A tryptophan metabolite made by a gut microbiome eukaryote induces pro-inflammatory T cells.

The large intestine harbors microorganisms playing unique roles in host physiology. The beneficial or detrimental outcome of host-microbiome coexistence depends largely on the balance between regulators and responder intestinal CD4+ T cells. We found that ulcerative colitis-like changes in the large intestine after infection with the protist Blastocystis ST7 in a mouse model are associated with reduction of anti-inflammatory Treg cells and simultaneous expansion of pro-inflammatory Th17 responders. These alterations in CD4+ T cells depended on the tryptophan metabolite indole-3-acetaldehyde (I3AA) produced by this single-cell eukaryote. I3AA reduced the Treg subset in vivo and iTreg development in vitro by modifying their sensing of TGFß, concomitantly affecting recognition of self-flora antigens by conventional CD4+ T cells. Parasite-derived I3AA also induces over-exuberant TCR signaling, manifested by increased CD69 expression and downregulation of co-inhibitor PD-1. We have thus identified a new mechanism dictating CD4+ fate decisions. The findings thus shine a new light on the ability of the protist microbiome and tryptophan metabolites, derived from them or other sources, to modulate the adaptive immune compartment, particularly in the context of gut inflammatory disorders.

AMPK activator 991 specifically activates SnRK1 and thereby affects seed germination in rice.

Sucrose non-fermenting-1-related protein kinase 1 (SnRK1) and AMP-activated protein kinase (AMPK) are highly conserved. Compound 991 is an AMPK activator in mammals. However, whether 991 also activates SnRK1 remains unknown. The addition of 991 significantly increased SnRK1 activity in desalted extracts from germinating rice seeds in vitro. To determine whether 991 has biological activity, rice seeds were treated with different concentrations of 991. Germination was promoted at low concentrations but inhibited at high concentrations. The effects of 991 on germination were similar to those of OsSnRK1a overexpression. To explore whether 991 affects germination by specifically affecting SnRK1, germination of an snrk1a mutant and the wild type under 1 µM 991 treatment was compared. The snrk1a mutant was insensitive to 991. Phosphoproteomic analysis showed that the differential phosphopeptides induced by 991 and OsSnRK1a overexpression largely overlapped. Furthermore, SnRK1 might regulate rice germination in a dosage-dependent manner by regulating the phosphorylation of three phosphosites, namely S285-PIP2;4, S1013-SOS1, and S110-ABI5. These results indicate that 991 is a specific SnRK1 activator in rice. The promotion and inhibition of germination by 991 also occurred in wheat seeds. Thus, 991 is useful for exploring SnRK1 function and the chemical regulation of growth and development in crops.

GLUT3-mediated cigarette smoke-induced epithelial-mesenchymal transition in chronic obstructive pulmonary disease through the NF-kB/ZEB1 pathway.

BACKGROUND: Airway remodelling plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Epithelial-mesenchymal transition (EMT) is a significant process during the occurrence of airway remodelling. Increasing evidence suggests that glucose transporter 3 (GLUT3) is involved in the epithelial mesenchymal transition (EMT) process of various diseases. However, the role of GLUT3 in EMT in the airway epithelial cells of COPD patients remains unclear. METHODS: We detected the levels of GLUT3 in the peripheral lung tissue of COPD patients and cigarette smoke (CS)-exposed mice. Two Gene Expression Omnibus GEO datasets were utilised to analyse GLUT3 gene expression profiles in COPD. Western blot and immunofluorescence were used to detect GLUT3 expression. In addition, we used the AAV9-GLUT3 inhibitor to reduce GLUT3 expression in the mice model. Masson's staining and lung function measurement were used detect the collagen deposition and penh in the mice. A cell study was performed to confirm the regulatory effect of GLUT3. Inhibition of GLUT3 expression with siRNA, Western blot, and immunofluorescence were used to detect the expression of E-cadherin, N-cadherin, vimentin, p65, and ZEB1. RESULTS: Based on the GEO data set analysis, GLUT3 expression in COPD patients was higher than in non-smokers. Moreover, GLUT3 was highly expressed in COPD patients, CS exposed mice, and BEAS-2B cells treated with CS extract (CSE). Further research revealed that down-regulation of GLUT3 significantly alleviated airway remodelling in vivo and in vitro. Lung function measurement showed that GLUT3 reduction reduced airway resistance in experimental COPD mice. Mechanistically, our study showed that reduction of GLUT3 inhibited CSE-induced EMT by down-regulating the NF-κB/ZEB1 pathway. CONCLUSION: We demonstrate that CS enhances the expression of GLUT3 in COPD and further confirm that GLUT3 may regulate airway remodelling in COPD through the NF-κB/ZEB1 pathway; these findings have potential value in the diagnosis and treatment of COPD. The down-regulation of GLUT3 significantly alleviated airway remodelling and reduced airway resistance in vivo. Our observations uncover a key role of GLUT3 in modulating airway remodelling and shed light on the development of GLUT3-targeted therapeutics for COPD.

Physiologically-based pharmacokinetic modelling guided dose evaluations of nirmatrelvir/ritonavir in renal impairment for the management of COVID-19.

We aimed to address factors contributing to the pharmacokinetic changes of nirmatrelvir/ritonavir in renal impaired (RI) patients and recommend dosing adjustment via a physiologically-based pharmacokinetic (PBPK) modelling approach. A PBPK model of nirmatrelvir/ritonavir was developed via Simcyp® Simulator. Sensitivity analysis of the influence of hepatic CYP3A4 intrinsic clearance and abundance, as well as hepatic non-CYP3A4 metabolism (other human liver microsomes [HLM] CLint) was performed to evaluate the effects of RI on oral clearance of nirmatrelvir. Other HLM CLint, the most sensitive parameter, was adjusted, and the simulated plasma concentration profiles of nirmatrelvir in severe RI subjects were within the therapeutic index of 292-10 000 ng/mL for dosing regimens of loading doses of 300/100 mg followed by 150/100 mg or 75/100 mg twice daily of nirmatrelvir/ritonavir. Considering that nirmatrelvir is available as a 150 mg tablet, we recommend 300/100 mg followed by 150/100 mg twice daily as the dosing regimen to be investigated in severe RI.

Forkhead O Transcription Factor 4 Restricts HBV Covalently Closed Circular DNA Transcription and HBV Replication through Genetic Downregulation of Hepatocyte Nuclear Factor 4 Alpha and Epigenetic Suppression of Covalently Closed Circular DNA via Interacting with Promyelocytic Leukemia Protein.

Nuclear located hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) remains the key obstacle to cure chronic hepatitis B (CHB). In our previous investigation, it was found that FoxO4 could inhibit HBV core promoter activity through downregulating the expression of HNF4α. However, the exact mechanisms whereby FoxO4 inhibits HBV replication, especially its effect on cccDNA, remain unclear. Here, our data further revealed that FoxO4 could effectively inhibit cccDNA mediated transcription and HBV replication without affecting cccDNA level. Mechanistic study showed that FoxO4 could cause epigenetic suppression of cccDNA. Although FoxO4-mediated downregulation of HNF4α contributed to inhibiting HBV core promoter activity, it had little effect on cccDNA epigenetic regulation. Further, it was found that FoxO4 could colocalize within promyelocytic leukemia protein (PML) nuclear bodies and interact with PML. Of note, PML was revealed to be critical for FoxO4-mediated inhibition of cccDNA epigenetic modification and of the following cccDNA transcription and HBV replication. Furthermore, FoxO4 was found to be downregulated in HBV-infected hepatocytes and human liver tissues, and it was negatively correlated with cccDNA transcriptional activity in CHB patients. Together, these findings highlight the role of FoxO4 in suppressing cccDNA transcription and HBV replication via genetic downregulation of HNF4α and epigenetic suppression of cccDNA through interacting with PML. Targeting FoxO4 may present as a new therapeutic strategy against chronic HBV infection. IMPORTANCE HBV cccDNA is a determining factor for viral persistence and the main obstacle for a cure of chronic hepatitis B. Strategies that target cccDNA directly are therefore of great importance in controlling persistent HBV infection. In present investigation, we found that FoxO4 could efficiently suppress cccDNA transcription and HBV replication without affecting the level of cccDNA itself. Further, our data revealed that FoxO4 might inhibit cccDNA function via a two-part mechanism: one is to epigenetically suppress cccDNA transcription via interacting with PML, and the other is to inhibit HBV core promoter activity via the genetic downregulation of HNF4α. Of note, HBV might dampen the expression of FoxO4 for its own persistent infection. We propose that manipulation of FoxO4 may present as a potential therapeutic strategy against chronic HBV infection.

Model-Based Risk Prediction of Rivaroxaban with Amiodarone for Moderate Renal Impaired Elderly Population.

PURPOSE: Increased bleeding risk was found associated with concurrent prescription of rivaroxaban and amiodarone. We previously recommended dose adjustment for rivaroxaban utilizing a physiologically based pharmacokinetic (PBPK) modeling approach. Our subsequent in vitro studies discovered the pivotal involvement of human renal organic anion transporter 3 (hOAT3) in the renal secretion of rivaroxaban and the inhibitory potency of amiodarone. This study aimed to redefine the disease-drug-drug interactions (DDDI) between rivaroxaban and amiodarone and update the potential risks. METHODS: Prospective simulations were conducted with updated PBPK models of rivaroxaban and amiodarone incorporating hOAT3-related parameters. RESULTS: Simulations to recapitulate previously explored DDDI in renal impairment showed a higher bleeding tendency in all simulation scenarios after integrating hOAT3-mediated clearance into PBPK models. Further sensitivity analysis revealed that both hOAT3 dysfunction and age could affect the extent of DDDI, and age was shown to have a more pivotal role on rivaroxaban in vivo exposure. When amiodarone was prescribed along with our recommended dose reduction of rivaroxaban to 10 mg in moderate renal impaired elderly people, it could result in persistently higher rivaroxaban peak concentrations at a steady state. To better manage the increased bleeding risk among such a vulnerable population, a dose reduction of rivaroxaban to 2.5 mg twice daily resulted in its acceptable in vivo exposure. CONCLUSION: Close monitoring of bleeding tendency is essential for elderly patients with moderate renal impairment receiving co-prescribed rivaroxaban and amiodarone. Further dose reduction is recommended for rivaroxaban to mitigate this specific DDDI risk.

The Urgent Need for Neuroscience Research to Consider Culture when Assessing the Development of Gait in Autistic Children: A Scoping Review.

BACKGROUND: Over the last decade, there has been a steady increase in the number of children diagnosed with autism spectrum disorder (ASD) on a global scale, impacting all racial and cultural groups. This increase in the diagnostic rate has prompted investigation into a myriad of factors that may serve as early signs of ASD. One of these factors includes the biomechanics of gait, or the manner of walking. Although ASD is a spectrum, many autistic children experience differences in gross motor function, including gait. It has been documented that gait is also impacted by racial and cultural background. Given that ASD is equally prevalent across all cultural backgrounds, it is urgent that studies assessing gait in autistic children consider the impact of cultural factors on children's development of gait. The purpose of the present scoping review was to assess whether recent empirical research studies focusing on gait in autistic children have taken culture into account. METHODS: To do so, we conducted a scoping review following PRISMA guidelines using a keyword searching with the terms autism, OR autism spectrum disorder, OR ASD, OR autis, AND gait OR walking in the following databases: CINAHL, ERIC (EBSCO), Medline, ProQuest Nursing & Allied Health Source, PsychInfo, PubMed, and Scopus. Articles were considered for review if they met all six of the following inclusionary criteria: (1) included participants with a diagnosis of autism spectrum disorder (ASD), (2) directly measured gait or walking, (3) the article was a primary study, (4) the article was written in English, (5) participants included children up to age 18, and (6) the article was published between 2014 and 2022. RESULTS: A total of 43 articles met eligibility criteria but none of the articles took culture into account in the data analysis process. CONCLUSIONS: There is an urgent need for neuroscience research to consider cultural factors when assessing gait characteristics of autistic children. This would allow for more culturally responsive and equitable assessment and intervention planning for all autistic children.

Legacy phosphorus delays the accomplishment of expected phosphorus management object.

Legacy phosphorus (P) in watersheds continuously affects the water quality. The time lag between anthropogenic P input and algal bloom has made P dynamics prediction in aquatic ecosystems more challenging. Whether the legacy P in the Yangtze River Watershed (YRW) exceeds its storage threshold remains unknown, and the continuous impact of legacy P on the water quality has not been analyzed. This study aimed to evaluate variation trends (1970-2018) and influencing factors for accumulated P in the YRW under different economic development periods, quantitatively identify the watershed P storage threshold based on the two split line models and estimate the time required for the return of legacy P to the baseline level using an exponential decay process. The results showed that the P storage threshold of the YRW was surpassed due to intense anthropogenic activities, and the residual P still had an impact on aquatic ecosystems for a long time. The dissolved total P loadings may become the top priority to achieve better P management goals. The time lags for the legacy P restoration would require for about 1000 years to be exhausted. The legacy P in the YRW would continuously undermine the restoration efforts of the water quality. The combined effects of watershed P surplus reductions and depletion of residual P may become essential to better manage P in the future. We still need to strengthen our efforts to make soil legacy P more absorbed by crops and improve sewage treatment capacity to achieve sustainable development of YRW.

Identification of Optimal Urinary Biomarkers of Synthetic Cannabinoids BZO-HEXOXIZID, BZO-POXIZID, 5F-BZO-POXIZID, and BZO-CHMOXIZID for Illicit Abuse Monitoring.

BACKGROUND: The continuous introduction of new synthetic cannabinoid (SC) subtypes and analogues remains a major problem worldwide. Recently, a new "OXIZID" generation of SCs surfaced in seized materials across various countries. Hence, there is an impetus to identify urinary biomarkers of the OXIZIDs to detect their abuse. METHODS: We adapted our previously reported two-pronged approach to investigate the metabolite profiles and disposition kinetics of 4 OXIZID analogues, namely, BZO-HEXOXIZID (MDA-19), BZO-POXIZID (5C-MDA-19), 5F-BZO-POXIZID (5F-MDA-19), and BZO-CHMOXIZID (CHM-MDA-19). First, bottom-up in vitro incubation experiments comprising metabolite identification, metabolic stability, and reaction phenotyping were performed using human liver microsomes and recombinant human cytochrome P450 enzymes. Second, top-down analysis of authentic urine samples from drug abusers was performed to corroborate the in vitro findings and establish a panel of urinary biomarkers. RESULTS: A total of 42 to 51 metabolites were detected for each OXIZID, and their major metabolic pathways included N-alkyl and phenyl hydroxylation, oxidative defluorination (for 5F-BZO-POXIZID), oxidation to ketone and carboxylate, amide hydrolysis, and N-dealkylation. The OXIZIDs were metabolically unstable, mainly metabolized by cytochromes P3A4, P3A5, and P2C9, and demonstrated mechanism-based inactivation of cytochrome P3A4. Integrating with the results of 4 authentic urine samples, the parent drug and both N-alkyl and phenyl mono-hydroxylated metabolites of each OXIZID were determined as suitable urinary biomarkers. CONCLUSIONS: Drug enforcement agencies worldwide may apply these biomarkers in routine monitoring procedures to identify abusers and counter the escalation of OXIZID abuse.

Inhibition of Cytochrome P450 2J2-Mediated Metabolism of Rivaroxaban and Arachidonic Acid by Ibrutinib and Osimertinib.

Covalent tyrosine kinase inhibitors (TKIs) ibrutinib and osimertinib are associated with cardiac arrhythmia. The interactions between these TKIs with CYP2J2 that is highly expressed in the human heart are unknown. In vitro metabolism experiments were performed to characterize CYP2J2-mediated metabolism of ibrutinib and osimertinib. Unbound distribution coefficient (Kpuu) for both TKIs was determined in AC16 cardiomyocytes. In vitro reversible and time-dependent CYP2J2 inhibition experiments were conducted with exogenous and endogenous substrates, namely rivaroxaban and arachidonic acid (AA), respectively, where kinetic parameters were estimated via one-site and multisite kinetic modeling. Ibrutinib was efficiently metabolized by CYP2J2 to a hydroxylated metabolite, M35, following substrate inhibition kinetics. Osimertinib is not a substrate of CYP2J2. Both TKIs depicted Kpuu values above 1 and equipotently inhibited CYP2J2-mediated hydroxylation of rivaroxaban in a concentration-dependent manner without time-dependency. The mode of reversible inhibition of CYP2J2-mediated metabolism of rivaroxaban and AA by osimertinib was described by Michaelis-Menten kinetics, whereas a two-site kinetic model recapitulated the atypical inhibitory kinetics of ibrutinib, assuming multiple substrate-binding domains within the CYP2J2 active site. The inhibition of ibrutinib and osimertinib on cardiac AA metabolism could be clinically significant considering the preferable distribution of both TKIs to cardiomyocytes with R cut-off values of 1.160 and 1.026, respectively. The dysregulation of CYP2J2-mediated metabolism of AA to cardioprotective epoxyeicosatrienoic acids by ibrutinib and osimertinib serves as a novel mechanism for TKI-induced cardiac arrhythmia. Mechanistic characterization of CYP2J2-mediated typical and atypical enzyme kinetics further illuminates the unique catalytic properties of CYP2J2. SIGNIFICANCE STATEMENT: We reported for the first time that ibrutinib is efficiently metabolized by CYP2J2. By using rivaroxaban and arachidonic acid (AA) as substrates, we characterized the typical and atypical inhibition kinetics of CYP2J2 by ibrutinib and osimertinib. The inhibition of both drugs on cardiac AA metabolism could be clinically significant considering their preferable distribution to cardiomyocytes. Our findings serve as a novel mechanism for drug-induced cardiac arrhythmia and shed insights into the multisite interactions between CYP2J2 and ligands.

Application of a physiologically based pharmacokinetic model of rivaroxaban to prospective simulations of drug-drug-disease interactions with protein kinase inhibitors in cancer-associated venous thromboembolism.

AIMS: Rivaroxaban is a viable anticoagulant for the management of cancer-associated venous thromboembolism (CA-VTE). A previously verified physiologically-based pharmacokinetic (PBPK) model of rivaroxaban established how its multiple pathways of elimination via both CYP3A4/2J2-mediated hepatic metabolism and organic anion transporter 3 (OAT3)/P-glycoprotein-mediated renal secretion predisposes rivaroxaban to drug-drug-disease interactions (DDDIs) with clinically relevant protein kinase inhibitors (PKIs). We proposed the application of PBPK modelling to prospectively interrogate clinically significant DDIs between rivaroxaban and PKIs (erlotinib and nilotinib) for dose adjustments in CA-VTE. METHODS: The inhibitory potencies of the PKIs on CYP3A4/2J2-mediated metabolism of rivaroxaban were characterized. Using prototypical OAT3 inhibitor ketoconazole, in vitro OAT3 inhibition assays were optimized to ascertain the in vivo relevance of derived transport inhibitory constants (Ki ). Untested DDDIs between rivaroxaban and erlotinib or nilotinib were simulated. RESULTS: Mechanism-based inactivation (MBI) of CYP3A4-mediated rivaroxaban metabolism by both PKIs and MBI of CYP2J2 by erlotinib were established. The importance of substrate specificity and nonspecific binding to derive OAT3-inhibitory Ki values of ketoconazole and nilotinib for the accurate prediction of interactions was illustrated. When simulated rivaroxaban exposure variations with concomitant erlotinib and nilotinib therapy were evaluated using published dose-exposure equivalence metrics and bleeding risk analyses, dose reductions from 20 to 15 and 10 mg in normal and mild renal dysfunction, respectively, were warranted. CONCLUSION: We established a PBPK-DDDI model to prospectively evaluate clinically relevant interactions between rivaroxaban and PKIs for the safe and efficacious management of CA-VTE.

Urinary Metabolite Biomarkers for the Detection of Synthetic Cannabinoid ADB-BUTINACA Abuse.

BACKGROUND: (S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-butyl-1H-indazole-3carboxamide (ADB-BUTINACA) is an emerging synthetic cannabinoid that was first identified in Europe in 2019 and entered Singapore's drug scene in January 2020. Due to the unavailable toxicological and metabolic data, there is a need to establish urinary metabolite biomarkers for detection of ADB-BUTINACA consumption and elucidate its biotransformation pathways for rationalizing its toxicological implications. METHODS: We characterized the metabolites of ADB-BUTINACA in human liver microsomes using liquid chromatography Orbitrap mass spectrometry analysis. Enzyme-specific inhibitors and recombinant enzymes were adopted for the reaction phenotyping of ADB-BUTINACA. We further used recombinant enzymes to generate a pool of key metabolites in situ and determined their metabolic stability. By coupling in vitro metabolism and authentic urine analyses, a panel of urinary metabolite biomarkers of ADB-BUTINACA was curated. RESULTS: Fifteen metabolites of ADB-BUTINACA were identified with key biotransformations being hydroxylation, N-debutylation, dihydrodiol formation, and oxidative deamination. Reaction phenotyping established that ADB-BUTINACA was rapidly eliminated via CYP2C19-, CYP3A4-, and CYP3A5-mediated metabolism. Three major monohydroxylated metabolites (M6, M12, and M14) were generated in situ, which demonstrated greater metabolic stability compared to ADB-BUTINACA. Coupling metabolite profiling with urinary analysis, we identified four urinary biomarker metabolites of ADB-BUTINACA: 3 hydroxylated metabolites (M6, M11, and M14) and 1 oxidative deaminated metabolite (M15). CONCLUSIONS: Our data support a panel of four urinary metabolite biomarkers for diagnosing the consumption of ADB-BUTINACA.

Predicting the dopamine D2 receptor occupancy of ropinirole in rats using positron emission tomography and pharmacokinetic-pharmacodynamic modeling.

1. The purpose of this study was to measure dopamine D2/3 receptor occupancy (RO) as a marker of the clinical efficacy of ropinirole in rats via positron emission tomography (PET) using 18F-fallypride as the radiotracer and to explore the relationship between dopamine RO and the plasma concentration of ropinirole via pharmacokinetic-pharmacodynamic modeling. 2. Plasma was collected from 16 rats treated with one of four doses of ropinirole. For the time-dependent study, the data of 16 rats in the 15 mg/kg dose group at four time points were averaged, and another 24 rats were divided into three dose groups (5 mg/kg, 30 mg/kg and 60 mg/kg) for the dose-dependent study; the animals were assessed via 18F-fallypride PET scans. The correlation between dopamine RO and the ropinirole plasma concentration was investigated, and a pharmacokinetic-pharmacodynamic (PK-PD) model was established with WinNonlin 6.3 software. Both the plasma concentration and the binding potential changed in a time- and dose-dependent manner, and the plasma concentration that induces 50% RO (EC50) as calculated by the PK-PD model was 1391 ng/mL. 3. 18F-fallypride appeared to be a suitable radiotracer for ropinirole imaging, and its binding to the dopamine D2 receptor has time- and concentration-dependent characteristics. A theory-based PK-PD model was developed to describe the relationship between the plasma ropinirole concentration and RO, providing a methodological foundation for noninvasive and in vivo clinical evaluations of ropinirole treatment.

The role of polyamines during exocarp formation in a russet mutant of 'Dangshansuli' pear (Pyrus bretschneideri Rehd.).

KEY MESSAGE: Differential genes of suberin, polyamine and transcription factors in transcriptome sequences and the contents of H 2 O 2 , spermidine, spermine, and putrescine changed significantly after treating with MGBG. Russeting is a commercially important process that restores the control of water loss through the skin via the formation of a waterproofing periderm just beneath the microcracked skin of pear primary fruit. A spontaneous russet skin mutant, the yellow-green 'Dangshansuli' pear, has been identified. To understand the role of polyamines in the formation of the russet skin of the mutant-type (MT) pear, it was treated with methylglyoxal-bis-(guanylhydrazone) (MGBG) for 4 weeks after full bloom. One week later, differentially expressed genes among the wild-type (WT), MT, and MGBG-treated MT pears were screened, hydrogen peroxide (H2O2) was localized using CeCl3, and the contents of H2O2 and polyamine were measured. A total of 57,086,772, 61,240,014, and 67,919,420 successful reads were generated from the transcriptomes of WT, MT, and MGBG-treated MT, with average unigene lengths of 701, 720, and 735 bp, respectively. Differentially expressed genes involved in polyamine metabolism and suberin synthesis were screened in 'Dangshansuli' and in the mutant libraries, and their relative expression was found to be significantly altered after treatment with MGBG, which was confirmed by real-time PCR. The expression patterns of differentially expressed transcription factors were identified and were found to be similar to those of the polyamine- and suberin-related genes. The results indicated that the H2O2 generated during polyamine metabolism might contribute to russet formation on the exocarp of the mutant pear. Furthermore, the contents of H2O2, spermidine, spermine, and putrescine and H2O2 localization provided a comprehensive transcriptomic view of russet formation in the mutant pear.

Complete de-Dopplerization and acoustic holography for external noise of a high-speed train.

Identification and measurement of moving sound sources are the bases for vehicle noise control. Acoustic holography has been applied in successfully identifying the moving sound source since the 1990s. However, due to the high demand for the accuracy of holographic data, currently the maximum velocity achieved by acoustic holography is just above 100 km/h. The objective of this study was to establish a method based on the complete Morse acoustic model to restore the measured signal in high-speed situations, and to propose a far-field acoustic holography method applicable for high-speed moving sound sources. Simulated comparisons of the proposed far-field acoustic holography with complete Morse model, the acoustic holography with simplified Morse model and traditional delay-and-sum beamforming were conducted. Experiments with a high-speed train running at the speed of 278 km/h validated the proposed far-field acoustic holography. This study extended the applications of acoustic holography to high-speed situations and established the basis for quantitative measurements of far-field acoustic holography.

PCL/Yam Polysaccharide nanofibrous membranes loaded with self-assembled HP-ß-CD/ECG inclusion complexes for food packaging.

In this study, Polycaprolactone (PCL)/Yam Polysaccharide (YP) fiber membranes loaded the ultrasound-mediated assembly of 2-Hydroxypropyl-ß-cyclodextrin (HP-ß-CD)/Epicatechin gallate (ECG) inclusion complexes were prepared by electrospinning technology for food packaging. Morphology, infrared spectroscopy and X-ray diffraction results showed that the inclusion complexes were successfully assembled. With the addition of inclusion complexes, the average diameter of the fibers increased from 2480.96 to 10179.12 nm, the crystallinity decreased, the thermal stability improved, the hydrophilicity enhanced, and the water vapor permeability enhanced. Meanwhile, thermogravimetry and differential scanning calorimetry results showed that the inclusion complexes formed hydrogen bonds between the fibers, which improved the thermal stability, but the mechanical behavior suffered a certain loss. In addition, the fiber membrane could continuously release ECG within 240 h, which showed excellent antibacterial effects both in vitro and in vivo. These results indicated that the fiber film developed based on electrospinning had a broad application prospect in food packaging.

Global scale identification of catchments phosphorus source shifts with urbanization: A phosphate oxygen isotope and Bayesian mixing model approach.

Different scenarios of urban expansion can influence the dynamic characteristics of catchments in terms of phosphorus (P). It is important to identify the changes in P sources that occur during the process of urbanization to develop targeted policies for managing P in catchments. However, there is a knowledge gap in quantifying the variations of potential P sources associated with urbanization. By combining phosphate oxygen isotopes from global catchments with a Bayesian model and the urbanization process, we demonstrate that the characteristics of potential P sources (such as fertilizers, urban wastewater, faeces, and bedrock) change as urban areas expand. Our results indicate that using phosphate oxygen isotopes in conjunction with a Bayesian model provides direct evidence of the proportions of potential P sources. We classify catchment P loadings into three stages based on shifts in potential P sources during urban expansion. During the initial stage of urbanization (urban areas < 1.5 %), urban domestic and industrial wastewater are the main contributors to P loadings in catchments. In the mid-term acceleration stage (1.5 % ≤ urban areas < 3.5 %), efforts to improve wastewater treatment significantly reduce wastewater P input, but the increase in fertilizer P input offsets this reduction in sewage-derived P. In the high-level urbanization stage (urban areas ≥ 3.5 %), the proportions of the four potential P sources tend to stabilize. Remote areas bear the burden of excessive P loadings to meet the growing food demand and improved diets resulting from the increasing urban population. Our findings support the development of strategies for water quality management that better consider the driving forces of urbanization on catchment P loadings.

Identification of the human Cytochrome P450 enzymes (P450s) responsible for metabolizing infigratinib to its pharmacologically active Metabolites, BHS697, and CQM157, and assessment of their in vitro inhibition of P450s and UDP-glucuronosyltransferases (UGTs).

Infigratinib, an oral FGFR inhibitor for advanced cholangiocarcinoma, yielded two active metabolites, BHS697 and CQM157, with similar receptor affinity. Our study characterized P450s that are responsible for the metabolism of infigratinib to its two major active metabolites, BHS697 and CQM157. In vitro inhibition of P450s and UGTs by infigratinib, BHS697 or CQM157 was further investigated. The unbound apparent Km values for metabolism of infigratinib to BHS697 by HLM, human recombinant CYP2C8, CYP2C19, CYP2D6 and CYP3A4 enzymes are 4.47, 0.65, 2.50, 30.6 and 2.08 µM, while Vmax values are 90.0 pmol/min/mg protein, 0.13, 0.027, 0.81, and 0.56 pmol/min/pmol protein, respectively. The unbound apparent Km value for metabolism of infigratinib to CQM157 by HLM is 0.049 µM, while the Vmax value is 0.32 pmol/min/mg protein respectively. In HLM, infigratinib displayed moderate inhibition of CYP3A4 and CYP2C19 and weak or negligible inhibition of other P450 isoforms. BHS697 exhibited weak inhibition of CYP2B6, CYP2C9, CYP2C19 and CYP3A4, and no inhibition of CYP2C8 and CYP2D6. CQM157 moderately inhibited CYP2C9 and CYP3A4, and weakly or negligibly inhibited other P450 isoforms. Regarding UGTs, infigratinib moderately inhibited UGT1A4 and weakly inhibited UGT1A1, respectively. BHS697 weakly inhibited UGT1A1. In contrast, CQM157 moderately inhibited both UGT1A1 and UGT1A4. Our findings provide novel insights into the metabolism of and potential DDIs implicating infigratinib.

PCL/Locust bean gum nanofibers loaded with HP-ß-CD/Epicatechin clathrate compounds for fruit packaging.

In this work, the hydroxypropyl-ß-cyclodextrin (HP-ß-CD)/Epicatechin (EC) clathrate compounds were rapidly prepared based on an ultrasound-mediated method, and Polycaprolactone (PCL)/Locust bean gum (LBG) nanofibers loaded clathrate compounds were fabricated by electrostatic spinning (ELS) for fruit packaging. The results of infrared spectrum and crystal type analysis proved that clathrate compounds were successfully prepared. With the addition of clathrate compounds, the diameter of fibers increased from 553.43 to 1273.47 nm, and hydrogen bonds were formed between clathrate compounds and fibrous membranes, which improved the thermal stability, reduced the crystallinity, and enhanced the hydrophilicity and gas permeability of fibrous membranes. The fibrous membranes indicated sustained release of EC for 240 h, retaining the activity of EC and demonstrating good bacteriostatic ability in vitro and in vivo. The test results showed that the antibacterial fibrous membranes prepared in this work have a positive application prospect for fruit packaging.

Engineering topological interface states in metal-wire waveguides for broadband terahertz signal processing.

Innovative terahertz waveguides are in high demand to serve as a versatile platform for transporting and manipulating terahertz signals for the full deployment of future six-generation (6G) communication systems. Metal-wire waveguides have emerged as promising candidates, offering the crucial advantage of sustaining low-loss and low-dispersion propagation of broadband terahertz pulses. Recent advances have opened up new avenues for implementing signal-processing functionalities within metal-wire waveguides by directly engraving grooves along the wire surfaces. However, the challenge remains to design novel groove structures to unlock unprecedented signal-processing functionalities. In this study, we report a plasmonic signal processor by engineering topological interface states within a terahertz two-wire waveguide. We construct the interface by connecting two multiscale groove structures with distinct topological invariants, i.e., featuring a π-shift difference in the Zak phases. The existence of this topological interface within the waveguide is experimentally validated by investigating the transmission spectrum, revealing a prominent transmission peak in the center of the topological bandgap. Remarkably, we show that this resonance is highly robust against structural disorders, and its quality factor can be flexibly controlled. This unique feature not only facilitates essential functions such as band filtering and isolating but also promises to serve as a linear differential equation solver. Our approach paves the way for the development of new-generation all-optical analog signal processors tailored for future terahertz networks, featuring remarkable structural simplicity, ultrafast processing speeds, as well as highly reliable performance.