Highly Specific Aptamer-Antibody Birecognized Sandwich Module for Ultrasensitive Detection of a Low Molecular Weight Compound.

Herein, the aptamer-antibody sandwich module was first introduced to accurately recognize a low molecular weight compound (mycotoxin). Impressively, compared with the large steric hindrance of a traditional dual-antibody module, the aptamer-antibody sandwich with low Gibbs free energy and a low dissociation constant has high recognition efficiency; thus, it could reduce false positives and false negatives caused by a dual-antibody module. As a proof of concept, a sensitive electrochemiluminescence (ECL) biosensor was constructed for detecting mycotoxin zearalenone (ZEN) based on an aptamer-antibody sandwich as a biological recognition element and porous ZnO nanosheets (Zn NSs) supported Cu nanoclusters (Cu NCs) as the signal transduction element, in which the antibody was modified on the vertex of a tetrahedral DNA nanostructure (TDN) with a rigid structure to increase the kinetics of target recognition for promoting the detection sensitivity. Moreover, the Cu NCs/Zn NSs exhibited an excellent ECL response that was attributed to the aggregation-induced ECL enhancement through electrostatic interactions. The sensing platform achieved trace detection of ZEN with a low detection limit of 0.31 fg/mL, far beyond that of the enzyme-linked immunosorbent assay (ELISA, the current rapid detection method) and high-performance liquid chromatography (HPLC, the national standard detection method). The strategy has great application potential in food analysis, environmental monitoring, and clinical diagnosis.

Chondroitin Sulfate Derivative Cross-Linking of Decellularized Heart Valve for the Improvement of Mechanical Properties, Hemocompatibility, and Endothelialization.

Tissue-engineered heart valve (TEHV) has emerged as a prospective alternative to conventional valve prostheses. The decellularized heart valve (DHV) represents a promising TEHV scaffold that preserves the natural three-dimensional structure and retains essential biological activity. However, the limited mechanical strength, fast degradation, poor hemocompatibility, and lack of endothelialization of DHV restrict its clinical use, which is necessary for ensuring its long-term durability. Herein, we used oxidized chondroitin sulfate (ChS), one of the main components of the extracellular matrix with various biological activities, to cross-link DHV to overcome the above problems. In addition, the ChS-adipic dihydrazide was used to react with residual aldehyde groups, thus preventing potential calcification. The results indicated notable enhancements in mechanical properties and resilience against elastase and collagenase degradation in vitro as well as the ability to withstand extended periods of storage without compromising the structural integrity of valve scaffolds. Additionally, the newly cross-linked valves exhibited favorable hemocompatibility in vitro and in vivo, thereby demonstrating exceptional biocompatibility. Furthermore, the scaffolds exhibited traits of gradual degradation and resistance to calcification through a rat subcutaneous implantation model. In the rat abdominal aorta implantation model, the scaffolds demonstrated favorable endothelialization, commendable patency, and a diminished pro-inflammatory response. As a result, the newly constructed DHV scaffold offers a compelling alternative to traditional valve prostheses, which potentially advances the field of TEHV.

Alleviation of Salt Stress and Changes in Glycyrrhizic Acid Accumulation by Dark Septate Endophytes in Glycyrrhiza glabra Grown under Salt Stress.

This study aimed to investigate the mechanisms by which dark septate endophytes (DSE) regulate salt tolerance and the accumulation of bioactive constituents in licorice. First, the salt stress tolerance and resynthesis with the plant effect of isolated DSE from wild licorice were tested. Second, the performance of licorice inoculated with DSE, which had the best salt-tolerant and growth-promoting effects, was examined under salt stress. All isolated DSE showed salt tolerance and promoted plant growth, withCurvularia lunata D43 being the most effective. Under salt stress, C. lunata D43 could promote growth, increase antioxidant enzyme activities, enhance glycyrrhizic acid accumulation, improve key enzyme activities in the glycyrrhizic acid synthesis pathway, and induce the expression of the key enzyme gene and salt tolerance gene of licorice. The structural equation model demonstrated that DSE alleviate the negative effects of salt stress through direct and indirect pathways. Variations in key enzyme activities, gene expression, and bioactive constituent concentration can be attributed to the effects of DSE. These results contribute to revealing the value of DSE for cultivating medicinal plants in saline soils.

CRISPR-Cas3 and type I restriction-modification team up against blaKPC-IncF plasmid transfer in Klebsiella pneumoniae.

OBJECTIVE: We explored whether the Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas and restriction-modification (R-M) systems are compatible and act together to resist plasmid attacks. METHODS: 932 global whole-genome sequences from GenBank, and 459 K. pneumoniae isolates from six provinces of China, were collected to investigate the co-distribution of CRISPR-Cas, R-M systems, and blaKPC plasmid. Conjugation and transformation assays were applied to explore the anti-plasmid function of CRISPR and R-M systems. RESULTS: We found a significant inverse correlation between the presence of CRISPR and R-M systems and blaKPC plasmids in K. pneumoniae, especially when both systems cohabited in one host. The multiple matched recognition sequences of both systems in blaKPC-IncF plasmids (97%) revealed that they were good targets for both systems. Furthermore, the results of conjugation assay demonstrated that CRISPR-Cas and R-M systems in K. pneumoniae could effectively hinder blaKPC plasmid invasion. Notably, CRISPR-Cas and R-M worked together to confer a 4-log reduction in the acquisition of blaKPC plasmid in conjugative events, exhibiting robust synergistic anti-plasmid immunity. CONCLUSIONS: Our results indicate the synergistic role of CRISPR and R-M in regulating horizontal gene transfer in K. pneumoniae and rationalize the development of antimicrobial strategies that capitalize on the immunocompromised status of KPC-KP.

Mechanistic insights into bismuth(iii) inhibition of SARS-CoV-2 helicase.

The COVID-19 pandemic caused by SARS-CoV-2 resulted in a global public health crisis. In addition to vaccines, the development of effective therapy is highly desirable. Targeting a protein that plays a critical role in virus replication may allow pan-spectrum antiviral drugs to be developed. Among SARS-CoV-2 proteins, helicase (i.e., non-structural protein 13) is considered as a promising antiviral drug target due to its highly conserved sequence, unique structure and function. Herein, we demonstrate SARS-CoV-2 helicase as a target of bismuth-based antivirals in virus-infected mammalian cells by a metal-tagged antibody approach. To search for more potent bismuth-based antivirals, we further screened a panel of bismuth compounds towards inhibition of ATPase and DNA unwinding activity of nsp13 and identified a highly potent bismuth compound Bi(5-aminotropolonate)3, namely Bi(Tro-NH2)3 with an IC50 of 30 nM for ATPase. We show that bismuth-based compounds inhibited nsp13 unwinding activity via disrupting the binding of ATP and the DNA substrate to viral helicase. Binding of Bi(iii) to nsp13 also abolished the interaction between nsp12 and nsp13 as evidenced by immunofluorescence and co-immunoprecipitation assays. Finally, we validate our in vitro data in SARS-CoV-2 infected mammalian cells. Notably, Bi(6-TG)3 exhibited an EC50 of 1.18 ± 0.09 µM with a selective index of 847 in VeroE6-TMPRSS2 infected cells. This study highlights the important role of helicase for the development of more effective antiviral drugs to combat SARS-CoV-2 infection.

Involvement of the Laboratory Department in MDT Discussion for the Diagnosis of Unexplained Leukocytosis.

BACKGROUND: This paper reports the diagnostic process of a case involving an 86-year-old male patient who was admitted with cough, sputum, and fever, accompanied by persistent leukocytosis. METHODS: Through a multidisciplinary team (MDT) discussion, the laboratory department identified elevated ferritin levels, prompting clinical consideration of potential malignancy. RESULTS: Further investigations confirmed the diagnosis of thyroid cancer with multiple lung metastases. CONCLUSIONS: This case highlights the potential value of ferritin in tumor diagnosis, offering new insights into the etiology of abnormal leukocyte elevation. Additionally, the active involvement of the laboratory department in MDT discussions proves to be crucial for diagnosing challenging cases.

Overexpression of USP8 inhibits inflammation and ferroptosis in chronic obstructive pulmonary disease by regulating the OTUB1/SLC7A11 signaling pathway.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a familiar disease, and owns high morbidity and mortality, which critically damages the health of patients. Ubiquitin-specific peptidase 8 (USP8) is a pivotal protein to join in the regulation of some diseases. In a previous report, it was determined that USP8 expression is down-regulated in LPS-treated BEAS-2B cells, and USP8 restrains inflammatory response and accelerates cell viability. However, the regulatory roles of USP8 on ferroptosis in COPD are rarely reported, and the associated molecular mechanisms keep vague. OBJECTIVE: To investigate the regulatory functions of USP8 in COPD progression. MATERIAL AND METHODS: The lung functions were measured through the Buxco Fine Pointe Series Whole Body Plethysmography (WBP). The Fe level was tested through the Fe assay kit. The protein expressions were assessed through western blot. The levels of tumor necrosis -factor-α, interleukin 6, and interleukin 8 were evaluated through enzyme-linked immunosorbent serologic assay. Cell viability was tested through CCK-8 assay. RESULTS: In this work, it was discovered that overexpression of USP8 improved lung function in COPD mice. In addition, overexpression of USP8 repressed ferroptosis by regulating glutathione peroxidase 4 and acyl-CoA synthetase long-chain family 4 expressions in COPD mice. Overexpression of USP8 suppressed inflammation in COPD mice. Furthermore, overexpression of USP8 suppressed ferroptosis in COPD cell model. At last, it was verified that overexpression of USP8 accelerated ubiquitin aldehyde-binding protein 1 (OTUB1)/solute carrier family 7 member 11 (SLC7A11) pathway. CONCLUSION: This study manifested that overexpression of USP8 restrained inflammation and ferroptosis in COPD by regulating the OTUB1/SLC7A11 signaling pathway. This discovery hinted that USP8 could be a potential target for COPD treatment.

Photocatalytic Formamide Synthesis via Coupling of Electrophilic and Nucleophilic Radicals over Atomically Dispersed Bi Sites.

Formamide (HCONH2) plays a pivotal role in the manufacture of a diverse array of chemicals, fertilizers, and pharmaceuticals. Photocatalysis holds great promise for green fabrication of carbon-nitrogen (C-N) compounds owing to its environmental friendliness and mild redox capability. However, the selective formation of the C-N bond presents a significant challenge in the photocatalytic synthesis of C-N compounds. This work developed a photocatalytic radical coupling method for the formamide synthesis from co-oxidation of ammonia (NH3) and methanol (CH3OH). An exceptional formamide yield rate of 5.47 ± 0.03 mmol·gcat-1·h-1 (911.87 ± 0.05 mmol·gBi-1·h-1) was achieved over atomically dispersed Bi sites (BiSAs) on TiO2. An accumulation of 45.0 mmol·gcat-1 (0.2 g·gcat-1) of formamide was achieved after long-term illumination, representing the highest level of photocatalytic C-N compounds synthesis. The critical C-N coupling for formamide formation originated from the "σ-σ" interaction between electrophilic ●CH2OH with nucleophilic ●NH2 radical. The  BiSAs sites facilitated the electron transfer between reactants and photocatalysts and enhanced the nucleophilic attack of â—NH2 radical at the â—CH2OH radical, thereby advancing the selective C-N bond formation. This work deepens the understanding of the C-N coupling mechanism and offers an alternative and intriguing photocatalytic approach for the efficient and sustainable production of C-N compounds.

Is the Homologous Recombination Repair Mutation Defined by a 15-Gene Panel Associated with the Prognosis of Epithelial Ovarian Cancer?

BACKGROUND: There is no consensus regarding the specific genes included in the homologous recombination repair (HRR) gene panel for identifying the HRR deficiency (HRD) status and predicting the prognosis of epithelial ovarian cancer (EOC) patients. OBJECTIVE: We aimed to explore a 15-gene panel involving the HRR pathway as a predictive prognostic indicator in Chinese patients newly diagnosed with EOC. PATIENTS AND METHODS: We reviewed the previously published reports about different HRR gene panels and prespecified the 15-gene panel. The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centers were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) and progression-free survival (PFS) with 15-gene panel HRR mutations (HRRm) status was assessed. RESULTS: 43.2% (133/308) of patients were determined to carry 144 deleterious HRRm, among which 68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2 gene lethal mutations. The hazard ratio (HR) (95% confidence interval, CI) for PFS (HRRm v HRR wild type, HRRwt) using the 15-gene panel HRRm was 0.42 (0.28-0.64) at all stages and 0.42 (0.27-0.65) at stages IIIC-IV. However, a prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. For the subgroups of patients not using PARPis, the HR (95% CI) was 0.41 (0.24-0.68) at stages IIIC-IV. CONCLUSIONS: This study provides evidence that 15-gene panel HRRm can predict the prognosis of EOC, of these only the BRCA1/2 mutations, not non-BRCA HRRm, contribute to prognosis prediction. Among patients without PARPis, the HRRm group presented a better PFS. This is the first study of this kind in the Chinese population.

Prognosis of Lung Transplantation in Patients with Acute Exacerbations of Interstitial Lung Disease: A Meta-Analysis Based on Cohort Studies.

PURPOSE: This meta-analysis aimed to examine the prognosis of patients with acute exacerbation of interstitial lung disease (AE-ILD) treated with lung transplantation compared to those with stable interstitial lung disease (ILD). METHODS: We conducted a detailed search in PubMed, Embase, Web of Science, and the Cochrane Library, with the primary outcomes being overall survival (OS), acute cellular rejection (ACR), primary graft dysfunction (PGD), and length of stay (LOS). RESULTS: Five cohort studies were included in this meta-analysis, with 183 patients enrolled in the AE-ILD group and 337 patients in the stable-ILD group. The results showed that in regard to perioperative outcomes, the AE-ILD group did not differ from the stable-ILD group in the incidence of ACR (relative risks [RR] = 0.34, p = 0.44) and the incidence of PGD Ⅲ (RR = 0.53, p = 0.43), but had a longer LOS (mean difference = 9.15, p = 0.02). Regarding prognosis, the two also did not differ in 90-day OS (RR = 0.97, p = 0.59), 1-year OS (RR = 1.05, p = 0.66), and 3-year OS (RR = 0.91, p = 0.76). CONCLUSION: Our study concluded that the efficacy of lung transplantation in patients with AE-ILD is not inferior to that of patients with stable ILD. Lung transplantation is one of the potential treatments for patients with AE-ILD.

Characterization of ST15-KL112 Klebsiella pneumoniae Co-Harboring Bla oxa-232 and rmtF in China.

Introduction: This study aimed to investigate the emergence and characteristics of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains that demonstrate resistance to multiple antibiotics, including aminoglycosides and tigecycline, in a Chinese hospital. Methods: A group of ten CRKP strains were collected from the nine patients in a Chinese hospital. Antimicrobial Susceptibility Testing (AST) and phenotypic inhibition assays precisely assess bacterial antibiotic resistance. Real-time quantitative PCR (RT-qPCR) was used to analyze the mRNA levels of efflux pump genes (acrA/acrB and oqxA/oqxB) and the regulatory gene (ramA). The core-genome tree and PFGE patterns were analyzed to assess the clonal and horizontal transfer expansion of the strains. Whole-genome sequencing was performed on a clinical isolate of K. pneumoniae named Kpn20 to identify key resistance genes and antimicrobial resistance islands (ARI). Results: The CRKP strains showed high resistance to carbapenems, aminoglycosides (CLSI, 2024), and tigecycline (EUCAST, 2024). The mRNA expression levels of efflux pump genes and regulatory genes were detected by RT-qPCR. All 10 isolates had significant differences compared to the control group of ATCC13883. The core-genome tree and PFGE patterns revealed five clusters, indicating clonal and horizontal transfer expansion. Three key resistance genes (blaoxa-232, blaCTX-M-15 , and rmtF) were observed in the K. pneumoniae clinical isolate Kpn20. Mobile antibiotic resistance islands were identified containing bla CTX-M-15 and rmtF, with multiple insertion sequences and transposons present. The coexistence of bla oxa-232 and rmtF in a high-risk K. pneumoniae strain was reported. Conjugation assay was utilized to investigate the transferability of bla oxa-232-encoding plasmids horizontally. Conclusion: The study highlights the emergence of ST15-KL112 high-risk CRKP strains with multidrug resistance, including to aminoglycosides and tigecycline. The presence of mobile ARI and clonal and horizontal transfer expansion of strains indicate the threat of transmission of these strains. Future research is needed to assess the prevalence of such isolates and develop effective control measures.

Melt-electrowriting-enabled anisotropic scaffolds loaded with valve interstitial cells for heart valve tissue Engineering.

Tissue engineered heart valves (TEHVs) demonstrates the potential for tissue growth and remodel, offering particular benefit for pediatric patients. A significant challenge in designing functional TEHV lies in replicating the anisotropic mechanical properties of native valve leaflets. To establish a biomimetic TEHV model, we employed melt-electrowriting (MEW) technology to fabricate an anisotropic PCL scaffold. By integrating the anisotropic MEW-PCL scaffold with bioactive hydrogels (GelMA/ChsMA), we successfully crafted an elastic scaffold with tunable mechanical properties closely mirroring the structure and mechanical characteristics of natural heart valves. This scaffold not only supports the growth of valvular interstitial cells (VICs) within a 3D culture but also fosters the remodeling of extracellular matrix of VICs. The in vitro experiments demonstrated that the introduction of ChsMA improved the hemocompatibility and endothelialization of TEHV scaffold. The in vivo experiments revealed that, compared to their non-hydrogel counterparts, the PCL-GelMA/ChsMA scaffold, when implanted into SD rats, significantly suppressed immune reactions and calcification. In comparison with the PCL scaffold, the PCL-GelMA/ChsMA scaffold exhibited higher bioactivity and superior biocompatibility. The amalgamation of MEW technology and biomimetic design approaches provides a new paradigm for manufacturing scaffolds with highly controllable microstructures, biocompatibility, and anisotropic mechanical properties required for the fabrication of TEHVs.

Plants attacked above-ground by leaf-mining flies change below-ground microbiota to enhance plant defense.

Root-associated microbiomes play a crucial role in plant responses to biotic and abiotic stresses. Plants can enrich beneficial microbes to increase their stress-relieving ability. Above-ground insect herbivory is among the most detrimental stresses for plants, especially to crop production. However, few studies have explored how root-associated microbiomes respond to herbivores and influence plant-defense functions under herbivory stress. We investigate the changes and functional role of root-associated microbial communities under herbivory stress using leafminer (Liriomyza trifolii) and cowpea (Vigna unguiculata) as a focal system. We did this by using a combination of 16S ribosomal RNA gene profiling and metagenomic sequencing to test for differences in co-occurrence networks and functions between cowpea plants infested and noninfested with leafminers. The results demonstrated that leafminer infestation caused a shift in the rhizosphere microbiome, which was characterized by a significant variation in microbiome community structure and composition, the selection of hub microbes involved in nitrogen (N) metabolism, and functional enrichment related to N metabolism. Notably, nitrogen-fixing bacteria Bradyrhizobium species were actively enriched and selected to be hubs in the rhizosphere. Inoculation with Bradyrhizobium enhanced cowpea performance under leafminer stress and increased protease inhibitor levels to decrease leafminer fitness. Overall, our study characterized the changes of root-associated microbiota between leafminer-infested and noninfested cowpea plants and revealed the mechanisms underlying the rhizosphere microbiome shift that enhance plant performance and defense against herbivory. Our findings provide further support for the notion that plants enrich rhizosphere microbes to counteract aboveground insect herbivores.

Fully Organic Sensors for Continuous Real-Time Digestion Monitoring.

Monitoring the gastric digestive function is important for the diagnosis of gastric disorders and drug development. However, there is no report on the in situ and real-time monitoring of digestive functions. Herein, we report a flexible fully organic sensor to effectively monitor protein digestion in situ in a simulated gastric environment for the first time. The sensors are made of a blend of gluten that is a protein and poly(3,4-ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS) that is a conducting polymer. During the protein digestion, the breakdown of the polypeptides increases the level of separation among the PEDOT chains, thereby increasing the resistance. The resistance variation is sensitive to various conditions, including the concentration of pepsin that is the enzyme for protein digestion, temperature, pH value, and digestive drugs. Hence, these sensors can provide real-time information about the digestion and efficacy of digestive drugs. In addition, the signals can be collected via a convenient wireless communication manner.

Transcriptome Study of rd1Mouse Brain and Association with Parkinson's Disease.

Degeneration of the retina is intrinsically associated with the pathogenesis and progression of neurodegenerative diseases. However, the cellular and molecular mechanisms underlying the association between neurodegeneration and retinal degeneration are still under exploration due to the complexity of the connectivity network of the nervous system. In this study, RNA-seq data from the brains of model retinitis pigmentosa (RP) mice and previously studied Parkinson's disease (PD) mice were analyzed to explore the commonalities between retinal degenerative and neurodegenerative diseases. Differentially expressed genes in RP were compared with neurodegenerative disease-related genes and intersecting genes were identified, including Cnr1 and Septin14. These genes were verified by quantitative real-time reverse transcription PCR and Western blotting experiments. The key proteins CNR1 and SEPTIN14 were found to be potential cotherapeutic targets for retinal degeneration and neurodegenerative disease. In conclusion, understanding the commonalities between retinal degenerative diseases and neurodegenerative processes in the brain will not only facilitate the interpretation of the underlying pathomechanisms but also contribute to early diagnosis and the development of new therapeutic strategies.

Bletilla striata polysaccharide-coated andrographolide nanomicelles for targeted drug delivery to enhance anti-colon cancer efficacy.

Background: Vitamin E, which is also known as tocopherol, is a compound with a polyphenol structure. Its esterified derivative, Vitamin E succinate (VES), exhibits unique anticancer and healthcare functions as well as immunomodulatory effects. Natural polysaccharides are proved to be a promising material for nano-drug delivery systems, which show excellent biodegradability and biocompatibility. In this study, we employed a novel bletilla striata polysaccharide-vitamin E succinate polymer (BSP-VES) micelles to enhance the tumor targeting and anti-colon cancer effect of andrographolide (AG). Methods: BSP-VES polymer was synthesized through esterification and its structure was confirmed using 1H NMR. AG@BSP-VES was prepared via the dialysis method and the drug loading, entrapment efficiency, stability, and safety were assessed. Furthermore, the tumor targeting ability of AG@BSP-VES was evaluated through targeted cell uptake and in vivo imaging. The antitumor activity of AG@BSP-VES was measured in vitro using MTT assay, Live&Dead cell staining, and cell scratch test. Results: In this study, we successfully loaded AG into BSP-VES micelles (AG@BSP-VES), which exhibited good stability, biosafety and sustained release effect. In addition, AG@BSP-VES also showed excellent internalization capability into CT26 cells compared with NCM460 cells in vitro. Meanwhile, the specific delivery of AG@BSP-VES micelles into subcutaneous and in-situ colon tumors was observed compared with normal colon tissues in vivo during the whole experiment process (1-24 h). What's more, AG@BSP-VES micelles exhibited significant antitumor activities than BSP-VES micelles and free AG. Conclusion: The study provides a meaningful new idea and method for application in drug delivery system and targeted treatment of colon cancer based on natural polysaccharides.

Nociceptive adenosine A2A receptor on trigeminal nerves orchestrates CGRP release to regulate the progression of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) associated pain commonly predicts adverse events among patients. This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy. However, it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression. In this study, we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo, as evidenced by clinical tissue microarray analysis and murine lingual denervation. We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort. Notably, such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A2A receptor (A2AR) on trigeminal ganglia. Antagonism of trigeminal A2AR with a selective A2AR inhibitor SCH58261 resulted in impeded OSCC growth in vivo. We showed that trigeminal A2AR overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP, an effect counteracted by SCH58261. We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP. Finally, we diminished the impact of CGRP on OSCC with istradefylline, a clinically available drug that targets neuronal A2AR. Therefore, we established trigeminal A2AR-mediated CGRP release as a promising druggable circuit in OSCC treatment.

High resistance risk of Phytophthora colocasiae to azoxystrobin in southeastern of China.

Quinone outside inhibitor (QoI) has been applied to manage taro leaf blight caused by Phytophthora colocasiae in southeastern of China for many years. The risk of P. colocasiae to QoI and the potential resistant mechanism remain unknown. In this study, the 74 P. colocasiae strains were sampled from southeastern of China. Sequence analysis of the QoI target Cytb showed one nucleotide variant in the fragment of this gene in this population, producing two haplotypes. The nucleotide variant leads to codon change at 142 (GGT to GCT) producing A142 (alanine) and G142 (glycine) in Hap_1 and Hap_2 strains, respectively. The sensitivity differentiation to azoxystrobin of two haplotypes were observed in vitro. The Hap_1 and Hap_2 strains were confirmed resistant and sensitive by control efficacy of label rate fungicide application, which was 3.0% and 88.8% treated with 500 µg/mL azoxystrobin, respectively. In addition, 10.0 µg/mL azoxystrobin plus 50 µg/mL salicylhydroxamic acid (SHAM) supplemented in PDA medium was identified as a discriminatory dose for differentiation of these two phenotype strains. The azoxystrobin resistant frequency reached 86.5%, indicating prevalence of QoI resistance in the field. Further fitness related features showed that no significant difference in temperature sensitivity, mycelial growth rate, sporangia production, zoospore release and aggressiveness between azoxystrobin-resistant and sensitive strains indicating no potential fitness cost for azoxystrobin resistance. Taken together, azoxystrobin resistance need to be taken into consideration to manage taro leaf blight in southeastern of China.

A GLM-based zero-inflated generalized Poisson factor model for analyzing microbiome data.

Motivation: High-throughput sequencing technology facilitates the quantitative analysis of microbial communities, improving the capacity to investigate the associations between the human microbiome and diseases. Our primary motivating application is to explore the association between gut microbes and obesity. The complex characteristics of microbiome data, including high dimensionality, zero inflation, and over-dispersion, pose new statistical challenges for downstream analysis. Results: We propose a GLM-based zero-inflated generalized Poisson factor analysis (GZIGPFA) model to analyze microbiome data with complex characteristics. The GZIGPFA model is based on a zero-inflated generalized Poisson (ZIGP) distribution for modeling microbiome count data. A link function between the generalized Poisson rate and the probability of excess zeros is established within the generalized linear model (GLM) framework. The latent parameters of the GZIGPFA model constitute a low-rank matrix comprising a low-dimensional score matrix and a loading matrix. An alternating maximum likelihood algorithm is employed to estimate the unknown parameters, and cross-validation is utilized to determine the rank of the model in this study. The proposed GZIGPFA model demonstrates superior performance and advantages through comprehensive simulation studies and real data applications.