Discovery of a Novel ASM Direct Inhibitor with a 1,5-Diphenyl-pyrazole Scaffold and Its Antidepressant Mechanism of Action.

Multiple studies have confirmed that acid sphingomyelinase (ASM) activity is associated with depression. The discovery of direct inhibitors against ASM is of great significance for exploring antidepressants and their mechanisms of action. Herein, a series of novel phenylpyrazole analogues were rationally designed and synthesized. Among them, compound 46 exhibited potent inhibitory activity (IC50 = 0.87 µM) and good drug-like properties. In vivo studies demonstrated that compound 46 was involved in multiple antidepressant mechanisms of action, which were associated with a decline of ceramide, including increasing the Bcl-2/Bax ratio and BDNF expression, down-regulating caspase-3 and caspase-9, ameliorating oxidative stress, reducing the levels of proinflammatory cytokines such as TNF-α, IL-1ß, and IL-6, and elevating 5-HT levels in the brains of mice, respectively. These meaningful results reveal for the first time that direct inhibitors exhibit remarkable antidepressant effects in the CUMS-induced mouse model through multiple mechanisms of antidepressant action.

Radiometric thermometry of point targets based on dual-band infrared imaging.

The observation area of a point target, which is usually inaccessible, is a necessary condition when utilizing the conventional single-band infrared radiometric thermometry method, as the image gray level inevitably undergoes dispersion. Otherwise, significant errors will be generated, seriously affecting the applicability of infrared radiometric thermometry for distant point targets in the external field. To address the above issue, the infrared radiometric thermometry method for point targets has been researched. A point target radiometric thermometry method based on dual-band infrared imaging is proposed, which can effectively measure radiance and temperature when the area of the point target is unknown. The experimental results show that, compared with conventional single-band algorithms, the proposed dual-band point target thermometry algorithm has a maximum error of 11.18°C under the condition of unknown area, which can meet the needs of infrared radiometric thermometry of point targets at long distances in the external field.

Beneficial rhizosphere bacteria provides active assistance in resisting Aphis gossypiis in Ageratina adenophora.

Ageratina adenophora can enhance its invasive ability by using beneficial rhizosphere bacteria. Bacillus cereus is able to promote plant growth and provide a positive feedback effect to A. adenophora. However, the interaction between A. adenophora and B. cereus under the influence of native polyphagous insect feeding is still unclear. In this study, Eupatorium lindleyanum, a local species closely related to A. adenophora, was used as a control, aimed to compare the content of B. cereus in the roots of A. adenophora and rhizosphere soil after different densities of Aphis gossypii feeding, and then investigated the variations in the population of A. gossypii and soil characteristics after the addition of B. cereus. The result showed that B. cereus content in the rhizosphere soil and root of A. adenophora increased significantly under A. gossypii feeding compared with local plants, which also led to the change of α-diversity and ß-diversity of the bacterial community, as well as the increase in nitrate nitrogen (NO3 -N) content. The addition of B.cereus in the soil could also inhibit the population growth of A. gossypii on A. adenophora and increase the content of ammonium nitrogen (NH4 +-N) in the soil. Our research demonstrated that B. cereus enhances the ability of A. adenophora to resist natural enemy by increasing soil ammonium nitrogen (NH4 +-N) and accumulating other beneficial bacteria, which means that rhizosphere microorganisms help invasive plants defend themselves against local natural enemies by regulating the soil environment.

Colonization of Piriformospora indica enhances rice resistance against the brown planthopper Nilaparvata lugens.

BACKGROUND: Piriformospora indica is an endophytic fungus that can promote the growth and confer resistance against diverse stresses in host plants by root colonization. However, the effects of P. indica colonization on improving plant resistance to insect pests are still less explored. The brown planthopper (BPH) Nilaparvata lugens is a serious monophagous pest that causes extensive damage to rice plants. Here, we aimed to evaluate the effects of P. indica colonization on rice resistance against BPH. RESULTS: The colonization of P. indica in rice roots resisted damage from BPH. Age-stage, two-sex life table analyses showed that feeding on P. indica-colonized rice plants affected BPH's female adult longevity, oviposition period, fecundity, population parameters and population size. BPH female adults feeding on P. indica-colonized plants excreted less honeydew. P. indica colonization remarkably increased the duration of np, N2, and N3 waveform, as well as the occurrences of N1 and N2, and decreased the duration of N4-b for BPH on rice plants. Meanwhile, the weight of BPH on the colonized plants was significantly lower than the control. In addition, the feeding and oviposition preferences of BPH to P. indica-colonized plants were reduced. qRT-RCR analyses revealed that P. indica colonization induced the expressions of jasmonic acid (JA)- and salicylic acid (SA)-related genes in rice plants. CONCLUSION: P. indica colonization can reduce BPH performance on rice plants with potential inhibitory effects on population growth. Collectively, these results support the potential for endophytically colonized P. indica as an effective strategy to improve insect resistance of crops. © 2024 Society of Chemical Industry.

Volatiles from essential oils of three Lamiaceae plants repel the winged cotton aphid, disturb its feeding behavior and reduce its fecundity.

BACKGROUND: Insects use odor detection to sense their surroundings. Use of volatile compounds, such as essential oils (EOs) of plants, to repel pests and disrupt their olfaction-driven behaviors has great practical potential for use in integrated pest management. Despite the available information on the repellent effects of EOs on herbivorous insects, the olfaction-based mechanisms remain unknown. RESULTS: Y-tube olfactometer tests showed that the EOs of three Lamiaceae plants - Mentha arvensis L., Mentha piperita L. and Lavandula angustifolia Mill. - were significantly repellent to winged cotton aphid, Aphis gossypii Glover. Electrical penetration graph (EPG) tests indicated the EOs reduced phloem feeding and increased the level of non-productive probing by the aphids. The EOs also reduced the fecundity of winged Aphis gossypii. Electrophysiological bioassays and gas chromatography-mass spectrometry (GC-MS) identified five physiologically active volatiles, that is menthone, isomenthone, neomenthol and menthol from Mentha piperita; menthone and menthol from Mentha arvensis; and linalool from L. angustifolia. Behavioral tests confirmed that all five compounds repelled winged Aphis gossypii. Under field conditions, the growth rate of aphid populations after 7 days was significantly lower in fields treated with these compounds than in the control fields. CONCLUSION: Our findings demonstrated that three EOs not only repelled winged Aphis gossypii but also interfered with the aphid's feeding behavior and reduced its fecundity. These EOs and their active constituents have great potential as eco-friendly control products for use against Aphis gossypii. The effects of these EOs also exceed other repellents that only keep pests away from host plants. © 2024 Society of Chemical Industry.

Chemical Synthesis of Fucosylated Chondroitin Sulfate Tetrasaccharide with Fucosyl Branch at the 6-OH of GalNAc Residue.

Fucosylated chondroitin sulfate is a unique glycosaminoglycan isolated from sea cucumbers, with excellent anticoagulant activity. The fucosyl branch in FCS is generally located at the 3-OH of D-glucuronic acid but, recently, a novel structure with α-L-fucose linked to the 6-OH of N-acetyl-galactosamine has been found. Here, using functionalized monosaccharide building blocks, we prepared novel FCS tetrasaccharides with fucosyl branches both at the 6-OH of GalNAc and 3-OH of GlcA. In the synthesis, the protective group strategy of selective O-sulfation, as well as stereoselective glycosylation, was established, which enabled the efficient synthesis of the specific tetrasaccharide compounds. This research enriches knowledge on the structural types of FCS oligosaccharides and facilitates the exploration of the structure-activity relationship in the future.

Discovery of a novel class of reversible monoacylglycerol lipase inhibitors for potential treatment of depression.

Biological studies on the endocannabinoid system (ECS) have suggested that monoacylglycerol lipase (MAGL), an essential enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), is a novel target for developing antidepressants. A decrease of 2-AG levels in the hippocampus of the brain has been observed in depressive-like models induced by chronic stress. Herein, employing a structure-based approach, we designed and synthesized a new class of (piperazine-1-carbonyl) quinolin-2(1H)-one derivatives as potent, reversible and selective MAGL inhibitors. And detailed structure-activity relationships (SAR) studies were discussed. Compound 27 (IC50 = 10.3 nM) exhibited high bioavailability (92.7%) and 2-AG elevation effect in vivo. Additionally, compound 27 exerted rapid antidepressant effects caused by chronic restraint stress (CRS) and didn't show signs of addictive properties in the conditioned place preference (CPP) assays. Our study is the first to report that reversible MAGL inhibitors can treat chronic stress-induced depression effectively, which may provide a new potential therapeutic strategy for the discovery of an original class of safe, rapid antidepressant drugs.

Hybrids of selective COX-2 inhibitors and active derivatives of edaravone as COX-2 selective NSAIDs with free radical scavenging activity: Design, synthesis and biological activities.

Novel hybrids of selective COX-2 inhibitors (coxibs) and active derivatives of free radical scavenger edaravone were designed to overcome the risk of cardiovascular events and stroke increased by NSAIDs (nonsteroidal anti-inflammatory drugs) in this study. All the hybrids were assayed for the COX-2 inhibitory and DPPH (2, 2-diphenyl-1-picrylhydrazyl) free radical scavenging activities in vitro. Finally, we found a series of hybrids with good inhibitory activity and selectivity of COX-2 and excellent free radical scavenging activity in vitro. The most promising compound 6a (WYZ90) exhibited very potent COX-2 inhibitory activity (COX-2, IC50 = 75 nM), weak COX-1 inhibitory activity (COX-1, IC50 = 5734 nM), better free radical scavenging activity (DPPH, IC50 = 19.9 µM) than edaravone, moderate drug-likeness and ADME properties in silico, acceptable pharmacokinetic properties (T1/2 = 4.16 h, 10 mg/kg, o.p.) and oral bioavailability (F% = 36.03 %) in mice. In addition, compound WYZ90 showed similar analgesic activity to the selective COX-2 inhibitor celecoxib in acetic acid-induced mice and better antioxidant activity in Fe2+-induced lipid peroxidation in mouse liver tissue homogenate than edaravone. In conclusion, this study provided a novel class of coxibs containing edaravone moiety as COX-2 selective NSAIDs with free radical scavenging activity and the candidate compound WYZ90 showed not only similar selective COX-2 inhibitory and analgesic activity to celecoxib but also better free radical scavenging and antioxidant activity than edaravone.

Skin-Integrated Electrodes Based on Room-Temperature Curable, Highly Conductive Silver/Polydimethylsiloxane Composites.

The quality of electrophysiological (EP) signals heavily relies on the electrode's contact with the skin. However, motion or exposure to water can easily destabilize this connection. In contrast to traditional methods of attaching electrodes to the skin surface, this study introduces a skin-integration strategy inspired by the skin's intergrown structure. A highly conductive and room-temperature curable composite composed of silver microflakes and polydimethylsiloxane (Ag/PDMS) is applied to the skin. Before curing, the PDMS oil partially diffuse into the stratum corneum (SC) layer of the skin. Upon curing, the composite solidifies into an electrode that seamlessly integrated with the skin, resembling a natural extension. This skin-integration strategy offers several advantages. It minimizes motion artifacts resulting from relative electrode-skin displacement, significantly reduces interface impedance (67% of commercial Ag/AgCl gel electrodes at 100 Hz) and withstands water flushes due to its hydrophobic nature. These advantages pave the way for promising advancements in EP signal recording, particularly during motion and underwater conditions.

Controlling Metal-Oxide Reducibility for Efficient C-H Bond Activation in Hydrocarbons.

Knowing the structure of catalytically active species/phases and providing methods for their purposeful generation are two prerequisites for the design of catalysts with desired performance. Herein, we introduce a simple method for precise preparation of supported/bulk catalysts. It utilizes the ability of metal oxides to dissolve and to simultaneously precipitate during their treatment in an aqueous ammonia solution. Applying this method for a conventional VOx -Al2 O3 catalyst, the concentration of coordinatively unsaturated Al sites was tuned simply by changing the pH value of the solution. These sites affect the strength of V-O-Al bonds of isolated VOx species and thus the reducibility of the latter. This method is also applicable for controlling the reducibility of bulk catalysts as demonstrated for a CeO2 -ZrO2 -Al2 O3 system. The application potential of the developed catalysts was confirmed in the oxidative dehydrogenation of ethylbenzene to styrene with CO2 and in the non-oxidative propane dehydrogenation to propene. Our approach is extendable to the preparation of any metal oxide catalysts dissolvable in an ammonia solution.

Highly Flexible and Self-Healing Supercapacitor Enabled by Physically Crosslinking Polymer Hydrogel Electrolyte.

Preparation of flexible supercapacitors with excellent mechanical properties and self-healing properties is of great significance but still remains a challenge. A self-healable conductive hydrogel based on poly N-hydroxyethyl acrylamide (PHEAA) is fabricated as electrolyte for supercapacitors. The design of the physically cross-linked dual network, and rich hydrogen bonds endow the hydrogel with robust mechanical properties and strong self-healing ability. The hydrogel exhibited an excellent stretchability (723 %) and a high ionic conductivity (21.8 mS/cm). Specially, by in situ growth of electrode film, a non-laminated supercapacitor is obtained with flexibility and self-healing ability. Due to the non-laminated structure, the supercapacitor can work stably under bending and punching. The supercapacitor possessed an areal capacitance of 253.1 mF/cm2 and the capacitance retention was 80 % after five cutting-healing cycles. The pseudo-capacitance contribution of the supercapacitor after self-healing was discussed. It is noteworthy that the supercapacitor maintains the ability to power a clock after self-healing.

Characterization and functional analysis of an α-adrenergic-like octopamine receptor in the small brown planthopper Laodelphax striatellus.

As an important biogenic amine in invertebrates and corresponding to the neurotransmitter norepinephrine in vertebrates, octopamine (OA) regulates diverse physiological and behavioral processes by binding to specific octopamine receptors (OARs) in invertebrates. At present, OARs have been identified and characterized in several insects. However, less is known about the OARs of Laodelphax striatellus, one of the most destructive pests in East Asian rice fields. In the present study, an α1-adrenergic-like OAR (LsOA1) from L. striatellus was cloned. LsOA1 has the typical characteristics of G-protein coupled receptors and is clustered with other insect homologs. The transcript level of LsOA1 varied in various stages and tissues, and was highly expressed at the egg stage and in the brain. Silencing of LsOA1 causes a reduction in vitellogenin (LsVg) and vitellogenin receptor (LsVgR) expression. Although LsOA1 interference did not affect the fecundity and survival of L. striatellus, the hatching rate of L. striatellus was significantly reduced, and the hatching period was prolonged. The decrease in the amount of honeydew excreted after silencing LsOA1 indicates that LsOA1 may be involved in regulating the feeding behavior of L. striatellus. In addition, the interference of LsOA1 significantly reduced the expression of capsid protein (CP) and viral RNA3 segment (RNA3) in rice stripe virus (RSV)-viruliferous L. striatellus, but did not affect the vertical transmission rate of RSV. The present study demonstrated that LsOA1 played a crucial role in the physiological and behavioral processes of L. striatellus, which will provide the basis for developing a new target gene for pest control.

Unbalanced Current Identification of Three-Core Power Cables Based on Phase Detection of Magnetic Fields.

Identifying unbalanced phase currents is crucial for control and fault alarm rates in power grids, especially in urban distribution networks. The zero-sequence current transformer, specifically designed for measuring unbalanced phase currents, offers advantages in measurement range, identity, and size, compared to using three separate current transformers. However, it cannot provide detailed information on the unbalance status beyond the total zero-sequence current. We present a novel method for identifying unbalanced phase currents based on phase difference detection using magnetic sensors. Our approach relies on analyzing phase difference data from two orthogonal magnetic field components generated by three-phase currents, as opposed to the amplitude data used in previous methods. This enables the differentiation of unbalance types (amplitude unbalance and phase unbalance) through specific criteria and allows for the simultaneous selection of an unbalanced phase current in the three-phase currents. In this method, the amplitude measurement range of magnetic sensors is no longer a critical factor, allowing for an easily attainable wide identification range for current line loads. This approach offers a new avenue for unbalanced phase current identification in power systems.

CT characteristics of recurrent acute pancreatitis and acute pancreatitis in different stages-a retrospective cross-sectional study.

Background: Acute pancreatitis (AP), recurrent acute pancreatitis (RAP), and chronic pancreatitis (CP) are a continuum of the same disease. The course of RAP and AP is a dynamic process. Previous studies are contradictory regarding the severity of RAP and AP. We conducted this study to investigate the computed tomography (CT) characteristics of RAP and AP in the early and late stages; respectively. Methods: Patients who underwent contrast-enhanced computed tomography for symptoms during RAP or AP episodes were retrospectively collected from three tertiary hospitals in Sichuan Province, China from January 2015 to December 2019. The patients were categorized into RAP and AP groups based on recurrence and initial events. Both the RAP and AP groups were divided into early (first week) and late stages (after the first week) based on the 2012 revised Atlanta classification (RAC). Patient demographic data, RAC, CT findings, CT severity index (CTSI) scores, and extrapancreatic inflammation on CT scores in the early and late phases were analyzed between the two groups. The Wilcoxon signed-rank test, χ2 test, and Fisher's exact test were used to compare continuous and categorical variables between the two groups respectively. Results: In 683 RAP and 1,829 AP patients, the most common etiologies were hypertriglyceridemia and cholelithiasis, respectively. The RAP group had lower extrapancreatic inflammation on CT scores and Acute Physiology and Chronic Health Evaluation II scores than the AP group in the early stage (both P<0.001). The RAP group had higher CTSI scores than the AP group in the late stage (P=0.022). Conclusions: Compared with AP patients, the most common cause of RAP patients was hypertriglyceridemia in China, and the severity of RAP was lower than that of initial AP in the early stage and higher than that of initial AP in the late stage.

Local Feature Matters: Cascade Multi-Scale MLP for Edge Segmentation of Medical Images.

Convolution-based methods are increasingly being used in medical image segmentation tasks and have shown good performance, but there are always problems in segmenting edge parts. These methods all have the following challenges: 1) Previous methods do not highlight the relationship between foreground and background in segmented regions, which is helpful for complex segmentation edges, 2) inductive bias of the convolutional layer leads to the fact that the extracted information is mainly the main part of the segmented area, and cannot effectively perceive complex edge changes and the aggregation of small and many segmented areas,3) different regions around the segmentation edge have different reference values for segmentation, and the ordering of these values is more important when the segmentation task is more complex. To address these challenges, we propose the CM-MLP framework on Multi-scale Feature Interaction (MFI) block and Axial Context Relation Encoder (ACRE) block for accurate segmentation of the edge of medical image. In the MFI block, we propose the Cascade Multi-scale MLP (Cascade MLP) to process all local information from the deeper layers of the network simultaneously, using Squeeze and Excitation in Space(SES) to process and redistribute the weights of all windows in Cascade MLP and utilize a cascade multi-scale mechanism to fuse discrete local information gradually. Then, multiple ACRE blocks cooperate with the deep supervision mechanism to gradually explore the boundary relationship between the foreground and the background, and gradually fine-tune the edges of the medical image. The segmentation accuracy (Dice) of our proposed CM-MLP framework reaches 96.98%, 96.67%, and 83.83% on three benchmark datasets: CVC-ClinicDB dataset, sub-Kvasir dataset, and our in-house dataset, respectively, which significantly outperform the state-of-the-art method. The source code and trained models will be available at https://github.com/ProgrammerHyy/CM-MLP.

Design and synthesis of a novel class of PDE4 inhibitors with antioxidant properties as bifunctional agents for the potential treatment of COPD.

It is well known that chronic obstructive pulmonary disease (COPD) patients are always trapped in the vicious circle of inflammation and oxidative stress, therefore anti-inflammatory and antioxidant bifunctional agents may interrupt this vicious cycle in COPD. Phosphodiesterase 4 (PDE4) inhibitors, as anti-inflammatory drugs, have been used for COPD treatment in clinical, and the PDE4 inhibitors with antioxidant properties may be a good strategy to design bifunctional agents for COPD. Sappanone A was the first PDE4 inhibitor with antioxidant properties we identified from natural products in our previous study, which was used by us as a hit compound to design new bifunctional agents for COPD in this study. 27 derivatives of sappanone A including homoisoflavonoids, aurones and chalcones were designed and synthesized by innovatively fusing the antioxidant pharmacophore of catechol from polyphenols and the pharmacophore of catechol ether abstracted from the PDE4 inhibitors of the catechol ether class such as rolipram, roflumilast and apremilast respectively. All the compounds were assayed for the PDE4 inhibitory and radical scavenging against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) activities in vitro. Herein we obtained a series of bifunctional compounds with better PDE4 inhibitory activity than sappanone A, and their free radical scavenging activities were superior to edaravone in vitro. In addition, they can reduce tumour necrosis factor-alpha (TNF-α) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages and malondialdehyde (MDA) production induced by Fe2+ in mouse lung homogenate. Meanwhile, it showed outstanding abilities in reducing Fe3+ and complexing Fe2+. 6o, as the candidate anti-inflammatory and antioxidant bifunctional compound, exhibited good drug-likeness, ADME (Absorption, Distribution, Metabolism, Excretion) properties and human liver microsomal stability. In vivo, 6o (50 mg/kg and 100 mg/kg, i. p.) distinctly prevented LPS-induced serum levels of TNF-α in mice. In conclusion, the preliminary investigation provided a novel class of PDE4 inhibitors with antioxidant properties as bifunctional agents for the potential treatment of COPD, which can interrupt the vicious cycle of chronic inflammation and oxidative stress in COPD.

Electroreductive Cross-Electrophile Coupling of Aziridines and Aryl Bromides.

Herein, a nickela-electrocatalyzed cross-electrophile coupling of readily available aryl aziridines and aryl bromides under mild and sustainable electrochemical conditions to access synthetic useful ß-arylethylamines is developed. This protocol is characterized by its exquisite chemo- and regioselectivity, broad substrate scope and good functional group compatibility. Mechanistic studies confirmed that the regioselectivity and reactivity observed are a result of electro-induced ring-opening of aziridines under electroreductive conditions to generate a benzyl radical intermediate as the active species. Furthermore, this strategy also enables cross-coupling with CO2 to access ß-amino acids under mild conditions.

Smart supply chain management in Industry 4.0: the review, research agenda and strategies in North America.

The emerging information and communication technologies (ICT) related to Industry 4.0 play a critical role to enhance supply chain performance. Employing the smart technologies has led to so-called smart supply chains. Understanding how Industry 4.0 and related ICT affect smart supply chains and how smart supply chains evolve with the support of the advanced technologies are vital to practical and academic communities. Existing review works on smart supply chains with ICT mainly rely on the academic literature alone. This paper presents an integrated approach to explore the effects of Industry 4.0 and related ICT on smart supply chains, by combining introduction of the current national strategies in North America, the research status analysis on ICT assisted supply chains from the major North American national research councils, and a systematic literature review of the subject. Besides, we introduce a smart supply chain hierarchical framework with multi-level intelligence. Furthermore, the challenges faced by supply chains under Industry 4.0 and future research directions are discussed as well.