Neuroinflammatory Inhibitors and Neurite Outgrowth Stimulators.

We describe the efficient synthesis of a series of new simplified hamigeran B and 1-hydroxy-9-epi-hamigeran B norditerpenoid analogs (23 new members in all), structurally related to cyathane diterpenoid scaffold, and their anti-neuroinflammatory and neurite outgrowth-stimulating (neurotrophic) activity. Compounds 9a, 9h, 9o, and 9q exhibited moderate nerve growth factor (NGF)-mediated neurite-outgrowth promoting effects in PC-12 cells at the concentration of 20 µm. Compounds 9b, 9c, 9o, 9q, and 9t showed significant nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-activated BV-2 microglial cells, of which 9c and 9q were the most potent inhibitors, with IC50 values of 5.85 and 6.31 µm, respectively. Two derivatives 9q and 9o as bifunctional agents displayed good activities as NO production inhibitors and neurite outgrowth-inducers. Cytotoxicity experiments, H2O2-induced oxidative injury assay, and ELISA reaction speculated that compounds may inhibit the TNF-α pathway to achieve anti-inflammatory effects on nerve cells. Moreover, molecular docking studies provided a better understanding of the key structural features affecting the anti-neuroinflammatory activity and displayed significant binding interactions of some derivatives (like 9c, 9q) with the active site of iNOS protein. The structure-activity relationships (SARs) were also discussed. These results demonstrated that this structural class compounds offered an opportunity for the development of a new class of NO inhibitors and NGF-like promotors.

Application and Structural Analysis of Triazole-Bridged Disulfide Mimetics in Cyclic Peptides.

Ruthenium-catalysed azide-alkyne cycloaddition (RuAAC) provides access to 1,5-disubstituted 1,2,3-triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied. We report synthetic strategies to install various triazole linkages into cyclic peptides through backbone cyclisation and RuAAC cross-linking reactions. These linkages were evaluated in four serine protease inhibitors based on sunflower trypsin inhibitor-1. NMR and X-ray crystallography revealed exceptional consensus of bridging distance and backbone conformations (RMSD<0.5 Å) of the triazole linkages compared to the parent disulfide molecules. The triazole-bridged peptides also displayed superior half-lives in liver S9 stability assays compared to disulfide-bridged peptides. This work establishes a foundation for the application of 1,5-disubstituted 1,2,3-triazoles as disulfide mimetics.

Natural Products with Analgesic Effect from Herbs and Nutraceuticals Used in Traditional Chinese Medicines.

BACKGROUND: Pain is one of the most common clinical symptoms . This review aims to describe research on herbs and their active ingredients in treating pain and provide a valuable reference for the development and utilization of analgesic traditional Chinese medicine (TCM). MATERIAL AND METHODS: The literature search was performed from 1995 to October 2016, covering the relevant studies that concern the treatment of pain with TCM. Active ingredients extracted from TCM with analgesic activity are summarized and classified into six categories, including polysaccharides, saponins, alkaloids, flavonoids, terpenoids, and other constituents. RESULTS: There are two pathways constituting the analgesic mechanisms of TCM: through the central nervous system and the peripheral nervous system. The former pathway includes increasing the content of endogenous analgesic substances like opiate peptide, cutting down the second messenger of neurotransmitter like nitric oxide (NO), reducing the content of prostaglandin E2 (PGE2) in brain tissues, blocking the central calcium channel, reducing excitatory amino acids in brain tissues, inhibiting their receptors and raising the content of the central 5-hydroxytryptamine (5-HT). The latter one usually involves the decrease in the secretion of peripheral algogenic substances, the induction of pain-sensitive substances, the accumulation of a local algogenic substance, the increase in the release of peripheral endogenous analgesia materials and the regulation of c-Fos gene (immediate early gene).

Structure and Function Characterization of the a1a2 Motifs of Streptococcus pyogenes M Protein in Human Plasminogen Binding.

Plasminogen (Plg)-binding M protein (PAM) is a group A streptococcal cell surface receptor that is crucial for bacterial virulence. Previous studies revealed that, by binding to the kringle 2 (KR2) domain of host Plg, the pathogen attains a proteolytic microenvironment on the cell surface that facilitates its dissemination from the primary infection site. Each of the PAM molecules in their dimeric assembly consists of two Plg binding motifs (called the a1 and a2 repeats). To date, the molecular interactions between the a1 repeat and KR2 have been structurally characterized, whereas the role of the a2 repeat is less well defined. Here, we report the 1.7-Å x-ray crystal structure of KR2 in complex with a monomeric PAM peptide that contains both the a1 and a2 motifs. The structure reveals how the PAM peptide forms key interactions simultaneously with two KR2 via the high-affinity lysine isosteres within the a1a2 motifs. Further studies, through combined mutagenesis and functional characterization, show that a2 is a stronger KR2 binder than a1, suggesting that these two motifs may play discrete roles in mediating the final PAM-Plg assembly.

Structural studies of plasmin inhibition.

Plasminogen (Plg) is the zymogen form of the serine protease plasmin (Plm), and it plays a crucial role in fibrinolysis as well as wound healing, immunity, tissue remodeling and inflammation. Binding to the targets via the lysine-binding sites allows for Plg activation by plasminogen activators (PAs) present on the same target. Cellular uptake of fibrin degradation products leads to apoptosis, which represents one of the pathways for cross-talk between fibrinolysis and tissue remodeling. Therapeutic manipulation of Plm activity plays a vital role in the treatments of a range of diseases, whereas Plm inhibitors are used in trauma and surgeries as antifibrinolytic agents. Plm inhibitors are also used in conditions such as angioedema, menorrhagia and melasma. Here, we review the rationale for the further development of new Plm inhibitors, with a particular focus on the structural studies of the active site inhibitors of Plm. We compare the binding mode of different classes of inhibitors and comment on how it relates to their efficacy, as well as possible future developments.

Synthetic Studies on Enantioselective Total Synthesis of Cyathane Diterpenoids: Cyrneines A and B, Glaucopine C, and (+)-Allocyathin B2.

The details for the synthetic studies on enantioselective total synthesis of cyathane diterpenoids cyrneine A (1) and B (2), glaucopine C (3), and (+)-allocyathin B2 are presented. We established a mild Suzuki coupling for heavily substituted nonactivated cyclopentenyl triflates using a phosphinamide-derived palladacycle as precatalyst and a chelation-controlled highly regioselective Friedel-Crafts cyclization. The utilization of these two key reactions enabled a rapid construction of the 5-6-6 tricyclic skeleton. In the middle stage of the synthesis, a Birch reductive methylation, a modified Wolff-Kishner-Huang reduction, and a carbenoid-mediated ring expansion were employed as the key reactions to furnish the 5-6-7 tricyclic core bearing two antiorientated all-carbon quaternary stereocenters at the C6 and C9 ring junctions. By applying these key transformations, a more efficient total synthesis of cyrneine A and allocyathin B2, and the first total synthesis of cyrneine B and glaucopine C, were accomplished through a collective manner. The late-stage conversions involving a base-mediated double bond migration and a double bond migration/aerobic γ-CH oxidation cascade for the stereoselective synthesis of cyrneine B and glaucopine C were interesting.

Highly Potent and Selective Plasmin Inhibitors Based on the Sunflower Trypsin Inhibitor-1 Scaffold Attenuate Fibrinolysis in Plasma.

Antifibrinolytic drugs provide important pharmacological interventions to reduce morbidity and mortality from excessive bleeding during surgery and after trauma. Current drugs used for inhibiting the dissolution of fibrin, the main structural component of blood clots, are associated with adverse events due to lack of potency, high doses, and nonselective inhibition mechanisms. These drawbacks warrant the development of a new generation of highly potent and selective fibrinolysis inhibitors. Here, we use the 14-amino acid backbone-cyclic sunflower trypsin inhibitor-1 scaffold to design a highly potent ( Ki = 0.05 nM) inhibitor of the primary serine protease in fibrinolysis, plasmin. This compound displays a million-fold selectivity over other serine proteases in blood, inhibits fibrinolysis in plasma more effectively than the gold-standard therapeutic inhibitor aprotinin, and is a promising candidate for development of highly specific fibrinolysis inhibitors with reduced side effects.