Cold tolerance SNPs and candidate gene mining in the soybean germination stage based on genome-wide association analysis.

KEY MESSAGE: Three QTLs associated with low-temperature tolerance were identified by genome-wide association analysis, and 15 candidate genes were identified by haplotype analysis and gene expression analyses. Low temperature is a critical factor affecting the geographical distribution, growth, development, and yield of soybeans, with cold stress during seed germination leading to substantial productivity loss. In this study, an association panel comprising 260 soybean accessions was evaluated for four germination traits and four cold tolerance index traits, revealing extensive variation in cold tolerance. Genome-wide association study (GWAS) identified 10 quantitative trait nucleotides (QTNs) associated with cold tolerance, utilizing 30,799 single nucleotide polymorphisms (SNPs) and four GWAS models. Linkage disequilibrium (LD) analysis positioned these QTNs within three cold-tolerance quantitative trait loci (QTL) and, with QTL19-1, was positioned by three multi-locus models, underscoring its importance as a key QTL. Integrative haplotype analysis, supplemented by transcriptome analysis, uncovered 15 candidate genes. The haplotypes within the genes Glyma.18G044200, Glyma.18G044300, Glyma.18G044900, Glyma.18G045100, Glyma.19G222500, and Glyma.19G222600 exhibited significant phenotypic variations, with differential expression in materials with varying cold tolerance. The QTNs and candidate genes identified in this study offer substantial potential for marker-assisted selection and gene editing in breeding cold-tolerant soybeans, providing valuable insights into the genetic mechanisms underlying cold tolerance during soybean germination.

STING inhibitors target the cyclic dinucleotide binding pocket.

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi-Goutière's syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2'3'-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2'3'-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1-/- mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.

Predictive effect of the systemic inflammation response index (SIRI) on the efficacy and prognosis of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer.

BACKGROUND: Inflammation is a part of tumours, and inflammatory cells can affect the proliferation, invasion, and development of tumour cells. An increasing number of peripheral blood inflammatory markers have been found to play very important roles in the treatment and prognosis of cancer patients. The systemic inflammatory response index (SIRI) is a newer inflammatory marker, and its role in colorectal cancer, especially in locally advanced rectal cancer, is still unclear. METHODS: From 2015 to 2020, 198 patients with locally advanced rectal cancer (LARC) who underwent surgery following neoadjuvant chemoradiotherapy (Neo-CRT) were analysed. Patients were categorized into good- and poor- response groups according to their pathological results, and clinical characteristics and baseline parameters were compared between the two groups. The optimal cutoff values for inflammatory indicators were determined using receiver operating characteristic (ROC) analysis. Univariate and multivariate analyses were performed using the Cox proportional hazard model. Survival analysis was performed via the Kaplan‒Meier method. RESULTS: After patients were grouped into good and poor response groups, indicator differences were found in CEA, neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and SIRI. According to the ROC analysis, the NLR (P = 0.015), SII (P = 0.001), and SIRI (P = 0.029) were significant prognostic factors. After univariate and multivariate analyses of the Cox proportional hazards regression model, only the SIRI was found to be an independent prognostic factor for overall survival (OS) and disease-free survival (DFS). Finally, Kaplan‒Meier survival curves also confirmed the ability of the SIRI to predict survival. CONCLUSION: The preoperative SIRI can be used to predict the response to Neo-CRT in LARC patients and is an independent predictor of OS and DFS in postoperative patients. A high SIRI was associated with poor radiotherapy response and predicted poor OS and DFS.

Correction: RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.

[This corrects the article DOI: 10.1371/journal.ppat.1009401.].

RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.

The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. By performing mass spectrometry, we identified Lys231 and Lys421 as essential neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense.

Stochastic Exceptional Points for Noise-Assisted Sensing.

Noise is a fundamental challenge for sensors deployed in daily environments for ambient sensing, health monitoring, and wireless networking. Current strategies for noise mitigation rely primarily on reducing or removing noise. Here, we introduce stochastic exceptional points and show the utility to reverse the detrimental effect of noise. The stochastic process theory illustrates that the stochastic exceptional points manifest as fluctuating sensory thresholds that give rise to stochastic resonance, a counterintuitive phenomenon in which the added noise increases the system's ability to detect weak signals. Demonstrations using a wearable wireless sensor show that the stochastic exceptional points lead to more accurate tracking of a person's vital signs during exercise. Our results may lead to a distinct class of sensors that overcome and are enhanced by ambient noise for applications ranging from healthcare to the internet of things.

Customizing a Hyperbranched Ligand Confers Supported Platinum Nanoclusters with Unexpected Catalytic Activity toward the Reduction of 4-Nitrophenol.

We here show that a dendritic molecule combined with ligand merit confers supported platinum nanoclusters (PtNCs) with unprecedented catalytic performance. Branched polyethylenimine (PEI, Mn = 2000 D) patched on a porous bead is modified with 2-(diphenylphosphino)benzaldehyde (dppb) before being used to mediate a platinum nanoparticle/nanocluster (Pt0). The catalytic activity of Pt0 toward the reduction of 4-nitrophenol (4-NP) is evaluated from the parameter of Pt-normalized rate constant (kc). Optimization of the dppb level along with transformation of the PEI hydrogens into diol or trimethylammonium groups imparts supported Pt0 unprecedented activity (kc = 19.2 L mmol-1 s-1 and turnover frequency (TOF) = 1041 h-1). The supported Pt0 at an extremely low dosage of 0.1 ppm promotes 98% conversion of 4-NP within minutes and is well recyclable. The striking catalytic activity is attributed to the combination of orthogonal ligand properties such as weak ligand nature, catalyst-activating ability, excellent substrate affinity, and effect on PtNC-size mediation of the ligand.

M2 Macrophage-Derived Extracellular Vesicles Containing MicroRNA-501-3p Promote Colon Cancer Progression Through the SETD7/DNMT1/SOCS3 Axis.

BACKGROUND: Macrophage-derived extracellular vesicles with microRNAs can cause and develop colon cancer. OBJECTIVE: To investigate M2 macrophage-derived extracellular vesicles and colon cancer. DESIGN: A prospective and experimental study of M2 macrophage-derived extracellular vesicles in colon cancer. SETTING: This study was completed at the Fourth Hospital of Hebei Medical University. PATIENTS: Patients with colon cancer who had undergone surgical resection. MAIN OUTCOME MEASURES: Suppressor of cytokine signaling 3, miR-501-3p, SET domain containing 7, and DNA methyltransferase 1 were measured in colon cancer samples. Multiple experiments determined suppressor of cytokine signaling 3, miR-501-3p, SET domain containing 7, and DNA methyltransferase 1 binding affinity. M2 macrophages were cultivated from M0 macrophages isolated from peripheral blood mononuclear cells of a healthy donor and polarized to produce extracellular vesicles. Gain- or loss-of-function tests using colon cancer cells and M2 macrophage-derived extracellular vesicles revealed cell biological processes. Finally, animal models were created to test how miR-501-3p from M2-extracellular vesicles affects tumor growth via the SET domain containing 7/DNA methyltransferase 1/suppressor of cytokine signaling 3. RESULTS: Colon cancer increased miR-501-3p and DNA methyltransferase 1 and downregulated suppressor of cytokine signaling 3 and SET domain containing 7. miR-151-3p inhibited SET domain containing 7, upregulating DNA methyltransferase 1. Increased promoter methylation by DNA methyltransferase 1 decreased suppressor of cytokine signaling 3 expression. M2-EVs with miR-501-3p regulated the SET domain containing 7/DNA methyltransferase 1/suppressor of cytokine signaling 3 axis to induce apoptosis and colon cancer cell growth, invasion, and migration. M2-EV-delivered miR-501-3p also regulated the SET domain containing 7/DNA methyltransferase 1/suppressor of cytokine signaling 3 axis to promote tumor growth in animals. LIMITATIONS: Further research is needed in clinical application of M2 macrophage-derived extracellular vesicles containing miR-501-3p as a biomarker of colon cancer. CONCLUSIONS: M2 macrophage-derived extracellular vesicles with miR-501-3p regulate the SET domain containing 7/DNA methyltransferase 1/suppressor of cytokine signaling 3 axis to promote colon cancer. LAS VESCULAS EXTRACELULARES DERIVADAS DE MACRFAGOS M QUE CONTIENEN MICROARNP PROMUEVEN LA PROGRESIN DEL CNCER DE COLON A TRAVS DEL EJE SETD/DNMT/SOCS: ANTECEDENTES:Las vesículas extracelulares derivadas de macrófagos con microARN pueden causar y desarrollar cáncer de colon.OBJETIVO:Investigamos las vesículas extracelulares derivadas de macrófagos M2 y el cáncer de colon.DISEÑO:Un estudio prospectivo y experimental de vesículas extracelulares derivadas de macrófagos M2 en el cáncer de colon.ESCENARIO:Este estudio se completó en el Cuarto Hospital de la Universidad Médica de Hebei.PACIENTES:Pacientes con cáncer de colon sometidos a resección quirúrgica.PRINCIPALES MEDIDAS DE RESULTADO:Se midieron el supresor de la señalización de citoquinas 3, miR-501-3p, SETD7 y la ADN metiltransferasa 1 en muestras de cáncer de colon. Múltiples experimentos determinaron la afinidad de unión del supresor de la señalización de citoquinas 3, de miR-501-3p, de SETD7 y de la ADN metiltransferasa 1. Los macrófagos M2 se cultivaron a partir de macrófagos M0 aislados de células mononucleares de sangre periférica de donantes sanos y se polarizaron para producir vesículas extracelulares. Las pruebas de ganancia o pérdida de función utilizando células de cáncer de colon y vesículas extracelulares derivadas de macrófagos M2 revelaron procesos biológicos celulares. Finalmente, se crearon modelos animales para probar cómo miR-501-3p de vesículas extracelulares M2 afecta el crecimiento tumoral a través del SETD7/ADN metiltransferasa 1/supresor de la señalización de citocinas 3.RESULTADOS:El cáncer de colon aumentó el miR-501-3p y la ADN metiltransferasa 1 y reguló negativamente el supresor de la señalización de citoquinas 3 y SETD7. miR-151-3p inhibió SETD7, regulando positivamente la ADN metiltransferasa 1. El aumento de la metilación del promotor por la ADN metiltransferasa 1 produjo disminución de la expresión del supresor de señalización de citocinas 3. Los M2-EV con miR-501-3p regularon el eje SETD7/ADN metiltransferasa 1/supresor de la señalización de citocinas 3 para inducir apoptosis y crecimiento, invasión y migración de células de cáncer de colon. El miR-501-3p administrado por M2-EV también reguló el eje SETD7/ADN metiltransferasa 1/supresor de la señalización de citocinas 3 para promover el crecimiento tumoral en animales.LIMITACIONES:Se necesita más investigación en la aplicación clínica de vesículas extracelulares derivadas de macrófagos M2 que contienen miR-501-3p como biomarcador de cáncer de colon.CONCLUSIONES:Las vesículas extracelulares derivadas de macrófagos M2 con miR-501-3p regulan el eje SETD7/ADN metiltransferasa 1/supresor de la señalización de citocinas 3 para promover el cáncer de colon. (Traducción-Dr. Felipe Bellolio ).

Momordica charantia saponins administration in low-protein-high-carbohydrate diet improves growth, blood biochemical, intestinal health and microflora composition of juvenile common carp (Cyprinus carpio).

An 8-week feeding trial was conducted to explore the feasibility of Momordica charantia saponins (MCS) administration to facilitate the protein-sparing action of high carbohydrate in diets for juvenile common carp (Cyprinus carpio) with initial mass of 5.41 ± 0.02 g. Based on our previous study, four diets with different the ratio of protein and carbohydrate (P/C ratio) were designed: 32%P/40%C, 30%P/43%C, 28%P/46%C, 28%P/46%C supplemented with 0.16% MCS (28%P/46%C + MCS). Each diet treatment was divided into 3 replicates. Results revealed that 30%P/43%C group increased growth performance and intestinal digestion, decreased intestinal inflammation, and optimized the intestinal microbiota compared to 32%P/40%C group, which presented the stronger protein-sparing action of high carbohydrate. But if the P/C ratio reduced to 28%P/46%C or less, the saving action would be restrained. However, compared to the 30%P/43%C and 28%P/46%C groups, 28%P/46%C + MCS group significantly elevated growth performance and activities of digestive enzymes and antioxidative enzymes, whilst the opposite trend occurred in the contents of glucose, triglyceride, total cholesterol, low density lipoprotein cholesterol, blood urea nitrogen, glutamic oxalacetic transaminase, glutamic-pyruvic transaminase and malondialdehyde. In addition, 28%P/46%C + MCS group markedly upregulated the expressions of GH/IGF axis genes, genes involved in protein synthesis, antioxidant genes and anti-inflammatory cytokine, whilst the opposite trend occurred in the expressions of pro-inflammatory cytokines. Moreover, 28%P/46%C + MCS group obtained the remarkably higher Enterococcus proportion and lower Lactococcus proportion compared to the 30%P/43%C and 28%P/46%C groups, whereas the opposite occurred in 30%P/43%C group, which indicated that there existed differences in the improvement mechanism on intestinal microflora composition between MCS and appropriate P/C ratio. Combined with the above mentioned changes in our research, we concluded that 0.16% MCS administration in a 28%P/46%C diet could facilitate the protein-sparing action of high carbohydrate in diets for common carp, which could decrease the 5% dosage of soybean meal and synchronously reduce the 4% crude protein of diets without affecting the growth and immune ability for common carp.

Elastic moduli and refractive index of γ-Ge3N4.

Germanium nitride, having cubic spinel structure, γ-Ge3N4, is a wide band-gap semiconductor with a large exciton binding energy that exhibits high hardness, elastic moduli and elevated thermal stability up to approximately 700°C. Experimental data on its bulk and shear moduli (B0 and G0, respectively) are strongly limited, inconsistent and, thus, require verification. Moreover, earlier first-principles density functional calculations provided significantly scattering B0 values but consistently predicted G0 much higher than the so far available experimental value. Here, we examined the elasticity of polycrystalline γ-Ge3N4, densified applying high pressures and temperatures, using the techniques of laser ultrasonics (LU) and Brillouin light scattering (BLS) and compared with our extended first-principles calculations. From the LU measurements, we obtained its longitudinal- and Rayleigh wave sound velocities and, taking into account the sample porosity, derived B0 = 322(44) GPa and G0 = 188(7) GPa for the dense polycrystalline γ-Ge3N4. While our calculations underestimated B0 by approximately 17%, most of the predicted G0 matched well with our experimental value. Combining the LU- and BLS data and taking into account the elastic anisotropy, we determined the refractive index of γ-Ge3N4 in the visible range of light to be n = 2.4, similarly high as that of diamond or GaN, and matching our calculated value. This article is part of the theme issue 'Exploring the length scales, timescales and chemistry of challenging materials (Part 1)'.

Characterization of exogenous lactate addition on the growth, photosynthetic performance, and biochemical composition of four bait microalgae strains.

AIMS: To quickly obtain the biomass of bait microalgae with high value-added products, researchers have examined the influence of biochemical and environmental factors on the growth rates and biochemical composition of microalgae. Previous studies have shown that lactate plays an important role in metabolic regulation in Phaeodactylum tricornutum. In this study, we investigated the effect of exogenous lactate on the growth rates, photosynthetic efficiency, and biochemical composition of four commonly used bait microalgae in aquaculture. METHODS AND RESULTS: The optical density of the algal cultures at specific time points, YII, Fv/Fm, and the total lipid, protein, soluble sugar, insoluble sugar, chlorophyll a, and carotenoid content of P. tricornutum, Isochrysis galbana (I. galbana), Chaetoceros muelleri, and Cylindrotheca fusiformis were determined. In I. galbana, the growth rate was enhanced with the addition of lactate, even though higher concentrations of lactate were associated with a decrease in YII and Fv/Fm. In general, the total lipid content of these microalgal strains increased gradually in a concentration-dependent manner over the range of lactate concentrations. In addition, higher concentrations of lactate also induced significant changes in the total soluble and insoluble sugar levels in all microalgal strains. However, chlorophyll a and carotenoid contents increased at lower but decreased at higher concentrations of lactate in all microalgal strains. The total protein content was significantly elevated at all concentrations of lactate in P. tricornutum, whereas there were no significant differences in that of C. fusiformis. CONCLUSIONS: Lactate effective influences in the growth, metabolism, and synthesis of important biochemical components in the four microalgal strains under investigation.

Multi-echo Dixon and breath-hold T2-corrected multi-echo single-voxel MRS for quantifying hepatic iron overload in rabbits.

BACKGROUND: Three-dimensional (3D) multi-echo-Dixon (ME-Dixon) and breath-hold T2-corrected multi-echo single-voxel MR spectroscopy (HISTO) can simultaneously quantify liver fat and liver iron. However, their diagnostic efficacy and application scope for quantitative iron in co-existing fatty liver have not been adequately evaluated. PURPOSE: To evaluate the accuracy of ME-Dixon and HISTO for quantitative analysis of hepatic iron in rabbits with iron deposition and fatty liver using liver-iron concentration (LIC) as a reference standard. MATERIAL AND METHODS: ME-Dixon, HISTO, and conventional two-dimensional multi-echo gradient echo (GRE) sequences were performed on 42 rabbits. The following parameters were calculated: R2* from ME-Dixon and GRE; proton density fat fraction (PDFF) from the ME-Dixon, HISTO (normal TE range), and HISTO-H (extended TE range); and R2_water from HISTO and HISTO-H. The LIC and liver-fat concentration (LFC) were measured through chemical analysis, and their relationship with the MRI parameters were assessed. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used to evaluate the diagnostic efficiency. RESULTS: LIC was significantly correlated with R2_HISTO-H, R2*_Dixon, and R2*_GRE (r = 0.858, 0.910, 0.931, respectively; P < 0.001) and weakly with R2_HISTO (r = 0.424; P = 0.008). A strong correlation was also observed between the LFC and PDFF obtained from HISTO, HISTO-H, and ME-Dixon (r = 0.776, 0.811, 0.888, respectively; P < 0.001). ME-Dixon showed the best performance with moderate iron overload (AUC = 0.983). CONCLUSION: 3D ME-Dixon is useful for quantifying the LIC, especially with co-existing fatty liver. Its diagnostic performance is also superior to that of the HISTO sequence.

Realizing High Utilization of High-Mass-Loading Sulfur Cathode via Electrode Nanopore Regulation.

One main challenge of realizing high-energy-density lithium-sulfur batteries is low active materials utilization, excessive use of inert components, high electrolyte intake, and mechanical instability of high-mass-loading sulfur cathodes. Herein, chunky sulfur/graphene particle electrodes were designed, where active sulfur was confined in vertically aligned nanochannels (width ∼12 nm) of chunky graphene-based particles (∼70 µm) with N, O-containing groups. The short charge transport distance and low tortuosity enabled high utilization of active materials for high-mass-loading chunky sulfur/graphene particle electrodes. The intermediate polysulfide trapping effect by capillary effect and heteroatoms-containing groups, and a mechanically robust graphene framework, helped to realize stable electrode cycling. The as-designed electrode showed high areal capacity (10.9 mAh cm-2) and high sulfur utilization (72.4%) under the rigorous conditions of low electrolyte/active material ratio (∼2.5 µL mg-1) and high sulfur loading (9.0 mg cm-2), realizing high energy densities (520 Wh kg-1, 1635 Wh L-1).

Application of solid-phase extraction: High-resolution mass spectrometry analysis strategy in the characterization and quantification of amide herbicides in aquatic products.

In this study, we developed a new method combining thin-layer ultrasonic extraction, efficient SPE purification, ultra-performance liquid chromatography separation, and high-resolution mass spectrometry characterization for seven amide herbicides in fishery products. In sample preparation, to rapidly increase the contact area between the fish meat and the extractant, the fish meat was smeared on a glass slide. This process resulted in quickly reaching the extraction equilibrium and relatively high extraction efficiency. In data analysis, a strategy for characterization and qualitative analysis was constructed by analyzing the fragmentation of amide herbicides using product ion scans. Isomeric pretilachlor and butachlor were separated chromatographically, while the coeluting isomers, alachlor and acetochlor, could be separated by differences in the fragmentation of their selected precursor ions. This method overcame the challenge of poor dispersion in the extractant caused by the high viscosity of fish meat, and the challenge of separation and characterization for isomers. Compared with other methods, the extraction efficiency was improved and the amide herbicides in aquatic products was characterized and quantified rapidly and accurately. Moreover, the qualitative information was much greater and provided an additional strategy for analytes identification. This rapid and accurate method will benefit workers involved in monitoring fishery.

PT symmetric single-mode line-defect photonic crystal lasers with asymmetric loss design.

The exploration of parity-time (PT) symmetry in micro-/nano-cavity lasers has recently gained immense research interest. The PT symmetric phase transition to single-mode lasing has been achieved by arranging the spatial distribution of optical gain and loss in single or coupled cavity systems. In terms of photonic crystal (PhC) lasers, a non-uniform pumping scheme is usually employed to enter the PT symmetry-breaking phase in a longitudinal PT symmetric system. Instead, we use a uniform pumping scheme to enable the PT symmetric transition to the desired single lasing mode in line-defect PhC cavities based on a simple design with asymmetric optical loss. The flexible control of gain-loss contrast is realized by removing a few rows of air holes in PhCs. We obtain single-mode lasing with a side mode suppression ratio (SMSR) of around 30 dB without affecting the threshold pump power and linewidth. The output power of the desired mode is six times higher than that in multimode lasing. This simple approach enables single-mode PhC lasers without sacrificing the output power, threshold pump power, and linewidth of a multimode cavity design.

Inhibition of TRPA1 reduces airway inflammation and hyperresponsiveness in mice with allergic rhinitis.

This study was conducted to investigate whether a transient receptor potential ankyrin 1 (TRPA1) antagonist (HC-030031) can reduce airway inflammation and hyperresponsiveness in a murine allergic rhinitis (AR) model. BALB/c mice were sensitized and challenged by ovalbumin (OVA) to induce AR. HC-030031 or vehicle was administrated to mice via intraperitoneal injection prior to OVA challenges. Nose-scratching events, histopathologic alterations of the airways, and bronchial hyperresponsiveness (BHR) were assessed. Differential cells and proinflammatory cytokines in the nasal lavage (NAL) and bronchoalveolar lavage (BAL) fluid were measured. Expressions of TRPA1 in nasal mucosa were examined by immunohistochemistry. TRPA1-expressing vagal neurons were labeled by immunofluorescent staining. HC-030031-treated AR mice had markedly reduced type-2 inflammation in nasal mucosa and ameliorated-nose-scratching events than AR mice received vehicle. HC-030031 treatment also dramatically reduced leucocyte numbers and IL-8 level in the BAL fluid, inhibited lower airway remodeling and fibrosis, and nearly abolished BHR. HC-0300031 treatment significantly inhibited the upregulated number of TRPA1 expressing nasal epithelial cells and TRPA1 expressing sensory neurons, leading to downregulation of SP in both upper and lower airways. Targeting TRPA1 may represent a promising strategy for treating AR and AR-related asthma.

Rapid and durable response to fifth-line lorlatinib plus olaparib in an ALK -rearranged, BRCA2-mutated metastatic lung adenocarcinoma patient with critical tracheal stenosis: a case report.

Treatment options for heavily treated anaplastic lymphona kinase (ALK )-positive nonsmall cell lung cancer (NSCLC) patients, who typically bear-resistant mechanisms to ALK tyrosine kinase inhibitors (TKIs), are usually limited to chemotherapy, which elicits limited clinical benefit and may incur severe toxicity. It is clinically relevant to explore other revenues for these patients. poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib are currently approved to treat BReast CAncer gene 1/2 ( BRCA1/2 )-mutated patients in a few tumor types. There have been a trial and two case reports of an olaparib-containing regimen in treating epidermal growth factor receptor (EGFR)-positive or driver-negative NSCLC. We report a case of a 27-year-old female nonsmoker diagnosed with ALK -rearranged metastatic lung adenocarcinoma. She was treated with alectinib and acquired ALK p.I1171N and p.V1180L mutations. Germline BRCA2 p.F2801fs was also identified. After sequential lines of ceritinib and chemotherapy, lorlatinib was chosen as the fourth-line therapy and maintained control for 6 months. Shortly after progression, the patient was admitted to the ICU due to critically severe stenosis caused by a tracheal mass and soon relieved by embolization and stenting. Afterward lorlatinib plus olaparib was started and elicited a rapid response within 1 month. The progression-free survival was 6 months as of the latest follow-up, with the best response of partial response. To the best of our knowledge, this case is the first to provide clinical evidence of antitumor activity of olaparib plus ALK TKI in ALK -positive, g BRCA -mutated metastatic NSCLC. Together with previous reports in EGFR -positive or driver-negative patients, our finding warrants further studies on PARP inhibition in BRCA1/2 -mutated NSCLC.

Lactobacillus plantarum strains attenuated DSS-induced colitis in mice by modulating the gut microbiota and immune response.

Gut microbiota has become a new therapeutic target in the treatment of inflammatory Bowel Disease (IBD). Probiotics are known for their beneficial effects and have shown good efficacy in the clinical treatment of IBD and animal models of colitis. However, how these probiotics contribute to the amelioration of IBD is largely unknown. In the current study, the DSS-induced mouse colitis model was treated with oral administration of Lactobacillus plantarum strains to investigate their effects on colitis. The results indicated that the L. plantarum strains improved dysbiosis and enhanced the abundance of beneficial bacteria related to short-chain fatty acids (SCFAs) production. Moreover, L. plantarum strains decreased the level of pro-inflammatory cytokines, i.e., IL-17A, IL-17F, IL-6, IL-22, and TNF-α and increased the level of anti-inflammatory cytokines, i.e., TGF-ß, IL-10. Our result suggests that L. plantarum strains possess probiotic effects and can ameliorate DSS colitis in mice by modulating the resident gut microbiota and immune response.

NSUN5 Facilitates Viral RNA Recognition by RIG-I Receptor.

The RIG-I receptor induces the innate antiviral responses upon sensing RNA viruses. The mechanisms through which RIG-I optimizes the strength of the downstream signaling remain incompletely understood. In this study, we identified that NSUN5 could potentiate the RIG-I innate signaling pathway. Deficiency of NSUN5 enhanced RNA virus proliferation and inhibited the induction of the downstream antiviral genes. Consistently, NSUN5-deficient mice were more susceptible to RNA virus infection than their wild-type littermates. Mechanistically, NSUN5 bound directly to both viral RNA and RIG-I, synergizing the recognition of dsRNA by RIG-I. Collectively, to our knowledge, this study characterized NSUN5 as a novel RIG-I coreceptor, playing a vital role in restricting RNA virus infection.

Selective magnetic solid-phase extraction of amide herbicides from fish samples coupled with ultra-high-performance liquid chromatography with tandem mass spectrometry.

An efficient magnetic dummy template molecularly imprinted polymer nanocomposite was prepared using multi-walled carbon nanotubes as a support and metolachlor deschloro as a dummy template. The obtained nanocomposites were characterized using Fourier transform infrared spectroscopy, vibrating sample magnetometry, scanning electron microscopy, and transmission electron microscopy. The adsorption performance of the obtained nanocomposites was evaluated through binding experiments, including static adsorption, kinetic adsorption, and selective recognition studies. The obtained nanocomposites were successfully applied as selective sorbents for the magnetic solid-phase extraction of seven amide herbicides (alachlor, acetochlor, pretilachlor, butachlor, metolachlor, diethatyl ethyl, and dimethachlor) coupled with liquid chromatography-tandem mass spectrometry from fish samples. Under the optimized conditions, the limit of detection was 0.01-0.1 µg/kg. The obtained recoveries of the amide herbicides from the fish samples were in the range of 88.0 to 102.1% with a relative standard deviation of less than 7.5%. This method, which eliminated the effect of template leakage on qualitative and quantitative analysis was found to be superior to the methods reported in the literature. The results indicated that it could be successfully applied to analyze amide herbicides in fish samples with satisfactory recoveries.