Diosmetin-7-O-ß-D-glucopyranoside from Pogostemonis Herba alleviated SARS-CoV-2-induced pneumonia by reshaping macrophage polarization and limiting viral replication.

ETHNOPHARMACOLOGICAL RELEVANCE: Viral pneumonia is the leading cause of death after SARS-CoV-2 infection. Despite effective at early stage, long-term treatment with glucocorticoids can lead to a variety of adverse effects and limited benefits. The Chinese traditional herb Pogostemonis Herba is the aerial part of Pogostemon Cablin (Blanco) Benth., which has potent antiviral, antibacterial, anti-inflammatory, and anticancer effects. It was used widely for treating various throat and respiratory diseases, including COVID-19, viral infection, cough, allergic asthma, acute lung injury and lung cancer. AIM OF THE STUDY: To investigate the antiviral and anti-inflammatory effects of chemical compounds from Pogostemonis Herba in SARS-CoV-2-infected hACE2-overexpressing mouse macrophage RAW264.7 cells and hACE2 transgenic mice. MATERIALS AND METHODS: The hACE2-overexpressing RAW264.7 cells were exposed with SARS-CoV-2. The cell viability was detected by CCK8 assay and cell apoptotic rate was by flow cytometric assay. The expressions of macrophage M1 phenotype markers (TNF-α and IL-6) and M2 markers (IL-10 and Arg-1) as well as the viral loads were detected by qPCR. The mice were inoculated intranasally with SARS-CoV-2 omicron variant to induce viral pneumonia. The levels of macrophages, neutrophils, and T cells in the lung tissues of infected mice were analyzed by full spectrum flow cytometry. The expressions of key proteins were detected by Western blot assay. RESULTS: Diosmetin-7-O-ß-D-glucopyranoside (DG) presented the strongest anti-SARS-CoV-2 activity. Intervention with DG at the concentrations of 0.625-2.5 µM not only reduced the viral replication, cell apoptosis, and the productions of inflammatory cytokines (IL-6 and TNF-α) in SARS-CoV-2-infected RAW264.7 cells, but also reversed macrophage polarity from M1 to M2 phenotype. Furthermore, treatment with DG (25-100 mg/kg) alleviated acute lung injury, and reduced macrophage infiltration in SARS-COV-2-infected mice. Mechanistically, DG inhibited SARS-COV-2 gene expression and HK3 translation via targeting YTHDF1, resulting in the inactivation of glycolysis-mediated NF-κB pathway. CONCLUSIONS: DG exerted the potent antiviral and anti-inflammatory activities. It reduced pneumonia in SARS-COV-2-infected mice via inhibiting the viral replication and accelerating M2 macrophage polarization via targeting YTHDF1, indicating its potential for COVID-19 treatment.

Developmental mouse brain common coordinate framework.

3D brain atlases are key resources to understand the brain's spatial organization and promote interoperability across different studies. However, unlike the adult mouse brain, the lack of developing mouse brain 3D reference atlases hinders advancements in understanding brain development. Here, we present a 3D developmental common coordinate framework (DevCCF) spanning embryonic day (E)11.5, E13.5, E15.5, E18.5, and postnatal day (P)4, P14, and P56, featuring undistorted morphologically averaged atlas templates created from magnetic resonance imaging and co-registered high-resolution light sheet fluorescence microscopy templates. The DevCCF with 3D anatomical segmentations can be downloaded or explored via an interactive 3D web-visualizer. As a use case, we utilize the DevCCF to unveil GABAergic neuron emergence in embryonic brains. Moreover, we map the Allen CCFv3 and spatial transcriptome cell-type data to our stereotaxic P56 atlas. In summary, the DevCCF is an openly accessible resource for multi-study data integration to advance our understanding of brain development.

Engineering of Covalent Organic Framework Nanosheet Membranes for Fast and Efficient Ion Sieving: Charge-Induced Cation Confined Transport.

Artificial membranes with ion-selective nanochannels for high-efficiency mono/divalent ion separation are of great significance in water desalination and lithium-ion extraction, but they remain a great challenge due to the slight physicochemical property differences of various ions. Here, the successful synthesis of two-dimensional TpEBr-based covalent organic framework (COF) nanosheets, and the stacking of them as consecutive membranes for efficient mono/divalent ion separation is reported. The obtained COF nanosheet membranes with intrinsic one-dimensional pores and abundant cationic sites display high permeation rates for monovalent cations (K+, Na+, Li+) of ≈0.1-0.3 mol m-2 h-1, while the value of divalent cations (Ca2+, Mg2+) is two orders of magnitude lower, resulting in an ultrahigh mono/divalent cation separation selectivity up to 130.4, superior to the state-of-the-art ion sieving membranes. Molecular dynamics simulations further confirm that electrostatic interaction controls the confined transport of cations through the cationic COF nanopores, where multivalent cations face i) strong electrostatic repulsion and ii) steric transport hindrance since the large hydrated divalent cations are retarded due to a layer of strongly adsorbed chloride ions at the pore wall, while smaller monovalent cations can swiftly permeate through the nanopores.

Novel Alkynylamide-Based Nonpeptidic Allosteric Inhibitors for SARS-CoV-2 3-Chymotrypsin-like Protease.

Although the coronavirus disease 2019 (COVID-19) crisis has passed, there remains a necessity for continuous efforts toward developing more targeted drugs and preparing for potential future virus attacks. Currently, most of the drugs received authorization for the treatment of COVID-19 have exhibited several limitations, such as poor metabolic stability, formidable preparation, and uncertain effectiveness. It is still significant to develop novel, structurally diverse small-molecule antiviral drugs targeting SARS-CoV-2 3-chymotrypsin-like protease (3CLpro). Herein, we report a class of alkynylamide-based nonpeptidic 3CLpro inhibitors that can be prepared conveniently by our previously developed one-pot synthetic method. The structure-activity relationships of alkynylamides as SARS-CoV-2 3CLpro inhibitors have been carefully investigated and discussed in this study. The two stereoisomers of the resulting molecules exhibit stereoselective interaction with 3CLpro, and the optimized compound (S,R)-4y inhibits 3CLpro with high potency (IC50 = 0.43 µM), low cytotoxicity, and acceptable cell permeability. Compound (S,R)-4y presents as a noncovalent inhibitor of 3CLpro against SARS-CoV-2 by the time-dependent inhibition assay (TDI) and mass spectrometry analysis. The Lineweaver-Burk plots, binding energy, surface plasmon resonance, and molecular docking studies suggest that (S,R)-4y specifically binds to an allosteric pocket of the SARS-CoV-2 3CLpro. These findings provide a novel class of nonpeptidic alkynylamide-based allosteric inhibitors with high selectivity against SARS-CoV-2 3CLpro featured by a simplified one-pot synthesis at room temperature in air.

Pituitary metastasis from lung adenocarcinoma.

Pituitary tumor is a common neuroendocrine tumor, but there are also rare clinical metastases at this site, which are generally transferred from extrabellar tumors. Although the clinical incidence is low, the prognosis is poor. The purpose of this editorial is to discuss further the relevant knowledge of pituitary metastases and remind clinicians to prevent missed diagnosis and improve the prognosis of these patients.

Research status of hormone replacement therapy on mood and sleep quality in menopausal women.

Menopausal syndrome is a common disease of clinical women, which refers to a series of physical and mental symptoms caused by the fluctuation or reduction of sex hormones before and after menopause. Many of these patients have sleep and mood abnormalities that affect their health and quality of life. At present, the understanding of it is gradually improving. This paper mainly analyzes its background and current treatment.

Deep Learning for Distinguishing Mucinous Breast Carcinoma From Fibroadenoma on Ultrasound.

PURPOSE: Mucinous breast carcinoma (MBC) tends to be misdiagnosed as fibroadenomas (FA) due to its benign imaging characteristics. We aimed to develop a deep learning (DL) model to differentiate MBC and FA based on ultrasound (US) images. The model could contribute to the diagnosis of MBC for radiologists. METHODS: In this retrospective study, 884 eligible patients (700 FA patients and 184 MBC patients) with 2257 US images were enrolled. The images were randomly divided into a training set (n = 1805 images) and a test set (n = 452 images) in a ratio of 8:2. First, we used the training set to establish DL model, DL+ age-cutoff model and DL+ age-tree model. Then, we compared the diagnostic performance of three models to get the optimal model. Finally, we evaluated the diagnostic performance of radiologists (4 junior and 4 senior radiologists) with and without the assistance of the optimal model in the test set. RESULTS: The DL+ age-tree model yielded higher areas under the receiver operating characteristic curve (AUC) than DL model and DL+ age-cutoff model (0.945 vs. 0.835, P < .001; 0.945 vs. 0.931, P < .001, respectively). With the assistance of DL+ age-tree model, both junior and senior radiologists' AUC had significant improvement (0.746-0.818, P = .010, 0.827-0.860, P = .005, respectively). CONCLUSIONS: The DL+ age-tree model based on US images and age showed excellent performance in the differentiation of MBC and FA. Moreover, it can effectively improve the performance of radiologists with different degrees of experience that may contribute to reducing the misdiagnosis of MBC.

[Water and heat transfer characteristics in summer maize farmland and its response to environmental factors in the old course of Yellow River]. / é»„æ²³æ• é“åŒºå¤çŽ‰ç±³å†œç”°æ°´çƒ­ä¼ è¾“ç‰¹å¾åŠå¯¹çŽ¯å¢ƒå› å­çš„å“åº”.

Accurate assessment of material and energy exchange between land and atmosphere is essential for water resources management and sustainable development of agriculture. To understand the characteristics of energy distribution and the dynamic change process of water and heat fluxes within the maize farmland ecosystem in the old course of Yellow River and their response to meteorological factors, we utilized the eddy covariance measurements and the full-element automatic weather station to continuously observe energy fluxes and conventional meteorological elements of summer maize farmland in the old course of Yellow River during 2019-2020. We analyzed the variation of energy fluxes and the effects of environmental factors, such as temperature, precipitation, and wind speed. Additionally, we calculated the energy closure rate and the proportion of energy distribution during the growth stage. The results showed that the peaks of net radiation, sensible heat flux, and latent heat flux occurred between 11:00 and 14:00, and the peak of soil heat flux occurred between 14:00 and 15:00. In terms of energy distribution, energy consumption of summer maize farmland during the whole growth period was dominated by latent heat flux and sensible heat flux. Energy was mainly consumed by sensible heat flux at sowing-emergence stage, accounting for 37.1% of net radiation, respectively. Energy in the rest of growth stages was dominated by latent heat flux. The energy closure rate during the whole growth period was better, with a coefficient of determination of 0.83, and the closure rate was higher in day and lower at night. Precipitation affected latent heat flux and sensible heat flux, and latent heat flux was more sensitive to precipitation. The increase of latent heat flux after rainfall was lower in late growth stage than in early growth stage. During the whole growth period of summer maize, solar radiation was the most significant meteorological factor affecting both sensible heat flux and latent heat flux, followed by vapor pressure deficit. The contribution of temperature and vapor pressure deficit to latent heat flux was significantly higher than sensible heat flux, while the relative contribution of wind speed, relative humidity, and solar radiation to latent heat flux was lower than sensible heat flux. Leaf area index and fractional vegetation cover had a significant positive correlation with latent heat flux and a significant negative correlation with sensible heat flux. Our results could deepen the understanding of water and heat transfer law of summer maize farmland in the old course of Yellow River, providing a theoretical basis for efficient water use of crops.

Mathematical Modeling of NaCl Scaling Development in Long-Distance Membrane Distillation for Improved Scaling Control.

Membrane distillation is a novel membrane-based separation technology with the potential to produce pure water from high-salinity brine. It couples transport behaviors along the membrane and across the membrane. The brine in the feed is gradually concentrated due to the permeate flux across the membrane, which is a significant factor in initiating the scaling behavior on the membrane surface along the feed flow direction. It is of great interest to investigate and estimate the development of scaling on the membrane surface. This work specifically focuses on a long-distance membrane distillation process with a sodium chloride solution as the feed. A modeling approach has been developed to estimate the sodium chloride scaling development on the membrane surface along the flow direction. A set of experiments was conducted to validate the results. Based on mathematical simplification and analytical fitting, a simplified model was summarized to predict the initiating position of sodium chloride scaling on the membrane, which is meaningful for scaling control in industrial-scale applications of membrane distillation.

Evaluation of teplizumab's efficacy and safety in treatment of type 1 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Islets of Langerhans beta cells diminish in autoimmune type 1 diabetes mellitus (T1DM). Teplizumab, a humanized anti-CD3 monoclonal antibody, may help T1DM. Its long-term implications on clinical T1DM development, safety, and efficacy are unknown. AIM: To assess the effectiveness and safety of teplizumab as a therapeutic intervention for individuals with T1DM. METHODS: A systematic search was conducted using four electronic databases (PubMed, Embase, Scopus, and Cochrane Library) to select publications published in peer-reviewed journals written in English. The odds ratio (OR) and risk ratio (RR) were calculated, along with their 95%CI. We assessed heterogeneity using Cochrane Q and I 2 statistics and the appropriate P value. RESULTS: There were 8 randomized controlled trials (RCTs) in the current meta-analysis with a total of 1908 T1DM patients from diverse age cohorts, with 1361 patients receiving Teplizumab and 547 patients receiving a placebo. Teplizumab was found to have a substantial link with a decrease in insulin consumption, with an OR of 4.13 (95%CI: 1.72 to 9.90). Teplizumab is associated with an improved C-peptide response (OR 2.49; 95%CI: 1.62 to 3.81) and a significant change in Glycated haemoglobin A1c (HbA1c) levels in people with type 1 diabetes [OR 1.75 (95%CI: 1.03 to 2.98)], and it has a RR of 0.71 (95%CI: 0.53 to 0.95). CONCLUSION: In type 1 diabetics, teplizumab decreased insulin consumption, improved C-peptide response, and significantly changed HbA1c levels with negligible side effects. Teplizumab appears to improve glycaemic control and diabetes management with good safety and efficacy.

Responses of CO2 and CH4 in the alpine wetlands of the Tibetan Plateau to warming and nitrogen and phosphorus additions.

Wetland ecosystems store large amounts of carbon, and CO2 and CH4 fluxes from this ecosystem receive the double impact of climate change and human activities. Nonetheless, research on how multi-gradient warming and nitrogen and phosphorus additions affect these wetland greenhouse gas emissions is still limited, particularly in alpine wetland ecosystems. Therefore, we conducted a field experiment on the Tibetan Plateau wetlands, investigating the effects of warming and nitrogen and phosphorus additions on the CO2 and CH4 fluxes in alpine wetlands. Results indicated that warming enhanced the CO2 absorption and CH4 emission in the alpine meadow ecosystem, possibly related to changes in plant growth and microbial activity induced by warming, while we noticed that the promotion of CO2 uptake weakened with the increase in the magnitude of warming, suggesting that there may be a temperature threshold beyond which the ecosystem's capacity for carbon sequestration may be reduced. Nitrogen addition increased CH4 emission, with the effect on CO2 absorption shifting from inhibition to enhancement as the amount of applied nitrogen or phosphorus increased. The interaction between warming and nitrogen and phosphorus additions further influenced CH4 emission, exhibiting a synergistic enhancement effect. This study deepens our understanding of the greenhouse gas responses of alpine wetland ecosystems to warming and nitrogen and phosphorus additions, which is significant for predicting and managing ecosystem carbon balance under global change.

[Cloning and functional characterization of oxidosqualene cyclase gene for α-amyrin synthesis].

Ursolic acid has gradually attracted much attention due to its unique pharmacological activities and valuable market value in recent years. Currently, ursolic acid is mostly extracted from loquat leaves, but the plant extraction method has low yield and high cost, and chemical synthesis is not readily available, so the biosynthesis method provides a new source for ursolic acid. α-amyrin acts as the main precursor for the synthesis of ursolic acid, and its yield is positively correlated with ursolic acid yield. Oxidosqualene cyclase(OSC) belongs to a multigene family which can catalyze the common precursor 2,3-oxidosqualene to generate different types of triterpene backbones, and plays a decisive role in the synthesis of triterpenoids. However, there are fewer reported key genes catalyzing the synthesis of α-amyrin in medicinal plants, and the yield and proportion of α-amyrin in the catalyzed products have always been a focus of research. In this study, ItOSC2, MdOSC1, AaOSC2 and CrAS, four enzymes capable of catalyzing the production of α-amyrin from 2,3-oxidosqualene, were cloned from Iris tectorum, Malus domestica, Artemisia annua and Catharanthus roseus, subject to sequence alignment and phylogenetic tree analyses, and transformed into Saccharomyces cerevisiae as plasmids. After 7 days of fermentation, the yield and proportions of α-amyrin, ß-amyrin and ergosterol were measured. Finally, AaOSC2 with the best ability to catalyze the generation of α-amyrin was filtered out, providing a key gene element for the later construction of engineered yeast strains with high production of α-amyrin and ursolic acid.

Identification of DDX5 as a Potential Therapeutic Target of Osteosarcoma Using Thiazolone Probes.

Osteosarcoma (OS) is a rare malignant tumor that has predominantly affected children and adolescents in the past 50 years. The genomes of OS tumors exhibit a high degree of complexity, which leads to the great challenge of target identification for anti-OS. To date, no efficient therapeutic target for the treatment of OS has been validated in clinical practice. In our previous drug hunting for the treatment of OS by phenotypic screening, we found that thiazolone derivate (R)-8i was an effective and selective inhibitor against OS in MNNG/HOS cells and in vivo. However, the mechanism of action and specific molecular targets of (R)-8i remain unclear. In this study, we design and synthesize the photo-cross-linking probes based on the lead compound (R)-8i and identify DDX5 as a potential target protein using an activity-based protein profiling strategy. Further experiments including Western blot, shRNA knockdown experiments, cell colony formation, wound healing assays, and cellular thermal shift assays support that (R)-8i binds to DDX5 and induces its degradation, which affect cell proliferation and migration through the PI3K-AKT-mTOR signaling pathway. The research shows that DDX5 is a potential therapeutic target for the treatment of OS.

Isolation and structure determination of a new bisabolane-type sesquiterpenoid with cytotoxicity from Penicillium oxalicum MZY-202312-521.

Endophytic fungi can produce attractive secondary metabolites with various biological activities that have contributed significantly to pharmacotherapy. In this study, three bisabolane-type sesquiterpenoids, including a new one, namely, inonotic acid C (1), together with previously reported compounds (S)-(+)-11-dehydrosydonic acid (2) and sydonic acid (3), were isolated from a marine algal-derived endophytic fungus Penicillium oxalicum MZY-202312-521. Their structures were determined by means of extensive spectroscopic analyses. The absolute configurations of inonotic acid C (1) were established by single-crystal X-ray diffraction method. In vitro cytotoxic experiments on human A549, MCF-7, HeLa, and HepG2 carcinoma cell lines were carried out. The new compound inonotic acid C (1) was found to possess strong inhibitory activity against the MCF-7 cell line, with an IC50 value of 7.7 µM.

Desloratadine ameliorates paclitaxel-induced peripheral neuropathy and hypersensitivity reactions in mice.

Paclitaxel (PTX) serves as a primary chemotherapy agent against diverse solid tumors including breast cancer, lung cancer, head and neck cancer and ovarian cancer, having severe adverse effects including PTX-induced peripheral neuropathy (PIPN) and hypersensitivity reactions (HSR). A recommended anti-allergic agent diphenhydramine (DIP) has been used to alleviate PTX-induced HSR. Desloratadine (DLT) is a third generation of histamine H1 receptor antagonist, but also acted as a selective antagonist of 5HTR2A. In this study we investigated whether DLT ameliorated PIPN-like symptoms in mice and the underlying mechanisms. PIPN was induced in male mice by injection of PTX (4 mg/kg, i.p.) every other day for 4 times. The mice exhibited 50% reduction in mechanical threshold, paw thermal response latency and paw cold response latency compared with control mice. PIPN mice were treated with DLT (10, 20 mg/kg, i.p.) 30 min before each PTX administration in the phase of establishing PIPN mice model and then administered daily for 4 weeks after the model was established. We showed that DLT administration dose-dependently elevated the mechanical, thermal and cold pain thresholds in PIPN mice, whereas administration of DIP (10 mg/kg, i.p.) had no ameliorative effects on PIPN-like symptoms. We found that the expression of 5HTR2A was selectively elevated in the activated spinal astrocytes of PIPN mice. Spinal cord-specific 5HTR2A knockdown by intrathecal injection of AAV9-5Htr2a-shRNA significantly alleviated the mechanical hyperalgesia, thermal and cold hypersensitivity in PIPN mice, while administration of DLT (20 mg/kg) did not further ameliorate PIPN-like symptoms. We demonstrated that DLT administration alleviated dorsal root ganglion neuronal damage and suppressed sciatic nerve destruction, spinal neuron apoptosis and neuroinflammation in the spinal cord of PIPN mice. Furthermore, we revealed that DLT administration suppressed astrocytic neuroinflammation via the 5HTR2A/c-Fos/NLRP3 pathway and blocked astrocyte-neuron crosstalk by targeting 5HTR2A. We conclude that spinal 5HTR2A inhibition holds promise as a therapeutic approach for PIPN and we emphasize the potential of DLT as a dual-functional agent in ameliorating PTX-induced both PIPN and HSR in chemotherapy. In summary, we determined that spinal 5HTR2A was selectively activated in PIPN mice and DLT could ameliorate the PTX-induced both PIPN- and HSR-like pathologies in mice. DLT alleviated the damages of DRG neurons and sciatic nerves, while restrained spinal neuronal apoptosis and CGRP release in PIPN mice. The underlying mechanisms were intensively investigated by assay against the PIPN mice with 5HTR2A-specific knockdown in the spinal cord by injection of adeno-associated virus 9 (AAV9)-5Htr2a-shRNA. DLT inhibited astrocytic NLRP3 inflammasome activation-mediated spinal neuronal damage through 5HTR2A/c-FOS pathway. Our findings have supported that spinal 5HTR2A inhibition shows promise as a therapeutic strategy for PIPN and highlighted the potential advantage of DLT as a dual-functional agent in preventing against PTX-induced both PIPN and HSR effects in anticancer chemotherapy.

Unveiling Collagen's Role in Breast Cancer: Insights into Expression Patterns, Functions and Clinical Implications.

Collagen, the predominant protein constituent of the mammalian extracellular matrix (ECM), comprises a diverse family of 28 members (I-XXVIII). Beyond its structural significance, collagen is implicated in various diseases or cancers, notably breast cancer, where it influences crucial cellular processes including proliferation, metastasis, apoptosis, and drug resistance, intricately shaping cancer progression and prognosis. In breast cancer, distinct collagens exhibit differential expression profiles, with some showing heightened or diminished levels in cancerous tissues or cells compared to normal counterparts, suggesting specific and pivotal biological functions. In this review, we meticulously analyze the expression of individual collagen members in breast cancer, utilizing Transcripts Per Million (TPM) data sourced from the GEPIA2 database. Through this analysis, we identify collagens that deviate from normal expression patterns in breast cancer, providing a comprehensive overview of their expression dynamics, functional roles, and underlying mechanisms. Our findings shed light on recent advancements in understanding the intricate interplay between these aberrantly expressed collagens and breast cancer. This exploration aims to offer valuable insights for the identification of potential biomarkers and therapeutic targets, thereby advancing the prospects of more effective interventions in breast cancer treatment.

Limitations and Innovative Application Methods of Surfactants for Solubilization of Poorly Water-Soluble Drugs.

Poor solubility of drugs leads to poor bioavailability and therapeutic efficiency. A large proportion of drugs that are not developed and marketed for use by patients are due to their extremely low solubility. Therefore, improving the solubility of poorly water-soluble drugs is one of the most important aspects of the field of drug research. With the continuous development of more and more formulation techniques and excipient applications, the solubility of poorly water-soluble drugs can be improved to a certain extent to obtain better pharmacokinetics and pharmacodynamics, including pH microenvironment regulation technology, inclusion complex, solid dispersion, nanotechnology, and application of surfactants. However, the most widely used among them is the application of surfactants. This technique can reduce the surface tension, improve wettability, and have a remarkable solubilizing ability after forming micelles. However, surfactants have also been found to possess certain limitations in solubilization. In this review, the factors affecting the solubilization of surfactants and limiting their application have been summarized from several aspects. These factors include drugs, additives, and media. Some ideas to solve these application limitations have also been put forward, which can lay a foundation for the wider application of surfactants in the future.

The effect of novel aromatic heterocycle substituted aminamidine derivatives on Necator americanus.

BACKGROUND: The efficacy of current drugs against hookworms at a single dose is highly variable across regions, age groups and infection intensity. Extensive and repeated use of these drugs also leads to potential drug resistance. Therefore, novel drugs are required for sustained disease control. OBJECTIVES: Novel aromatic heterocycle substituted aminamidine derivatives (AADs) were synthesized based on tribendimine (TBD), and their in vivo potency against Necator americanus was tested. METHODS: The efficacy of the AADs was tested in male hamsters. Oral and IV pharmacokinetic parameters were determined in male Sprague-Dawley rats. The proteomic profiles of N. americanus samples treated with AADs were compared using tandem mass tag-based quantitative proteomic analyses. RESULTS: Most AADs exhibited better anthelmintic activity than TBD at a single oral dose. Compound 3c exhibited improved solubility (>50×), and the curative dose was as low as 25 mg/kg. Similar to TBD, 3c was rapidly metabolized after oral administration and transformed into p-(1-dimethylamino ethylimino)aniline (dADT), an active metabolite against intestinal nematodes. dADT from 3c had better pharmacokinetic profiles than that from TBD and achieved an oral bioavailability of 99.5%. Compound 3c possessed rapid anthelmintic activity, clearing all worms within 24 h after an oral dose of 50 mg/kg. Quantitative proteomic analysis indicated that it might be related to ATP metabolism and cuticle protein synthesis. CONCLUSIONS: Compound 3c is a novel and promising compound against N. americanus in vivo.

Nonlinear optical diode effect in a magnetic Weyl semimetal.

Diode effects are of great interest for both fundamental physics and modern technologies. Electrical diode effects (nonreciprocal transport) have been observed in Weyl systems. Optical diode effects arising from the Weyl fermions have been theoretically considered but not probed experimentally. Here, we report the observation of a nonlinear optical diode effect (NODE) in the magnetic Weyl semimetal CeAlSi, where the magnetization introduces a pronounced directionality in the nonlinear optical second-harmonic generation (SHG). We demonstrate a six-fold change of the measured SHG intensity between opposite propagation directions over a bandwidth exceeding 250 meV. Supported by density-functional theory, we establish the linearly dispersive bands emerging from Weyl nodes as the origin of this broadband effect. We further demonstrate current-induced magnetization switching and thus electrical control of the NODE. Our results advance ongoing research to identify novel nonlinear optical/transport phenomena in magnetic topological materials and further opens new pathways for the unidirectional manipulation of light.

The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background.

Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the Caenorhabditis Intervention Testing Program and thought to promote longevity in different ways - NP1 (nitrophenyl piperazine-containing compound 1), propyl gallate, and resveratrol. Overall, we find the relationships among median lifespan, oxidative stress resistance, thermotolerance, and mobility vigor to be complex. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. In this study, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Notably, some compounds exert strong impact on some health measures without an equally strong impact on lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible anti-aging interventions, with data underscoring how personalized treatments might be required to optimize health benefits.