Polymeric monolithic columns based on natural wood for rapid purification of targeted protein.

With multiscale hierarchical structure, wood is suitable for a range of high-value applications, especially as a chromatographic matrix. Here, we have aimed to provide a weak anion-exchange polymeric monolithic column based on natural wood with high permeability and stability for effectively separating the targeted protein. The wood-polymeric monolithic column was synthesized by in situ polymerization of glycidyl methacrylate and ethylene glycol dimethacrylate in wood, and coupled with diethylaminoethyl hydrochloride. The wood-polymeric monolithic column can be integrated with fast-protein liquid chromatography for large-scale protein purification. According to the results, the wood-polymeric monolithic column showed high hydrophilicity, permeability and stability. Separation experiments verified that the wood-polymeric monolithic column could purify the targeted protein (spike protein of SARS-COV-2 and ovalbumin) from the mixed proteins by ion exchange, and the static adsorption capacity was 33.04 mg mL-1 and the dynamic adsorption capacity was 24.51 mg mL-1. In addition, the wood-polymerized monolithic column had good stability, and a negligible decrease in the dynamic adsorption capacity after 20 cycles. This wood-polymerized monolithic column can provide a novel, efficient, and green matrix for monolithic chromatographic columns.

A Nomogram Prediction Model for Persistent Pulmonary Hypertension of the Newborn in Neonates Hospitalized for the First Time After Birth.

OBJECTIVE: Persistent pulmonary hypertension of the newborn (PPHN) is one of the critical neonatal diseases associated with high morbidity and mortality. This study attempted to conduct a nomogram prediction model for performing early identification of PPHN and providing effective information for clinical practice. METHODS: A total of 456 newborns who first admitted to the hospital after birth were included in the analysis, including 138 newborns with PPHN and 318 newborns without PPHN (as controls). The optimal predictive variables selection was performed based on LASSO (least absolute shrinkage and selection operator) regression and multivariate logistic regression. Using the selected variables, a nomogram prediction model was developed. To validate the model, the model was assessed using the receiver operating characteristic curve, calibration plot, and clinical impact curve. RESULTS: Six predictors, namely, gestational age, neonatal respiratory distress syndrome, the levels of hemoglobin and creatine kinase-MB, gestational thyroid dysfunction, and Pao2, were identified by LASSO and multivariate logistic regression analysis from the original 30 variables studied. The constructed model, using these predictors, exhibited favorable predictive ability for PPHN, with an area under the receiver operating characteristic of 0.897 (sensitivity = 0.876, specificity = 0.785) in the training set and 0.871 (sensitivity = 0.902, specificity = 0.695) in the validation set, and was well calibrated, as indicated by the PHosmer-Lemeshow test values of 0.233 and 0.876 for the training and validation sets, respectively. CONCLUSIONS: The model included gestational age, neonatal respiratory distress syndrome, the levels of hemoglobin and creatine kinase-MB, gestational thyroid dysfunction, and Pao2 had good prediction performance for predicting PPHN among newborns first admitted to the hospital after birth.

Whole Genome Sequence Analysis of Two Oxacillin-Resistant and mecA-Positive Strains of Staphylococcus haemolyticus Isolated from Ear Swab Samples of Patients with Otitis Media.

Objective: Staphylococcus haemolyticus can cause a series of infections including otitis media (OM), and the oxacillin-resistant S. haemolyticus has become a serious health concern. This study aimed to investigate the genomic characteristics of two strains of oxacillin-resistant and mecA-positive S. haemolyticus isolated from the samples of ear swabs from patients with OM and explore their acquired antibiotic resistance genes (ARGs) and the mobile genetic elements (MGEs). Methods: Two oxacillin-resistant S. haemolyticus strains, isolated from ear swab samples of patients with OM, underwent antimicrobial susceptibility evaluation, followed by whole-genome sequencing. The acquired ARGs and the MGEs carried by the ARGs, harbored by the genomes of two strains of S. haemolyticus were identified. Results: The two strains of oxacillin-resistant S. haemolyticus (strain SH1275 and strain SH9361) both carried the genetic contexts of mecA with high similarity with the SCCmec type V(5C2&5) subtype c. Surprisingly, the chromosomal aminoglycoside resistance gene aac(6')-aph(2") harbored by S. haemolyticus strain SH936 was flanked by two copies of IS256, forming the IS256-element (IS256-GNAT-[aac(6')-aph(2")]-IS256), which was widely present in strains of both Staphylococcus and Enterococcus genus. Furthermore, the two strains of oxacillin-resistant and MDR S. haemolyticus were found to harbor antimicrobial resistance plasmids, including one 26.9-kb plasmid (pSH1275-2) containing msr(A)-mph(C)) and qacA, one mobilizable plasmid pSH1275-3 harboring vga(A)LC, one plasmid (pSH9361-1) carrying erm(C), and one plasmid (pSH9361-2) carrying qacJ. Conclusion: The systematic analysis of whole-genome sequences provided insights into the mobile genetic elements responsible for multi-drug resistance in these two strains of oxacillin-resistant and mecA-positive S. haemolyticus, which will assist clinicians in devising precise, personalized, and clinical therapeutic strategies for treating otitis media caused by multi-drug resistant S. haemolyticus.

Stretchable and Transparent Heaters Based on Hydrophobic Ionogels with Superior Moisture Insensitivity.

Flexible and stretchable transparent heaters (THs) have been widely used in various applications, including deicing and defogging of flexible screens as well as thermotherapy pads. Ionic THs based on ionogels have emerged as a promising alternative to conventional electronic THs due to their unique advantages in terms of transparency-conductance conflict, uniform heating, and interfacial adhesion. However, the commonly used hydrophilic ionogels inevitably introduce a moisture-sensitive issue. In this work, we present a stretchable and transparent hydrophobic ionogel-based heater that utilizes ionic current-induced Joule heating under high-frequency alternating current. This ionogel-based TH exhibits exceptional multifunctional properties with low hysteresis, a fracture strain of 840%, transmittance of 93%, conductivity of 0.062 S m-1, temperature resistance up to 165 °C, voltage resistance up to 120 V, heating rate of 0.1 °C s-1, steady-state temperature at 115 °C, and uniform heating even when bent or stretched (up to 200%). Furthermore, it maintains its heating performance when it is directly exposed to water. This hydrophobic ionogel-based TH expands the range of materials available for ionic THs and paves the way for their practical applications.

Visual outcomes and patient satisfaction after implantations of three types of presbyopia-correcting intraocular lenses that have undergone corneal refractive surgery.

This prospective, non-randomized, comparative study aimed to compare the visual outcomes and patient satisfaction after implantations of three presbyopia-correcting intraocular lenses (IOLs) after myopic refractive surgery. It was conducted from January 2020 to December 2021 in Shanghai Heping Eye Hospital. Patients were divided into three groups based on the type of IOL implanted. The visual acuity, refractive stability, high-order aberrations, objective visual quality, spectacle independence, and visual function index 14 questionnaire scores of the three groups were compared. This study included 78 eyes of 39 patients: 26 eyes with 839MP, 26 eyes with MF30, and 26 eyes with ZXR00. Uncorrected distance visual acuity improved significantly for all three groups. For a pupil diameter of 4.0 mm, the spherical aberrations of the three groups were 0.33 ± 0.16 µ, 0.50 ± 0.08 µ, and 0.39 ± 0.10 µ, respectively. The spectacle independence for distance vision was over 90% in each group; for near vision, it was only 25% for the ZXR00 group. All three types of presbyopia-correcting IOLs improved visual quality in post-LASIK or PRK patients. However, the high incidence of photic phenomena after presbyopia-correcting IOL implantation in patients who have undergone myopic LASIK should not be neglected.

Microbial species pool-mediated diazotrophic community assembly in crop microbiomes during plant development.

Plant-associated diazotrophs strongly relate to plant nitrogen (N) supply and growth. However, our knowledge of diazotrophic community assembly and microbial N metabolism in plant microbiomes is largely limited. Here we examined the assembly and temporal dynamics of diazotrophic communities across multiple compartments (soils, epiphytic and endophytic niches of root and leaf, and grain) of three cereal crops (maize, wheat, and barley) and identified the potential N-cycling pathways in phylloplane microbiomes. Our results demonstrated that the microbial species pool, influenced by site-specific environmental factors (e.g., edaphic factors), had a stronger effect than host selection (i.e., plant species and developmental stage) in shaping diazotrophic communities across the soil-plant continuum. Crop diazotrophic communities were dominated by a few taxa (~0.7% of diazotrophic phylotypes) which were mainly affiliated with Methylobacterium, Azospirillum, Bradyrhizobium, and Rhizobium. Furthermore, eight dominant taxa belonging to Azospirillum and Methylobacterium were identified as keystone diazotrophic taxa for three crops and were potentially associated with microbial network stability and crop yields. Metagenomic binning recovered 58 metagenome-assembled genomes (MAGs) from the phylloplane, and the majority of them were identified as novel species (37 MAGs) and harbored genes potentially related to multiple N metabolism processes (e.g., nitrate reduction). Notably, for the first time, a high-quality MAG harboring genes involved in the complete denitrification process was recovered in the phylloplane and showed high identity to Pseudomonas mendocina. Overall, these findings significantly expand our understanding of ecological drivers of crop diazotrophs and provide new insights into the potential microbial N metabolism in the phyllosphere.IMPORTANCEPlants harbor diverse nitrogen-fixing microorganisms (i.e., diazotrophic communities) in both belowground and aboveground tissues, which play a vital role in plant nitrogen supply and growth promotion. Understanding the assembly and temporal dynamics of crop diazotrophic communities is a prerequisite for harnessing them to promote plant growth. In this study, we show that the site-specific microbial species pool largely shapes the structure of diazotrophic communities in the leaves and roots of three cereal crops. We further identify keystone diazotrophic taxa in crop microbiomes and characterize potential microbial N metabolism pathways in the phyllosphere, which provides essential information for developing microbiome-based tools in future sustainable agricultural production.

Solamargine Induces Hepatocellular Carcinoma Cell Apoptosis and Ferroptosis via Regulating STAT1/MTCH1 Axis.

BACKGROUND: Solamargine (SM) has been shown to play anti-tumor role in hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of SM in HCC progression deserve further exploration. METHODS: HCC cell proliferation and apoptosis were assessed by cell counting kit 8 assay, colony formation assay and flow cytometry. Ferroptosis was evaluated by detecting the levels of Fe2+, iron, MDA, ROS and GSH in HCC cells. In addition, mitochondrial carrier 1 (MTCH1) mRNA level was detected by quantitative real-time PCR. Western blot was used to test MTCH1 and signal transduction and activation of transcription 1 (STAT1) protein levels. Dual-luciferase reporter assay was employed to analyze the interaction between STAT1 and MTCH1. A mouse xenograft model was also constructed to explore the role of SM in vivo. RESULTS: SM could potentially suppress HCC cell growth by inducing ferroptosis. MTCH1 was highly expressed in HCC tissues and cells, and its silencing inhibited HCC cell proliferation, promoted apoptosis and ferroptosis. MTCH1 expression was reduced by SM, and its overexpression reversed SM-induced HCC cell apoptosis and ferroptosis. Furthermore, STAT1 facilitated MTCH1 transcription and promoted its expression. Besides, STAT1 expression could be reduced by SM, and its overexpression abolished the decreasing effect of SM on MTCH1 expression. In vivo, SM suppressed HCC tumor growth by reducing MTCH1 expression. CONCLUSION: SM promoted HCC cell apoptosis and ferroptosis via the STAT1/MTCH1 axis.

Streptomyces-triggered coordination between rhizosphere microbiomes and plant transcriptome enables watermelon Fusarium wilt resistance.

The use of microbial inoculant is a promising strategy to improve plant health, but their efficiency often faces challenges due to difficulties in successful microbial colonization in soil environments. To this end, the application of biostimulation products derived from microbes is expected to resolve these barriers via direct interactions with plants or soil pathogens. However, their effectiveness and mechanisms for promoting plant growth and disease resistance remain elusive. In this study, we showed that root irrigation with the extracts of Streptomyces ahygroscopicus strain 769 (S769) solid fermentation products significantly reduced watermelon Fusarium wilt disease incidence by 30% and increased the plant biomass by 150% at a fruiting stage in a continuous cropping field. S769 treatment led to substantial changes in both bacterial and fungal community compositions, and induced a highly interconnected microbial association network in the rhizosphere. The root transcriptome analysis further suggested that S769 treatment significantly improved the expression of the MAPK signalling pathway, plant hormone signal transduction and plant-pathogen interactions, particular those genes related to PR-1 and ethylene, as well as genes associated with auxin production and reception. Together, our study provides mechanistic and empirical evidences for the biostimulation products benefiting plant health through coordinating plant and rhizosphere microbiome interaction.

AOB Nitrosospira cluster 3a.2 (D11) dominates N2O emissions in fertilised agricultural soils.

Ammonia-oxidation process directly contribute to soil nitrous oxide (N2O) emissions in agricultural soils. However, taxonomy of the key nitrifiers (within ammonia oxidising bacteria (AOB), archaea (AOA) and complete ammonia oxidisers (comammox Nitrospira)) responsible for substantial N2O emissions in agricultural soils is unknown, as is their regulation by soil biotic and abiotic factors. In this study, cumulative N2O emissions, nitrification rates, abundance and community structure of nitrifiers were investigated in 16 agricultural soils from major crop production regions of China using microcosm experiments with amended nitrogen (N) supplemented or not with a nitrification inhibitor (nitrapyrin). Key nitrifier groups involved in N2O emissions were identified by comparative analyses of the different treatments, combining sequencing and random forest analyses. Soil cumulative N2O emissions significantly increased with soil pH in all agricultural soils. However, they decreased with soil organic carbon (SOC) in alkaline soils. Nitrapyrin significantly inhibited soil cumulative N2O emissions and AOB growth, with a significant inhibition of the AOB Nitrosospira cluster 3a.2 (D11) abundance. One Nitrosospira multiformis-like OTU phylotype (OTU34), which was classified within the AOB Nitrosospira cluster 3a.2 (D11), had the greatest importance on cumulative N2O emissions and its growth significantly depended on soil pH and SOC contents, with higher growth at high pH and low SOC conditions. Collectively, our results demonstrate that alkaline soils with low SOC contents have high N2O emissions, which were mainly driven by AOB Nitrosospira cluster 3a.2 (D11). Nitrapyrin can efficiently reduce nitrification-related N2O emissions by inhibiting the activity of AOB Nitrosospira cluster 3a.2 (D11). This study advances our understanding of key nitrifiers responsible for high N2O emissions in agricultural soils and their controlling factors, and provides vital knowledge for N2O emission mitigation in agricultural ecosystems.

Bioinspired and biomimetic strategies for inflammatory bowel disease therapy.

Inflammatory bowel disease (IBD) is an idiopathic chronic inflammatory bowel disease with high morbidity and an increased risk of cancer or death, resulting in a heavy societal medical burden. While current treatment modalities have been successful in achieving long-term remission and reducing the risk of complications, IBD remains incurable. Nanomedicine has the potential to address the high toxic side effects and low efficacy in IBD treatment. However, synthesized nanomedicines typically exhibit some degree of immune rejection, off-target effects, and a poor ability to cross biological barriers, limiting the development of clinical applications. The emergence of bionic materials and bionic technologies has reshaped the landscape in novel pharmaceutical fields. Biomimetic drug-delivery systems can effectively improve biocompatibility and reduce immunogenicity. Some bioinspired strategies can mimic specific components, targets or immune mechanisms in pathological processes to produce targeting effects for precise disease control. This article highlights recent research on bioinspired and biomimetic strategies for the treatment of IBD and discusses the challenges and future directions in the field to advance the treatment of IBD.

Chicken Interferon-Alpha and -Lambda Exhibit Antiviral Effects against Fowl Adenovirus Serotype 4 in Leghorn Male Hepatocellular Cells.

Hydropericardium hepatitis syndrome (HHS) is primarily caused by fowl adenovirus serotype 4 (FAdV-4), causing high mortality in chickens. Although vaccination strategies against FAdV-4 have been adopted, HHS still occurs sporadically. Furthermore, no effective drugs are available for controlling FAdV-4 infection. However, type I and III interferon (IFN) are crucial therapeutic agents against viral infection. The following experiments were conducted to investigate the inhibitory effect of chicken IFN against FadV-4. We expressed recombinant chicken type I IFN-α (ChIFN-α) and type III IFN-λ (ChIFN-λ) in Escherichia coli and systemically investigated their antiviral activity against FAdV-4 infection in Leghorn male hepatocellular (LMH) cells. ChIFN-α and ChIFN-λ dose dependently inhibited FAdV-4 replication in LMH cells. Compared with ChIFN-λ, ChIFN-α more significantly inhibited viral genome transcription but less significantly suppressed FAdV-4 release. ChIFN-α- and ChIFN-λ-induced IFN-stimulated gene (ISG) expression, such as PKR, ZAP, IRF7, MX1, Viperin, IFIT5, OASL, and IFI6, in LMH cells; however, ChIFN-α induced a stronger expression level than ChIFN-λ. Thus, our data revealed that ChIFN-α and ChIFN-λ might trigger different ISG expression levels, inhibiting FAdV-4 replication via different steps of the FAdV-4 lifecycle, which furthers the potential applications of IFN antiviral drugs in chickens.

Whole-Genome Sequencing of an Escherichia coli ST69 Strain Harboring blaCTX-M-27 on a Hybrid Plasmid.

Objective: Escherichia coli is a common Gram-negative human pathogen. The emergence of E. coli with multiple-antibiotic-resistant phenotypes has become a serious health concern. This study reports the whole-genome sequences of third-generation cephalosporin-resistant (3GC-R) and multidrug-resistant (MDR) E. coli EC6868 and explores the acquired antibiotic-resistance genes (ARGs) as well as their genetic contexts. Methods: E. coli EC6868 was isolated from a vaginal secretion sample of a pregnant patient in China. The antimicrobial susceptibility was assessed, and whole-genome sequencing was conducted. The acquired ARGs, insertion sequence (IS) elements, and integrons within the genome of E. coli EC6868 were identified, and the genetic contexts associated with the ARGs were analyzed systematically. Results: E. coli EC6868 was determined to belong to ST69 and harbored a 144.9-kb IncF plasmid (pEC6868-1) with three replicons (Col156, IncFIBAP001918, and IncFII). The ESBL gene blaCTX-M-27 was located on the structure "∆ISEcp1-blaCTX-M-27-IS903B", which was widely present in the species of Enterobacteriales. Other ARGs carried by plasmid pEC6868-1 were mainly located on the 18.9-kb IS26-composite transposon (five copies of intact IS26 and one copy of truncated IS26) composing of IS26-mphA-mrx(A)-mphR(A)-IS6100, ∆TnAs3-eamA-tet(A)-tetR(A)-aph(6)-Id-aph(3")-Ib-sul2-IS26, and a class 1 integron, which was widely present on IncF plasmids of E. coli, mainly distributed in ST131, ST38, and ST405. Notably, pEC6868 in our study was the first report on a plasmid harboring the 18.9-kb structure in E. coli ST69 in China. Conclusion: The 3GC-R E. coli ST69 strain with an MDR IncF plasmid carrying blaCTX-M-27 and other ARGs, conferring resistance to aminoglycosides, macrolides, sulfonamides, tetracycline, and trimethoprim, was identified in a hospital in China. Mobile genetic elements including ISEcp1, IS903B, IS26, Tn3, IS6100 and class 1 integron were found within the MDR region, which could play important roles in the global dissemination of these resistance genes.

Labile Carbon from Artificial Roots Alters the Patterns of N2O and N2 Production in Agricultural Soils.

Labile carbon (C) continuously delivered from the rhizosphere profoundly affects terrestrial nitrogen (N) cycling. However, nitrous oxide (N2O) and dinitrogen (N2) production in agricultural soils in the presence of continuous root C exudation with applied N remains poorly understood. We conducted an incubation experiment using artificial roots to continuously deliver small-dose labile C combined with 15N tracers to investigate N2O and N2 emissions in agricultural soils with pH and organic C (SOC) gradients. A significantly negative exponential relationship existed between N2O and N2 emissions under continuous C exudation. Increasing soil pH significantly promoted N2 emissions while reducing N2O emissions. Higher SOC further promoted N2 emissions in alkaline soils. Native soil-N (versus fertilizer-N) was the main source of N2O (average 67%) and N2 (average 80%) emissions across all tested soils. Our study revealed the overlooked high N2 emissions, mainly derived from native soil-N and strengthened by increasing soil pH, under relatively real-world conditions with continuous root C exudation. This highlights the important role of N2O and N2 production from native soil-N in terrestrial N cycling when there is a continuous C supply (e.g., plant-root exudate) and helps mitigate emissions and constrain global budgets of the two concerned nitrogenous gases.

Triplet-constrained deep hashing for chest X-ray image retrieval in COVID-19 assessment.

Radiology images of the chest, such as computer tomography scans and X-rays, have been prominently used in computer-aided COVID-19 analysis. Learning-based radiology image retrieval has attracted increasing attention recently, which generally involves image feature extraction and finding matches in extensive image databases based on query images. Many deep hashing methods have been developed for chest radiology image search due to the high efficiency of retrieval using hash codes. However, they often overlook the complex triple associations between images; that is, images belonging to the same category tend to share similar characteristics and vice versa. To this end, we develop a triplet-constrained deep hashing (TCDH) framework for chest radiology image retrieval to facilitate automated analysis of COVID-19. The TCDH consists of two phases, including (a) feature extraction and (b) image retrieval. For feature extraction, we have introduced a triplet constraint and an image reconstruction task to enhance discriminative ability of learned features, and these features are then converted into binary hash codes to capture semantic information. Specifically, the triplet constraint is designed to pull closer samples within the same category and push apart samples from different categories. Additionally, an auxiliary image reconstruction task is employed during feature extraction to help effectively capture anatomical structures of images. For image retrieval, we utilize learned hash codes to conduct searches for medical images. Extensive experiments on 30,386 chest X-ray images demonstrate the superiority of the proposed method over several state-of-the-art approaches in automated image search. The code is now available online.

Curcumin Promotes Diabetic Foot Ulcer Wound Healing by Inhibiting miR-152-3p and Activating the FBN1/TGF-ß Pathway.

The objective of this study was to investigate the mechanism of curcumin in diabetic foot ulcer (DFU) wound healing. A DFU rat model was established, and fibroblasts were cultured in a high-glucose (HG) environment to create a cell model. Various techniques, including Western blot, RT‒qPCR, flow cytometry, Transwell, cell scratch test and H&E staining, were employed to measure the levels of relevant genes and proteins, as well as to assess cell proliferation, apoptosis, migration, and pathological changes. The results showed that miR-152-3p was overexpressed in DFU patients, while FBN1 was underexpressed. Curcumin was found to inhibit fibroblast apoptosis, promote proliferation, migration, and angiogenesis in DFU rats, and accelerate wound healing in DFU rats. In addition, overexpression of miR-152-3p weakened the therapeutic effect of curcumin, while overexpression of FBN1 reversed the effects of the miR-152-3p mimic. Further investigations into the underlying mechanisms revealed that curcumin expedited wound healing in DFU rats by restoring the FBN1/TGF-ß pathway through the inhibition of miR-152-3p. In conclusion, curcumin can suppress the activity of miR-152-3p, which, in turn, leads to the rejuvenation of the FBN1/TGF-ß pathway and accelerates DFU wound healing.

CCT020312 exerts anti-prostate cancer effect by inducing G1 cell cycle arrest, apoptosis and autophagy through activation of PERK/eIF2α/ATF4/CHOP signaling.

PERK/eIF2α/ATF4/CHOP signaling pathway is one of three major branches of unfolded protein response (UPR) and has been implicated in tumor progression. CCT020312 is a selective PERK activator and may have a potential anti-tumor effect. Here we investigated the anti-prostate cancer effect and its underlying mechanism of CCT020312. Our results showed that CCT020312 inhibited prostate cancer cell viability by inducing cell cycle arrest, apoptosis and autophagy through activation of PERK/eIF2α/ATF4/CHOP signaling. CCT020312 treatment caused cell cycle arrest at G1 phase and increased the levels of cleaved-Caspase3, cleaved-PARP and Bax in prostate cancer C4-2 and LNCaP cells. Moreover, CCT020312 increased LC3II/I, Atg12-Atg5 and Beclin1 levels and induced autophagosome formation. Furthermore, knockdown of CHOP reversed CCT020312-induced cell viability decrease, apoptosis and autophagy. Bafilomycin A1 reversed CCT020312-induced cell viability decrease but had no effect on CCT020312-induced CHOP activation in C4-2 and LNCaP cells. In vivo, CCT020312 suppressed tumor growth in C4-2 cells-derived xenograft mouse model, activated PERK pathway, and induced autophagy and apoptosis. Our study illustrates that CCT020312 exerts an anti-tumor effect in prostate cancer via activating the PERK pathway, thus indicating that CCT020312 may be a potential drug for prostate cancer.

Inflammatory response signature score model for predicting immunotherapy response and pan-cancer prognosis.

Background: Inflammatory responses influence the outcome of immunotherapy and tumorigenesis by modulating host immunity. However, systematic inflammatory response assessment models for predicting cancer immunotherapy (CIT) responses and survival across human cancers remain unexplored. Here, we investigated an inflammatory response score model to predict CIT responses and patient survival in a pan-cancer analysis. Methods: We retrieved 12 CIT response gene expression datasets from the Gene Expression Omnibus database (GSE78220, GSE19423, GSE100797, GSE126044, GSE35640, GSE67501, GSE115821 and GSE168204), Tumor Immune Dysfunction and Exclusion database (PRJEB23709, PRJEB25780 and phs000452.v2.p1), European Genome-phenome Archive database (EGAD00001005738), and IMvigor210 cohort. The tumor samples from six cancers types: metastatic urothelial cancer, metastatic melanoma, gastric cancer, primary bladder cancer, renal cell carcinoma, and non-small cell lung cancer.We further established a binary classification model to predict CIT responses using the least absolute shrinkage and selection operator (LASSO) computational algorithm. Findings: The model had high predictive accuracy in both the training and validation cohorts. During sub-group analysis, area under the curve (AUC) values of 0.82, 0.80, 0.71, 0.7, 0.67, and 0.64 were obtained for the non-small cell lung cancer, gastric cancer, metastatic urothelial cancer, primary bladder cancer, metastatic melanoma, and renal cell carcinoma cohorts, respectively. CIT response rates were higher in the high-scoring training cohort subjects (51%) than the low-scoring subjects (27%). The five-year survival rates in the high- and low score groups of the training cohorts were 62% and 21%, respectively, while those of the validation cohorts were 54% and 22%, respectively (P < 0·001 in all cases). Inflammatory response signature score derived from on-treatment tumor specimens are highly predictive of response to CIT in patients with metastatic melanoma. A significant correlation was observed between the inflammatory response scores and tumor purity. Regardless of the tumor purity, patients in the low score group had a significantly poorer prognosis than those in the high score group. Immune cell infiltration analysis indicated that in the high score cohort, tumor-infiltrating lymphocytes were significantly enriched, particularly effector and natural killer cells. Inflammatory response scores were positively correlated with immune checkpoint genes, suggesting that immune checkpoint inhibitors may have benefited patients with high scores. Analysis of signature scores across different cancer types from The Cancer Genome Atlas revealed that the prognostic performance of inflammatory response scores for survival in patients who have not undergone immunotherapy can be affected by tumor purity. Interleukin 21 (IL21) had the highest weight in the inflammatory response model, suggesting its vital role in the prediction mode. Since the number of metastatic melanoma patients (n = 429) was relatively large among CIT cohorts, we further performed a co-culture experiment using a melanoma cell line and CD8 + T cell populations generated from peripheral blood monocytes. The results showed that IL21 therapy combined with anti-PD1 (programmed cell death 1) antibodies (trepril monoclonal antibodies) significantly enhanced the cytotoxic activity of CD8 + T cells against the melanoma cell line. Conclusion: In this study, we developed an inflammatory response gene signature model that predicts patient survival and immunotherapy response in multiple malignancies. We further found that the predictive performance in the non-small cell lung cancer and gastric cancer group had the highest value among the six different malignancy subgroups. When compared with existing signatures, the inflammatory response gene signature scores for on-treatment samples were more robust predictors of the response to CIT in metastatic melanoma.

Genomic characteristics of two strains of ESBL-producing Klebsiella pneumoniae ST268 isolated from different samples of one patient.

OBJECTIVES: This study reports the whole-genome sequences of two strains of extended-spectrum beta-lactamase (ESBL)-producing and multidrug-resistant (MDR) K. pneumoniae ST268 and explores their acquired antibiotic resistance genes (ARGs) and the mobile genetic elements (MGEs). METHODS: Two strains of K. pneumoniae ST268 were isolated from different samples of one patient. Assessment of antimicrobial susceptibility was performed, and then whole-genome sequencing was conducted. Acquired ARGs, insertion sequences, and transposons harboured by the two strains of K. pneumoniae ST268 were identified, and then the genetic contexts associated with the ARGs were analysed systematically. RESULTS: Two strains of K. pneumoniae ST268 were found to carry the 118.6-kb hybrid IncFIIK:IncQ1:repBR1701 plasmid. All the acquired ARGs carried by the IncF plasmid were found to be situated on the 25.3-kb MDR region bracketed by ISKpn19 and IS26, which was widely present in the plasmids in 14 STs of strains in K. pneumoniae but also in IncF plasmids from Shigella flexneri and Klebsiella quasipneumoniae. Notably, the IncF plasmids harbouring the 25.3-kb MDR region were geographically distributed mainly in China, and the pKP161637-1/pKP160802-1 in our study was the first report on the IncF plasmid carrying the 25.3-kb MDR region bracketed in K. pneumoniae ST268. CONCLUSIONS: Two strains of ESBL-producing K. pneumoniae ST268 with a MDR IncF plasmid were identified in a hospital in China. The ARGs were identified on the 25.3-kb MDR region, bracketed by ISKpn19 and IS26, of the IncF plasmids, which were present not only in the K. pneumoniae but also in the S. flexneri and K. quasipneumoniae.

Regulation of nociception threshold by norepinephrine through adrenergic α2 receptor in rat models of Parkinson's disease.

BACKGROUND: The mechanism of pain symptoms in Parkinson's disease (PD) is unclear. Norepinephrine (NE) regulates neuropathic pain through ascending and descending pathways. However, the loss of NE neurons in the brain of patients with PD is obvious, it is speculated that NE is involved in the occurrence of PD pain symptoms. AIMS: To investigate the effect of NE on the activation of brain cells through adrenergic α2 receptor, so as to regulate the nociception threshold in a 6-OHDA-induced animal model of PD. METHODS: PD rat model was established by 6-OHDA injection (6-OHDA group). DSP-4 (or anti-DBH-saporin) was used to reduce the NE level of the PD rat brain. The heat sensitivity threshold (HST) and pressure withdrawal threshold (PWT) were measured. Tyrosine hydroxylase and NE in rat brains were detected by Elisa. The percentage of GFAP-positive cells in the prefrontal cortex, cingulate gyrus and striatum of rats was detected by immunohistochemistry and immunofluorescence. GFAP protein was semiquantified by method of western blot. Then yohimbine and guanfacine were used to increase the NE level in PD rats, and the above experimental changes were observed after drug application. RESULTS: The contents of NE in the brain of 6-OHDA-induced PD rats were lower than that of control group. After DSP-4 (or anti-DBH-saporin) injection, PD rats showed the lowest NE level (compared with 6-OHDA group, p ≤ 0.05), and after yohimbine and guanfacine were applied to 6-OHDA group, the contents of NE increased in the prefrontal cortex of rats. The HST and PWT of 6-OHDA group were significantly lower than those of control group, and after DSP-4 (or anti-DBH-saporin) injection, the HST and PWT of rats were lower than those of 6-OHDA group, and after the administration of yohimbine and guanfacine, both HST and PWT were significantly increased. GFAP-positive cells increased in prefrontal cortex and anterior cingulate gyrus of 6-OHDA group rats, and more significantly increased after DSP-4 (or anti-DBH-saporin) injection, and significantly reduced after yohimbine and guanfacine were used. CONCLUSIONS: The change of norepinephrine content can affect the activation of prefrontal and cingulate gyrus glial cells and participate in the regulation of nociception threshold in PD rats. Adrenergic α2 receptor agonist and central presynaptic membrane α2 receptor blocker both affect cell activation and improve hyperalgesia.

Bioinspired Heterogeneous Construction of Lignocellulose-Reinforced COF Membranes for Efficient Proton Conduction.

The exponential interest in covalent organic frameworks (COFs) arises from the direct correlation between their diverse and intriguing properties and the modular design principle. However, the insufficient interlamellar interaction among COF nanosheets greatly hinders the formation of defect-free membranes. Therefore, developing a methodology for the facile fabrication of these materials remains an enticing and highly desirable objective. Herein, ultrahigh proton conductivity and superior stability are achieved by taking advantage of COF composite membranes where 2D TB-COF nanosheets are linked by 1D lignocellulosic nanofibrils (LCNFs) through π-π and electrostatic interactions to form a robust and ordered structure. Notably, the high concentration of -SO3 H groups within the COF pores and the abundant proton transport paths at COFs-LCNFs interfaces impart composite membranes ultrahigh proton conductivity (0.348 S cm-1 at 80 °C and 100% RH). Moreover, the directional migration of protons along the stacked nanochannels of COFs is facilitated by oxygen atoms on the keto groups, as demonstrated by density functional theory (DFT) calculations. The simple design concept and reliable operation of the demonstrated mixed-dimensional composite membrane are expected to provide an ideal platform for next-generation conductive materials.