Inactivation of a wheat protein kinase gene confers broad-spectrum resistance to rust fungi.

Wheat crops are frequently devastated by pandemic stripe rust caused by Puccinia striiformis f. sp. tritici (Pst). Here, we identify and characterize a wheat receptor-like cytoplasmic kinase gene, TaPsIPK1, that confers susceptibility to this pathogen. PsSpg1, a secreted fungal effector vital for Pst virulence, can bind TaPsIPK1, enhance its kinase activity, and promote its nuclear localization, where it phosphorylates the transcription factor TaCBF1d for gene regulation. The phosphorylation of TaCBF1d switches its transcriptional activity on the downstream genes. CRISPR-Cas9 inactivation of TaPsIPK1 in wheat confers broad-spectrum resistance against Pst without impacting important agronomic traits in two years of field tests. The disruption of TaPsIPK1 leads to immune priming without constitutive activation of defense responses. Taken together, TaPsIPK1 is a susceptibility gene known to be targeted by rust effectors, and it has great potential for developing durable resistance against rust by genetic modifications.

Transcriptional repression of TaNOX10 by TaWRKY19 compromises ROS generation and enhances wheat susceptibility to stripe rust.

Reactive oxygen species (ROS) are vital for plant immunity and regulation of their production is crucial for plant health. While the mechanisms that elicit ROS production have been relatively well studied, those that repress ROS generation are less well understood. Here, via screening Brachypodium distachyon RNA interference mutants, we identified BdWRKY19 as a negative regulator of ROS generation whose knockdown confers elevated resistance to the rust fungus Puccinia brachypodii. The three wheat paralogous genes TaWRKY19 are induced during infection by virulent P. striiformis f. sp. tritici (Pst) and have partially redundant roles in resistance. The stable overexpression of TaWRKY19 in wheat increased susceptibility to an avirulent Pst race, while mutations in all three TaWRKY19 copies conferred strong resistance to Pst by enhancing host plant ROS accumulation. We show that TaWRKY19 is a transcriptional repressor that binds to a W-box element in the promoter of TaNOX10, which encodes an NADPH oxidase and is required for ROS generation and host resistance to Pst. Collectively, our findings reveal that TaWRKY19 compromises wheat resistance to the fungal pathogen and suggest TaWRKY19 as a potential target to improve wheat resistance to the commercially important wheat stripe rust fungus.

Interplay between quantum anomalous Hall effect and magnetic skyrmions.

SignificanceQuantum anomalous Hall effect (QAHE) and magnetic skyrmion (SK), as two typical topological states in momentum (K) and real (R) spaces, attract much interest in condensed matter physics. However, the interplay between these two states remains to be explored. We propose that the interplay between QAHE and SK may generate an RK joint topological skyrmion (RK-SK), characterized by the SK surrounded by nontrivial chiral boundary states (CBSs). Furthermore, the emerging external field-tunable CBS in RK-SK could create additional degrees of freedom for SK manipulations, beyond the traditional SK. Meanwhile, external field can realize a rare topological phase transition between K and R spaces. Our work opens avenues for exploring unconventional quantum states and topological phase transitions in different spaces.

Association of the m6 A reader IGF2BP3 with tumor progression and brain-specific metastasis in breast cancer.

BACKGROUND: This study aimed to determine the role of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an N6 -methyladinosine reader, in the progression and distant metastasis of breast cancer. METHODS: IGF2BP3 expression was assessed in 152 pairs of breast cancer and adjacent normal tissue (ANT) by real-time quantitative polymerase chain reaction and in 561 cases of breast cancer and 163 cases of ANT by immunohistochemistry. Survival curves were estimated using the Kaplan-Meier method and then compared statistically using the log-rank test. The prognostic role of IGF2BP3 was determined by Cox regression analysis. RESULTS: Analysis of public gene data sets revealed that IGF2PB3 predicted distant metastasis in breast cancer and was highly correlated with brain metastasis. In the clinical retrospective cohort, the positive rate of IGF2BP3 increased gradually with breast cancer progression. Positive IGF2BP3 expression was related to poor distant metastasis-free survival (DMFS, p = .030) and Cox regression analysis identified IGF2BP3 as an independent risk factor for DMFS (hazard ratio, 1.876; 95% confidence interval, 1.128-3.159; p = .019). Positive IGF2BP3 expression was markedly related to breast cancer brain metastasis (p = .011) but not to lung and bone metastasis. Moreover, patients with IGF2BP3-positive brain metastasis had lower survival than patients with IGF2BP3-negative brain metastasis (p = .041). Gene expression profiling results indicated that high IGF2BP3 expression was associated with the PD-1 checkpoint pathway, HER2-HER3 signaling, and epithelial-mesenchymal transition. CONCLUSIONS: IGF2BP3 may serve as a novel predictive biomarker and a potential therapeutic target for breast cancer brain metastasis, which warrants further investigation. PLAIN LANGUAGE SUMMARY: As an m6 A reader, IGF2BP3 is dysregulated and implicated in various cancers but its role in breast cancer has not been fully clarified. In this study, we found that IGF2BP3 was upregulated in breast cancer and IGF2BP3 expression increased gradually during breast cancer progression. IGF2BP3 expression exerted no effect on the overall survival and breast cancer-specific survival of breast cancer patients; however, IGF2BP3-positive patients were more likely to develop distant metastasis than IGF2BP3-negative patients. In addition, IGF2BP3 was associated with brain-specific metastasis in breast cancer patients. These findings warrant further investigation because they provide a rationale for novel predictive or therapeutic approaches.

Comprehensive characterization of stemness-related lncRNAs in triple-negative breast cancer identified a novel prognostic signature related to treatment outcomes, immune landscape analysis and therapeutic guidance: a silico analysis with in vivo experiments.

BACKGROUND: Cancer stem cells (CSCs) and long non-coding RNAs (lncRNAs) are known to play a crucial role in the growth, migration, recurrence, and drug resistance of tumor cells, particularly in triple-negative breast cancer (TNBC). This study aims to investigate stemness-related lncRNAs (SRlncRNAs) as potential prognostic indicators for TNBC patients. METHODS: Utilizing RNA sequencing data and corresponding clinical information from the TCGA database, and employing Weighted Gene Co-expression Network Analysis (WGCNA) on TNBC mRNAsi sourced from an online database, stemness-related genes (SRGs) and SRlncRNAs were identified. A prognostic model was developed using univariate Cox and LASSO-Cox analysis based on SRlncRNAs. The performance of the model was evaluated using Kaplan-Meier analysis, ROC curves, and ROC-AUC. Additionally, the study delved into the underlying signaling pathways and immune status associated with the divergent prognoses of TNBC patients. RESULTS: The research identified a signature of six SRlncRNAs (AC245100.6, LINC02511, AC092431.1, FRGCA, EMSLR, and MIR193BHG) for TNBC. Risk scores derived from this signature were found to correlate with the abundance of plasma cells. Furthermore, the nominated chemotherapy drugs for TNBC exhibited considerable variability between different risk score groups. RT-qPCR validation confirmed abnormal expression patterns of these SRlncRNAs in TNBC stem cells, affirming the potential of the SRlncRNAs signature as a prognostic biomarker. CONCLUSION: The identified signature not only demonstrates predictive power in terms of patient outcomes but also provides insights into the underlying biology, signaling pathways, and immune status associated with TNBC prognosis. The findings suggest the possibility of guiding personalized treatments, including immune checkpoint gene therapy and chemotherapy strategies, based on the risk scores derived from the SRlncRNA signature. Overall, this research contributes valuable knowledge towards advancing precision medicine in the context of TNBC.

Comprehensive investigation of malignant epithelial cell-related genes in clear cell renal cell carcinoma: development of a prognostic signature and exploration of tumor microenvironment interactions.

Clear cell renal cell carcinoma (ccRCC) is a prevalent malignancy with complex heterogeneity within epithelial cells, which plays a crucial role in tumor progression and immune regulation. Yet, the clinical importance of the malignant epithelial cell-related genes (MECRGs) in ccRCC remains insufficiently understood. This research aims to undertake a comprehensive investigation into the functions and clinical relevance of malignant epithelial cell-related genes in ccRCC, providing valuable understanding of the molecular mechanisms and offering potential targets for treatment strategies. Using data from single-cell sequencing, we successfully identified 219 MECRGs and established a prognostic model MECRGS (MECRGs' signature) by synergistically analyzing 101 machine-learning models using 10 different algorithms. Remarkably, the MECRGS demonstrated superior predictive performance compared to traditional clinical features and 92 previously published signatures across six cohorts, showcasing its independence and accuracy. Upon stratifying patients into high- and low-MECRGS subgroups using the specified cut-off threshold, we noted that patients with elevated MECRGS scores displayed characteristics of an immune suppressive tumor microenvironment (TME) and showed worse outcomes after immunotherapy. Additionally, we discovered a distinct ccRCC tumor cell subtype characterized by the high expressions of PLOD2 (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2) and SAA1 (Serum Amyloid A1), which we further validated in the Renji tissue microarray (TMA) cohort. Lastly, 'Cellchat' revealed potential crosstalk patterns between these cells and other cell types, indicating their potential role in recruiting CD163 + macrophages and regulatory T cells (Tregs), thereby establishing an immunosuppressive TME. PLOD2 + SAA1 + cancer cells with intricate crosstalk patterns indeed show promise for potential therapeutic interventions.

NCAPG2 promotes prostate cancer malignancy and stemness via STAT3/c-MYC signaling.

BACKGROUND: Prostate cancer (PCa) is the second leading cause of cancer-related mortality among men worldwide, and its incidence has risen substantially in recent years. Therefore, there is an urgent need to identify novel biomarkers and precise therapeutic targets for managing PCa progression and recurrence. METHODS: We investigated the clinical significance of NCAPG2 in PCa by exploring public datasets and our tissue microarray. Receiver operating characteristic (ROC) curve and survival analyses were performed to evaluate the correlation between NCAPG2 and PCa progression. Cell proliferation, wound healing, transwell, flow cytometry, cell cycle, tumor sphere formation, immunofluorescence (IF), co-immunoprecipitation (co-IP), and chromatin immunoprecipitation (ChIP) assays were conducted to further elucidate the molecular mechanism of NCAPG2 in PCa. Subcutaneous and orthotopic xenograft models were applied to investigate the effects of NCAPG2 on PCa proliferation in vivo. Tandem mass tag (TMT) quantitative proteomics was utilized to detect proteomic changes under NCAPG2 overexpression. RESULTS: NCAPG2 was significantly upregulated in PCa, and its overexpression was associated with PCa progression and unfavorable prognosis. Knockdown of NCAPG2 inhibited the malignant behavior of PCa cells, whereas its overexpression promoted PCa aggressiveness. NCAPG2 depletion attenuated the development and growth of PCa in vivo. TMT quantitative proteomics analyses indicated that c-MYC activity was strongly correlated with NCAPG2 expression. The malignancy-promoting effect of NCAPG2 in PCa was mediated via c-MYC. NCAPG2 could directly bind to STAT3 and induce STAT3 occupancy on the MYC promoter, thus to transcriptionally activate c-MYC expression. Finally, we identified that NCAPG2 was positively correlated with cancer stem cell (CSC) markers and enhanced self-renewal capacity of PCa cells. CONCLUSIONS: NCAPG2 is highly expressed in PCa, and its level is significantly associated with PCa prognosis. NCAPG2 promotes PCa malignancy and drives cancer stemness via the STAT3/c-MYC signaling axis, highlighting its potential as a therapeutic target for PCa.

Effects of right ventricular remodeling in chronic thromboembolic pulmonary hypertension on the outcomes of balloon pulmonary angioplasty: a 2D-speckle tracking echocardiography study.

BACKGROUND: Balloon pulmonary angioplasty (BPA) improves the prognosis of chronic thromboembolic pulmonary hypertension (CTEPH). Right ventricle (RV) is an important predictor of prognosis in CTEPH patients. 2D-speckle tracking echocardiography (2D-STE) can evaluate RV function. This study aimed to evaluate the effectiveness of BPA in CTEPH patients and to assess the value of 2D-STE in predicting outcomes of BPA. METHODS: A total of 76 patients with CTEPH underwent 354 BPA sessions from January 2017 to October 2022. Responders were defined as those with mean pulmonary artery pressure (mPAP) ≤ 30 mmHg or those showing ≥ 30% decrease in pulmonary vascular resistance (PVR) after the last BPA session, compared to baseline. Logistic regression analysis was performed to identify predictors of BPA efficacy. RESULTS: BPA resulted in a significant decrease in mPAP (from 50.8 ± 10.4 mmHg to 35.5 ± 11.9 mmHg, p < 0.001), PVR (from 888.7 ± 363.5 dyn·s·cm-5 to 545.5 ± 383.8 dyn·s·cm-5, p < 0.001), and eccentricity index (from 1.3 to 1.1, p < 0.001), and a significant increase in RV free wall longitudinal strain (RVFWLS: from 15.7% to 21.0%, p < 0.001). Significant improvement was also observed in the 6-min walking distance (from 385.5 m to 454.5 m, p < 0.001). After adjusting for confounders, multivariate analysis showed that RVFWLS was the only independent predictor of BPA efficacy. The optimal RVFWLS cutoff value for predicting BPA responders was 12%. CONCLUSIONS: BPA was found to reduce pulmonary artery pressure, reverse RV remodeling, and improve exercise capacity. RVFWLS obtained by 2D-STE was an independent predictor of BPA outcomes. Our study may provide a meaningful reference for interventional therapy of CTEPH.

Repurposing harmaline as a novel approach to reverse tmexCD1-toprJ1-mediated tigecycline resistance against klebsiella pneumoniae infections.

BACKGROUND: A novel plasmid-mediated resistance-nodulation-division (RND) efflux pump gene cluster tmexCD1-toprJ1 in Klebsiella pneumoniae tremendously threatens the use of convenient therapeutic options in the post-antibiotic era, including the "last-resort" antibiotic tigecycline. RESULTS: In this work, the natural alkaloid harmaline was found to potentiate tigecycline efficacy (4- to 32-fold) against tmexCD1-toprJ1-positive K. pneumoniae, which also thwarted the evolution of tigecycline resistance. Galleria mellonella and mouse infection models in vivo further revealed that harmaline is a promising candidate to reverse tigecycline resistance. Inspiringly, harmaline works synergistically with tigecycline by undermining tmexCD1-toprJ1-mediated multidrug resistance efflux pump function via interactions with TMexCD1-TOprJ1 active residues and dissipation of the proton motive force (PMF), and triggers a vicious cycle of disrupting cell membrane integrity and metabolic homeostasis imbalance. CONCLUSION: These results reveal the potential of harmaline as a novel tigecycline adjuvant to combat hypervirulent K. pneumoniae infections.

Inoculum Sources of Puccinia striiformis f. sp. tritici for Stripe Rust Epidemics on the Eastern Coast of China.

Stripe rust, a fungal disease caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most destructive diseases affecting wheat production areas worldwide. In recent years in China, wheat stripe rust has caused huge yield losses throughout the vast Huang-Huai-Hai region, including the eastern coast regions, especially Shandong province. The aim of the present study was to explore the population structure and potential inoculum sources of the pathogen in this region. A total of 234 Pst isolates in 2021 were collected and isolated from seven provinces and identified for virulence phenotypes using 19 Chinese differentials and for genotypes using 17 single-nucleotide polymorphism-based Kompetitive allele-specific PCR markers. The virulence phenotype tests identified predominant races CYR34 (18.0%) and CYR32 (16.0%) in Shandong, which were similar to the results in Henan province, also with the predominant races CYR34 (21.9%) and CYR32 (18.8%). Based on the virulence data of phenotyping, the Pst populations in Shandong, Hubei, and Henan were similar. The genotypic analysis revealed remarkable gene flows among the Shandong, Hubei, Henan, Yunnan, and Guizhou populations, showing a migration of Pst from the southwestern oversummering regions to Shandong through the winter spore production regions. Genetic structure analysis also indicated an additional migration route from the northwestern oversummering regions through winter spore production regions to Shandong. The results are useful for understanding stripe rust epidemiology in the eastern coast region and improving control of the disease throughout the country.

Cucurbit[8]uril-based supramolecular theranostics.

Different from most of the conventional platforms with dissatisfactory theranostic capabilities, supramolecular nanotheranostic systems have unparalleled advantages via the artful combination of supramolecular chemistry and nanotechnology. Benefiting from the tunable stimuli-responsiveness and compatible hierarchical organization, host-guest interactions have developed into the most popular mainstay for constructing supramolecular nanoplatforms. Characterized by the strong and diverse complexation property, cucurbit[8]uril (CB[8]) shows great potential as important building blocks for supramolecular theranostic systems. In this review, we summarize the recent progress of CB[8]-based supramolecular theranostics regarding the design, manufacture and theranostic mechanism. Meanwhile, the current limitations and corresponding reasonable solutions as well as the potential future development are also discussed.

Density-independent plasmons for terahertz-stable topological metamaterials.

To efficiently integrate cutting-edge terahertz technology into compact devices, the highly confined terahertz plasmons are attracting intensive attention. Compared to plasmons at visible frequencies in metals, terahertz plasmons, typically in lightly doped semiconductors or graphene, are sensitive to carrier density (n) and thus have an easy tunability, which leads to unstable or imprecise terahertz spectra. By deriving a simplified but universal form of plasmon frequencies, here, we reveal a unified mechanism for generating unusual n-independent plasmons (DIPs) in all topological states with different dimensions. Remarkably, we predict that terahertz DIPs can be excited in a two-dimensional nodal line and one-dimensional nodal point systems, confirmed by the first-principle calculations on almost all existing topological semimetals with diverse lattice symmetries. Besides n-independence, the feature of Fermi velocity and degeneracy factor dependencies in DIPs can be applied to design topological superlattice and multiwalled carbon nanotube metamaterials for broadband terahertz spectroscopy and quantized terahertz plasmons, respectively. Surprisingly, high spatial confinement and quality factor, also insensitive to n, can be simultaneously achieved in these terahertz DIPs. Our findings pave the way for developing topological plasmonic devices for stable terahertz applications.

Integrative study of transcriptome and microbiome to reveal the response of Rhododendron decorum to cadmium stress.

The anomalies of cadmium (Cd) in karst region pose a severe threat to plant growth and development. In this study, the responses of Rhododendron decorum to Cd stress were investigated at physiological, molecular, and endophytic microbial levels, and the potential correlation among these responses was assessed. The Cd stress impeded R. decorum growth and led to an increase in malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels, as well as enhanced superoxide dismutase (SOD) and catalase (CAT) activities. Meanwhile, Cd stress increased the Cd (up to 80 times compared to the control), sodium (Na), aluminum (Al), and zinc (Zn) contents, while decreased the magnesium (Mg) and manganese (Mn) contents in R. decorum leaves. Transcriptome suggested that Cd significantly regulated the pathways including "protein repair", "hormone-mediated signaling pathway", and "ATP-binding cassette (ABC) transporters". Additionally, q-PCR analysis showed that Cd stress significantly up-regulated the expressions of ABCB19-like and pleiotropic drug resistance, while down-regulated the expressions of indole-3-acetic acid-amido synthetase and cytokinin dehydrogenase. The Cd stress influenced the composition of endophytic microbial communities in R. decorum leaves and enhanced the interspecific bacterial associations. Furthermore, the bacterial genera Achromobacter, Aureimonas and fungal genus Vishniacozyma exhibited a high degree of connectivity with other nodes in networks constructed by the metal element contents, differentially expressed genes (DEGs), and microbial communities, respectively. These findings provide a comprehensive insight into the response of R. decorum to Cd-induced stress, which might facilitate the breeding of the Cd-tolerant R. decorum.

Phosphorylated CPI-17 and MLC2 as Biomarkers of Coronary Artery Spasm-Induced Sudden Cardiac Death.

Coronary artery spasm (CAS) plays an important role in the pathogeneses of various ischemic heart diseases and has gradually become a common cause of life-threatening arrhythmia. The specific molecular mechanism of CAS has not been fully elucidated, nor are there any specific diagnostic markers for the condition. Therefore, this study aimed to examine the specific molecular mechanism underlying CAS, and screen for potential diagnostic markers. To this end, we successfully constructed a rat CAS model and achieved in vitro culture of a human coronary-artery smooth-muscle cell (hCASMC) contraction model. Possible molecular mechanisms by which protein kinase C (PKC) regulated CAS through the C kinase-potentiated protein phosphatase 1 inhibitor of 17 kDa (CPI-17)/myosin II regulatory light chain (MLC2) pathway were studied in vivo and in vitro to screen for potential molecular markers of CAS. We performed hematoxylin and eosin staining, myocardial zymogram, and transmission electron microscopy to determine myocardial and coronary artery injury in CAS rats. Then, using immunohistochemical staining, immunofluorescence staining, and Western blotting, we further demonstrated a potential molecular mechanism by which PKC regulated CAS via the CPI-17/MLC2 pathway. The results showed that membrane translocation of PKCα occurred in the coronary arteries of CAS rats. CPI-17/MLC2 signaling was observably activated in coronary arteries undergoing CAS. In addition, in vitro treatment of hCASMCs with angiotensin II (Ang II) increased PKCα membrane translocation while consistently activating CPI-17/MLC2 signaling. Conversely, GF-109203X and calphostin C, specific inhibitors of PKC, inactivated CPI-17/MLC2 signaling. We also collected the coronary artery tissues from deceased subjects suspected to have died of CAS and measured their levels of phosphorylated CPI-17 (p-CPI-17) and MLC2 (p-MLC2). Immunohistochemical staining was positive for p-CPI-17 and p-MLC2 in the tissues of these subjects. These findings suggest that PKCα induced CAS through the CPI-17/MLC2 pathway; therefore, p-CPI-17 and p-MLC2 could be used as potential markers for CAS. Our data provide novel evidence that therapeutic strategies against PKC or CPI-17/MLC2 signaling might be promising in the treatment of CAS.

A new function of thymol nanoemulsion for reversing colistin resistance in Salmonella enterica serovar Typhimurium infection.

BACKGROUND: Adjuvant addition of approved drugs or foodborne additives to colistin might be a cost-effective strategy to overcome the challenge of plasmid-mediated mobile colistin resistance gene emergence, which poses a threat in the clinic and in livestock caused by infections with Gram-negative bacteria, especially carbapenem-resistant Enterobacteriaceae. METHODS: Chequerboard assay was applied to screen the colistin adjuvants from natural compounds. The killing-time curve, combined disc test and membrane permeation assay were conducted to identify the synergy efficacy of thymol and colistin in vitro. Thin-layer chromatography (TLC), LC-MS and fluorescence spectra were used to indicate the interaction of thymol and MCR-1. The potential binding sites were then investigated by molecular simulation dynamics. Finally, a thymol nanoemulsion was prepared with high-pressure homogenization as the clinical dosage form. RESULTS: Thymol presented an excellent synergistic effect in vitro with colistin against Salmonella enterica serovar Typhimurium and Escherichia coli bacteria. Thymol addition, forming a complex with MCR-1, might interfere with the efficacy of MCR-1. Moreover, thymol strengthened colistin activity associated with potentiating membrane damage, destroying the biofilm and enhancing reactive oxygen species-mediated oxidative damage. Thymol nanoemulsion combined with colistin remarkably prevented the intestinal damage caused by S. Typhimurium infection, resulting in a survival rate higher than 60%. CONCLUSIONS: This study achieved a promising thymol oral formulation as colistin adjuvant to combat S. Typhimurium infection, which could be used to extend the lifespan of colistin in clinical veterinary medicine.

Double-sided asymmetric metasurfaces achieving sub-microscale focusing from a GaN green laser diode.

We proposed and demonstrated a highly efficient sub-microscale focusing from a GaN green laser diode (LD) integrated with double-sided asymmetric metasurfaces. The metasurfaces consist of two nanostructures in a GaN substrate: nanogratings on one side and a geometric phase based metalens on the other side. When it was integrated on the edge emission facet of a GaN green LD, linearly polarized emission was firstly converted to the circularly polarized state by the nanogratings functioning as a quarter-wave plate, the phase gradient was then controlled by the metalens on the exit side. In the end, the double-sided asymmetric metasurfaces achieve a sub micro-focusing from linearly polarized states. Experimental results show the full width at half maximum of the focused spot size is about 738 nm at the wavelength 520 nm and the focusing efficiency is about 72.8%. Our results lay a foundation for the multi-functional applications in optical tweezers, laser direct writing, visible light communication, and biological chip.

Isorhamnetin as a novel inhibitor of pneumolysin against Streptococcus pneumoniae infection in vivo/in vitro.

The increasing incidence of Streptococcus pneumoniae (S. pneumoniae) infection severely threatened the global public heath, causing a significant fatality in immunocompromised hosts. Notably, pneumolysin (PLY) as a pore-forming cytolysin plays a crucial role in the pathogenesis of pneumococcal pneumonia and lung injury. In this study, a natural flavonoid isorhamnetin was identified as a PLY inhibition to suppress PLY-induced hemolysis by engaging the predicted residues and attenuate cytolysin PLY-mediated A549 cells injury. Underlying mechanisms revealed that PLY inhibitor isorhamnetin further contributed to decrease the formation of bacterial biofilms without affecting the expression of PLY. In vivo S. pneumoniae infection confirmed that the pathological injury of lung tissue evoked by S. pneumoniae was ameliorated by isorhamnetin treatment. Collectively, these results presented that isorhamnetin could inhibit the biological activity of PLY, thus reducing the pathogenicity of S. pneumoniae. In summary, our study laid a foundation for the feasible anti-virulence strategy targeting PLY, and provided a promising PLY inhibitor for the treatment of S. pneumoniae infection.

Development of a two-beveled-fiber polarized fiber-optic Raman probe coupled with a ball lens for in vivo superficial epithelial Raman measurements in endoscopy.

We report on the development of a two-beveled-fiber polarized (TBFP) fiber-optic Raman probe coupled with a ball lens for in vivo superficial epithelial Raman measurements in endoscopy. The two-beveled fibers positioned symmetrically along a ball lens, in synergy with paired parallel-polarized polarizers integrated between the fibers and the ball lens, maximize the Raman signal excitation and collection from the superficial epithelium where gastrointestinal (GI) precancer arises. Monte Carlo (MC) simulations and two-layer tissue phantom experiments show that the probe developed detects ∼90% of the Raman signal from the superficial epithelium. The suitability of the probe developed for rapid (<3 s) superficial epithelial Raman measurements is demonstrated on fresh swine esophagus, stomach, and colon tissues, followed by their differentiation with high accuracies (92.1% for esophagus [sensitivity: 89.3%, specificity: 93.2%], 94.1% for stomach [sensitivity: 86.2%, specificity: 97.2%], and 94.1% for colon [sensitivity: 93.2%, specificity: 94.7%]). The presented results suggest the great potential of the developed probe for enhancing in vivo superficial epithelial Raman measurements in endoscopy.

Giant Bulk Electrophotovoltaic Effect in Heteronodal-Line Systems.

The realization of a giant and continuously tunable second-order photocurrent is desired for many nonlinear optical (NLO) and optoelectronic applications, which remains a great challenge. Here, based on a two-band model, we propose a concept of the bulk electrophotovoltaic effect, that is, an out-of-plane external electric field (E_{ext}) that can continuously tune in-plane shift current along with its sign flip in a heteronodal-line (HNL) system. While strong linear optical transition around the nodal loop may potentially generate giant shift current, an E_{ext} can effectively control the radius of the nodal loop, which can continuously modulate the shift-vector components inside and outside the nodal loop holding opposite signs. This concept has been demonstrated in the HNL HSnN/MoS_{2} system using first-principles calculations. The HSnN/MoS_{2} heterobilayer can not only produce a shift-current conductivity with magnitude that is one to two orders larger than other reported systems, but it can also realize a giant bulk electrophotovoltaic effect. Our finding opens new routes to create and manipulate NLO responses in 2D materials.

Dissemination feature based on PET/CT is a risk factor for diffuse large B cell lymphoma patients outcome.

BACKGROUND: 18F-FDG PET/CT provides precise information about dissemination of lymphoma lesions. Dmax, defined as distance between the two lesions that were farthest apart by PET/CT, was found to be a promising predictor of Diffuse large B-cell lymphoma (DLBCL) outcome in a small size of clinical trial data. We analyzed the impact of Dmax on the outcome of a large real-world DLBCL cohort. METHODS: Data of newly diagnosed DLBCL at the Third Affiliated Hospital of Soochow University were retrospectively collected. Baseline Dmax, clinical data and survival information were recorded. A metabolic parameter, metabolic bulk volume (MBV), was also measured to verify the independent impact of Dmax. RESULTS: Optimal cut-off values for Dmax and MBV were 45.34 cm and 21.65 cm3. With a median follow-up of 32 months, Dmax significantly impacted progression-free survival (PFS) and overall survival (OS) in 253 DLBCL patients. For Dmaxlow and Dmaxhigh groups, estimated 3-year OS were 87.0% and 53.8% (p < 0.001), while 3-year PFS were 77.3% and 37.3% (p < 0.001). And for MBVlow and MBVhighgroups, 3-year OS were 84.5% and 58.8% (p < 0.001), and 3-year PFS were 68.7% and 50.4% (p = 0.003). Multivariate analysis identified Dmax and Eastern Cooperative Oncology Group performance status (ECOG PS) independently associated with PFS and OS, while MBV only independently associated with OS. A Dmax revised prognostic index (DRPI) combining Dmax and ECOG PS identified an ultra-risk DLBCL population with 3-year PFS of 31.7% and 3-year OS of 38.5%. The area under the curve (AUC) showed that this model performed better than International prognostic Index (IPI). CONCLUSION: Dmax is a new and promising indicator to investigate dissemination of lymphoma lesions associated with the outcome of DLBCL. It significantly contributes to stratification of patients with disparate outcomes. TRIAL REGISTRATION: This research has been retrospectively registered in the Ethics Committee institutional of the Third Affiliated Hospital of Soochow University, and the registration number was approval No. 155 (approved date: 31 May 2022).