The Molecular Mechanism of Cold-Stress Tolerance: Cold Responsive Genes and Their Mechanisms in Rice (Oryza sativa L.).

Rice (Oryza sativa L.) production is highly susceptible to temperature fluctuations, which can significantly reduce plant growth and development at different developmental stages, resulting in a dramatic loss of grain yield. Over the past century, substantial efforts have been undertaken to investigate the physiological, biochemical, and molecular mechanisms of cold stress tolerance in rice. This review aims to provide a comprehensive overview of the recent developments and trends in this field. We summarized the previous advancements and methodologies used for identifying cold-responsive genes and the molecular mechanisms of cold tolerance in rice. Integration of new technologies has significantly improved studies in this era, facilitating the identification of essential genes, QTLs, and molecular modules in rice. These findings have accelerated the molecular breeding of cold-resistant rice varieties. In addition, functional genomics, including the investigation of natural variations in alleles and artificially developed mutants, is emerging as an exciting new approach to investigating cold tolerance. Looking ahead, it is imperative for scientists to evaluate the collective impacts of these novel genes to develop rice cultivars resilient to global climate change.

Characterization and the first complete genome sequence of a novel strain of Bergeyella porcorum isolated from pigs in China.

BACKGROUND: Bergeyella porcorum is a newly identified bacterium that has an ambiguous relationship with pneumonia in pigs. However, few studies have adequately characterized this species. RESULTS: In this study, we analyzed the morphological, physiological, and genomic characteristics of the newly identified B. porcorum sp. nov. strain QD2021 isolated from pigs. The complete genome sequence of the B. porcorum QD2021 strain consists of a single circular chromosome (2,271,736 bp, 38.51% G + C content), which encodes 2,578 genes. One plasmid with a size of 70,040 bp was detected. A total of 121 scattered repeat sequences, 319 tandem repeat sequences, 4 genomic islands, 5 prophages, 3 CRISPR sequences, and 51 ncRNAs were predicted. The coding genes of the B. porcorum genome were successfully annotated across eight databases (NR, GO, KEGG, COG, TCDB, Pfam, Swiss-Prot and CAZy) and four pathogenicity-related databases (PHI, CARD, VFDB and ARDB). In addition, a comparative genome analysis was performed to explore the evolutionary relationships of B. porcorum QD2021. CONCLUSIONS: To our knowledge, this is the first study to provide fundamental phenotypic and whole-genome sequences for B. porcorum. Our results extensively expand the current knowledge and could serve as a valuable genomic resource for future research on B. porcorum.

Integrated analysis of single-cell and bulk RNA sequencing data reveals a cellular senescence-related signature in hepatocellular carcinoma.

The mortality of hepatocellular carcinoma (HCC) is on the rise globally, particularly in the Western world, with etiology gradually shifting from virus-related liver diseases to metabolic disorders such as non-alcoholic fatty liver disease. Early detection of HCC is challenging, and effective prognostic indicators are currently lacking, urgently necessitating reliable markers to assist in treatment planning and clinical management. Here, we introduce hepatocellular carcinoma senescence genes (HSG) to assess cellular senescence in HCC and devise a hepatocellular carcinoma senescence score (HSS) for prognostic prediction. Higher HSS levels signify poorer prognosis and increased tumor proliferation activity. Additionally, we observe alterations in the tumor immune microenvironment with higher HSS levels, such as increased infiltration of Treg, potentially providing a basis for immunotherapy. Furthermore, we identify key genes, such as PTTG1, within the senescence gene set and demonstrate their regulatory roles in HCC cells and Treg through experimentation. In summary, we establish a scoring system based on hepatocellular carcinoma senescence genes for prognostic prediction in HCC, potentially offering guidance for clinical treatment planning.

Single-cell analysis reveals hypoxia-induced immunosuppressive microenvironment in intrahepatic cholangiocarcinoma.

The role of hypoxia in the tumor microenvironment of intrahepatic cholangiocarcinoma (iCCA) remains unclear. Here, we generated a comprehensive atlas of the entire tumor microenvironment and delineated the multifaceted cell-cell interactions to decipher hypoxia-induced pro-tumor immune suppression. We discovered hypoxia is significantly associated with iCCA progression via the activation of HIF1A expression. Moreover, hypoxia-dependent PPARγ-mediated fatty acid oxidation in APOE+ TAMs promoted M2 macrophage polarization by activating the HIF1A-PPARG-CD36 axis. These polarized APOE+ TAMs recruited Treg cell infiltration via the CCL3-CCR5 pair to form an immunosuppressive microenvironment. APOE+ TAMs tended to co-localize spatially with Treg cells in the malignant tissue based on spatial transcriptome data and immunofluorescence analysis results. We identified tumor-reactive CXCL13+ CD8-PreTex with specific high expression of ENTPD1 and ITGAE, which acted as precursors of CD8-Tex and had higher cytotoxicity, lower exhaustion, and more vigorous proliferation. Consequently, CXCL13+ CD8-PreTex functioned as a positive regulator of antitumor immunity by expressing the pro-inflammatory cytokines IFNG and TNF, associated with a better survival outcome. Our study reveals the mechanisms involved in hypoxia-induced immunosuppression and suggests that targeting precursor-exhausted CXCL13+CD8+ T cells might provide a pratical immunotherapeutic approach.

Pan-cancer analysis of DCTN2 and its tumour-promoting role in HCC by modulating the AKT pathway.

Dynactin subunit 2 (DCTN2) has been reported to play a role in progression of several tumours; however, the involvement of DCTN2 in potential mechanism or the tumour immune microenvironment among various cancers still remains largely unknown. Therefore, the objective of this study was to comprehensively investigate the expression status and potential function of DCTN2 in various malignancies through different database, such as The Cancer Genome Atlas, the Genotype-Tissue Expression and Gene Expression Omnimus databases. We discovered that DCTN2 expression was high in many type of tumours tissues compared to adjacent non-tumour ones. High DCTN2 signified poor prognosis for patients with tumours. Additionally, Gene Set Enrichment Analysis (GSEA) analysis revealed that DCTN2 was positively correlated with oncogenic pathways, including cell cycle, tumour metastasis-related pathway, while it was negatively with anti-tumour immune signalling pathway, such as INF-γ response. More importantly, we elucidated the functional impact of DCTN2 on hepatocellular carcinoma (HCC) progression and its underlying mechanisms. DCTN2 expression was much higher in HCC tissues than in adjacent non-tumour tissues. Silencing DCTN2 dramatically suppressed the proliferative and metastasis capacities of tumour cell in vitro. Mechanistically, DCTN2 exerted tumour-promoting effects by modulating the AKT signalling pathway. DCTN2 knockdown in HCC cells inhibited AKT phosphorylation and its downstream targets as well. Rescue experiments revealed that the anti-tumour effects of DCTN2 knockdown were partially reversed upon AKT pathway activation. Overall, DCTN2 may be a potent biomarker signifying tumour prognosis and a promising therapeutic target for tumour treatment, particularly in HCC.

The consistency of Anti-Toxocara IgG between the Aqueous Humor and Vitreous of Patients with Clinically Suspected Ocular Toxocariasis.

PURPOSE: To assess the consistencies of anti-Toxocara IgG (T-IgG) and Goldmann-Witmer coefficient (GWC) between paired aqueous humor (AH) and vitreous samples from patients with clinically-suspected ocular toxocariasis (OT). DESIGN: Inter-test reliability assessment. METHODS: A total of 47 patients with clinically-suspected OT who underwent vitrectomy were included. AH, vitreous and serum samples from each patient were collected and levels of specific T-IgG in them were detected. The association and agreement of T-IgG and GWC between AH and vitreous were evaluated. The area under the receiver operating characteristic curve (AUROC) was generated to assess the diagnostic performance of AH. RESULTS: The T-IgG levels and GWC values in vitreous were higher than those in AH (P = 0.023 and P = 0.029, respectively), but similar positivity rates in the T-IgG (P = 1.000) and GWC>3 (P = 1.000) were apparent between vitreous and AH. In addition, there was a positive correlations between the AH and vitreous T-IgG levels (rs = 0.944, P < 0.001) and the GWC values (rs = 0.455, P = 0.022). Moreover, the consistencies between AH and vitreous samples in their T-IgG and GWC positivity rates were almost perfect (both, κ = 0.915, 95% CI, 0.799-1.000) in both. The AUROC reached 0.991, with a 95% confidence interval of 0.971-1.000. The best cut-off value for accurate OT diagnosis was found at 1.434, yielding 96% sensitivity and 100% specificity. CONCLUSIONS: Our findings demonstrate that AH and vitreous samples had significant correlations and perfect agreements for both T-IgG and GWC, suggesting that the AH may serve as a proxy for vitreous to provide a safer, earlier, and more convenient screening of OT.

Giant Carrier Mobility in a Room-Temperature Ferromagnetic VSi2N4 Monolayer.

Using density functional theory (DFT), we investigate that two possible phases of VSi2N4 (VSN) may be realized, one called the "H phase" corresponding to what is known from calculation and herein the other new "T phase" being stabilized by a biaxial tensile strain of 3%. Significantly, the H phase is predicted to display a giant carrier mobility of 1 × 106 cm2 V-1 s-1, which exceeds that for most 2D magnetic materials, with a Curie temperature (TC) exceeding room temperature and a band gap of 2.01 eV at the K point. Following the H-T phase transition, the direct band gap shifts to the Γ point and increases to 2.59 eV. The Monte Carlo (MC) simulations also indicate that TC of the T phase VSN can be effectively modulated by strain, reaching room temperature under a biaxial strain of -4%. These results show that VSN should be a promising functional material for future nanoelectronics.

ViroISDC: a method for calling integration sites of hepatitis B virus based on feature encoding.

BACKGROUND: Hepatitis B virus (HBV) integrates into human chromosomes and can lead to genomic instability and hepatocarcinogenesis. Current tools for HBV integration site detection lack accuracy and stability. RESULTS: This study proposes a deep learning-based method, named ViroISDC, for detecting integration sites. ViroISDC generates corresponding grammar rules and encodes the characteristics of the language data to predict integration sites accurately. Compared with Lumpy, Pindel, Seeksv, and SurVirus, ViroISDC exhibits better overall performance and is less sensitive to sequencing depth and integration sequence length, displaying good reliability, stability, and generality. Further downstream analysis of integrated sites detected by ViroISDC reveals the integration patterns and features of HBV. It is observed that HBV integration exhibits specific chromosomal preferences and tends to integrate into cancerous tissue. Moreover, HBV integration frequency was higher in males than females, and high-frequency integration sites were more likely to be present on hepatocarcinogenesis- and anti-cancer-related genes, validating the reliability of the ViroISDC. CONCLUSIONS: ViroISDC pipeline exhibits superior precision, stability, and reliability across various datasets when compared to similar software. It is invaluable in exploring HBV infection in the human body, holding significant implications for the diagnosis, treatment, and prognosis assessment of HCC.

Biogenic selenium nanoparticles alleviate intestinal barrier injury in mice through TBC1D15/Fis1/Rab7 pathway.

Intestinal diseases often stem from a compromised intestinal barrier. This barrier relies on a functional epithelium and proper turnover of intestinal cells, supported by mitochondrial health. Mitochondria and lysosomes play key roles in cellular balance. Our previous researches indicate that biogenic selenium nanoparticles (SeNPs) can alleviate intestinal epithelial barrier damage by enhancing mitochondria-lysosome crosstalk, though the detailed mechanism is unclear. This study aimed to investigate the role of mitochondria-lysosome crosstalk in the protective effect of SeNPs on intestinal barrier function in mice exposed to lipopolysaccharide (LPS). The results showed that LPS exposure increased intestinal permeability in mice, leding to structural and functional damage to mitochondrial and lysosomal. Oral administration of SeNPs significantly upregulated the expression levels of TBC1D15 and Fis1, downregulated the expression levels of Rab7, Caspase-3, Cathepsin B, and MCOLN2, effectively alleviated LPS-induced mitochondrial and lysosomal dysfunction and maintained the intestinal barrier integrity in mice. Furthermore, SeNPs notably inhibited mitophagy caused by adenovirus-associated virus (AAV)-mediated RNA interference the expression of TBC1D15 in the intestine of mice, maintained mitochondrial and lysosomal homeostasis, and effectively alleviated intestinal barrier damage. These results suggested that SeNPs can regulate mitochondria-lysosome crosstalk and inhibit its damage by regulating the TBC1D15/Fis1/Rab7- signaling pathway. thereby alleviating intestinal barrier damage. It lays a theoretical foundation for elucidating the mechanism of mitochondria-lysosome crosstalk in regulating intestinal barrier damage and repair, and provides new ideas and new ways to establish safe and efficient nutritional regulation strategies to prevent and treat intestinal diseases caused by inflammation.

Gender differences in the relationship between serum uric acid and the long-term prognosis in heart failure: a nationwide study.

BACKGROUND: Serum uric acid (SUA) is an important pathogenetic and prognostic factor for heart failure (HF). Gender differences are apparent in HF. Furthermore, gender differences also exist in the association between SUA and prognosis in various cardiovascular diseases. However, the gender difference for SUA in the prediction of long-term prognosis in HF is still ambiguous. METHODS: A total of 1593 HF patients (897 men, 696 women) from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 cycle were enrolled in our final analysis. Participants were categorized according to gender-specific SUA tertile. We assessed the association between SUA and long-term prognosis of HF patients, defined as all-cause mortality and cardiovascular mortality, in different genders via Kaplan-Meier curve analysis, Cox proportional hazard model, and Fine-Gray competing risk model. The restricted cubic spline (RCS) was performed to investigate the dose-response relationship between SUA and outcomes. RESULTS: Gender differences exist in demographic characteristics, clinical parameters, laboratory tests, and medication of HF patients. After a median follow-up of 127 months (95% CI 120-134 months), there were 853 all-cause deaths (493 events in men, 360 events in women) and 361 cardiovascular deaths (206 events in men, 155 events in women). Kaplan-Meier analysis showed that SUA had gender difference in the prediction of cardiovascular mortality (Log-rank p < 0.001, for male, Log-rank p = 0.150, for female), but not in all-cause mortality. Multivariate Cox regression analysis revealed that elevated SUA levels were associated with higher all-cause mortality and cardiovascular mortality in men (HR 1.11, 95% CI 1.05-1.18, p < 0.001, for all-cause death; HR 1.18, 95% CI 1.09-1.28, p < 0.001, for cardiovascular death), but not in women (HR 1.05, 95% CI 0.98-1.12, p = 0.186, for all-cause death; HR 1.01, 95% CI 0.91-1.12, p = 0.902, for cardiovascular death). Even using non-cardiovascular death as a competitive risk, adjusted Fine-Gray model also illustrated that SUA was an independent predictor of cardiovascular death in men (SHR 1.17, 95% CI 1.08-1.27, p < 0.001), but not in women (SHR 0.98, 95% CI 0.87 - 1.10, p = 0.690). CONCLUSIONS: Gender differences in the association between SUA and long-term prognosis of HF existed. SUA was an independent prognostic predictor for long-term outcomes of HF in men, but not in women.

Responses of streamflow to forest expansion in a typical subhumid watershed under future climate conditions.

Water availability in the subhumid region is highly vulnerable to frequent droughts. Water scarcity in this region has become a limiting factor for ecosystem health, human livelihood, and regional economic development. A notable pattern of land cover change in the subhumid region of the United States is the increasing forest area due to afforestation/reforestation and woody plant encroachment (WPE). Given the distinct hydrological processes and runoff generation between forests and grasslands, it is important to evaluate the impacts of forest expansion on water resources, especially under future climate conditions. In this study, we focused on a typical subhumid watershed in the United States - the Little River Watershed (LRW). Utilizing SWAT + simulations, we projected streamflow dynamics at the end of the 21st century in two climate scenarios (RCP45 and RCP85) and eleven forest expansion scenarios. In comparison to the period of 2000-2019, future climate change during 2080-2099 will increase streamflow in the Little River by 5.1% in the RCP45 but reduce streamflow significantly by 30.1% in the RCP85. Additionally, our simulations revealed a linear decline in streamflow with increasing forest coverage. If all grasslands in LRW were converted into forests, it would lead to an additional 41% reduction in streamflow. Of significant concern is Lake Thunderbird, the primary reservoir supplying drinking water to the Oklahoma City metropolitan area. Our simulation showed that if all grasslands were replaced by forests, Lake Thunderbird during 2080-2099 would experience an average of 8.6 years in the RCP45 and 9.4 years in the RCP85 with water inflow amount lower than that during the extreme drought event in 2011/2012. These findings hold crucial implications for the formulation of policies related to afforestation/reforestation and WPE management in subhumid regions, which is essential to ensuring the sustainability of water resources.

Connection of pre-competition anxiety with gut microbiota and metabolites in wrestlers with varying sports performances based on brain-gut axis theory.

OBJECTIVE: The purpose of this study is to investigate the connection of pre-competition anxiety with gut microbiota and metabolites in wrestlers with different sports performances. METHODS: One week prior to a national competition, 12 wrestlers completed anxiety questionnaires. Faecal and urine samples were collected for the analysis of gut microbiota and metabolites through the high-throughput sequencing of the 16 S rRNA gene in conjunction with untargeted metabolomics technology. The subjects were divided into two groups, namely, achievement (CP) and no-achievement (CnP) wrestlers, on the basis of whether or not their performances placed them in the top 16 at the competition. The relationship amongst the variations in gut microbiota, metabolites, and anxiety indicators was analyzed. RESULTS: (1) The CP group exhibited significantly higher levels of "state self-confidence," "self-confidence," and "somatic state anxiety" than the CnP group. Conversely, the CP group displayed lower levels of "individual failure anxiety" and "sports competition anxiety" than the CnP group. (2) The gut microbiota in the CP group was more diverse and abundant than that in the CnP group. Pre-competition anxiety was linked to Oscillospiraceae UCG_005, Paraprevotella, Ruminococcaceae and TM7x. (3) The functions of differential metabolites in faeces and urine of the CP/CnP group were mainly enriched in caffeine metabolism, lipopolysaccharide biosynthesis and VEGF and mTOR signaling pathways. Common differential metabolites in feces and urine were significantly associated with multiple anxiety indicators. CONCLUSIONS: Wrestlers with different sports performance have different pre-competition anxiety states, gut microbiota distribution and abundance and differential metabolites in faeces and urine. A certain correlation exists between these psychological and physiological indicators.

Ultrasensitive upconverting nanoprobes for in situ imaging of drug-induced liver injury using miR-122 as the biomarker.

Drug-induced liver injury (DILI) is a frequent adverse drug reaction. The current clinical diagnostic methods are inadequate for accurate and early detection of DILI due to the lack of effective diagnostic biomarkers. Hepatocyte-specific miR-122 is released from injured hepatocytes promptly and its efflux is significantly correlated with the progression of DILI. Therefore, achieving precise in situ detection of miR-122 with high sensitivity is vital for early visualization of DILI. Herein, a new nanoprobe, consisting of miR-122 aptamer, upconversion nanoparticles (UCNPs) and Prussian blue nanoparticles (PBNPs) was introduced for the early and sensitive detection of DILI in situ. As the nanoprobes reached in the liver, miR-122 aptamer-based entropy-driven strand displacement (ESDR) signal amplification reaction was triggered and luminescence resonance energy transfer (LRET) between UCNPs and PBNPs was responded to achieve the high-fidelity detection of DILI. A negative correlation was observed between the intensity of upconversion luminescence (UCL) and the concentration of miR-122. UCL imaging conducted both in vivo and ex vivo indicated that a reduction in miR-122 concentration led to an increase in UCL intensity, revealing a precise state of DILI. The detection technique demonstrated a positive correlation between signal intensity and severity, offering a more straightforward and intuitive method of visualizing DILI.

Comprehensive multi-omics analysis of resectable locally advanced gastric cancer: Assessing response to neoadjuvant camrelizumab and chemotherapy in a single-center, open-label, single-arm phase II trial.

BACKGROUND: The current standard of care for locally advanced gastric cancer (GC) involves neoadjuvant chemotherapy followed by radical surgery. Recently, neoadjuvant treatment for this condition has involved the exploration of immunotherapy plus chemotherapy as a potential approach. However, the efficacy remains uncertain. METHODS: A single-arm, phase 2 study was conducted to evaluate the efficacy and tolerability of neoadjuvant camrelizumab combined with mFOLFOX6 and identify potential biomarkers of response through multi-omics analysis in patients with resectable locally advanced GC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the R0 rate, near pCR rate, progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). Multi-omics analysis was assessed by whole-exome sequencing, transcriptome sequencing, and multiplex immunofluorescence (mIF) using biopsies pre- and post-neoadjuvant therapy. RESULTS: This study involved 60 patients, of which 55 underwent gastrectomy. Among these, five (9.1%) attained a pathological complete response (pCR), and 11 (20.0%) reached near pCR. No unexpected treatment-emergent adverse events or perioperative mortality were observed, and the regimen presented a manageable safety profile. Molecular changes identified through multi-omics analysis correlated with treatment response, highlighting associations between HER2-positive and CTNNB1 mutations with treatment sensitivity and a favourable prognosis. This finding was further supported by immune cell infiltration analysis and mIF. Expression data uncovered a risk model with four genes (RALYL, SCGN, CCKBR, NTS) linked to poor response. Additionally, post-treatment infiltration of CD8+ T lymphocytes positively correlates with pathological response. CONCLUSION: The findings suggest the combination of PD-1-inhibitor and mFOLFOX6 showed efficacy and acceptable toxicity for locally advanced GC. Extended follow-up is required to determine the duration of the response. This study lays essential groundwork for developing precise neoadjuvant regimens.

The optimal CUSUM control chart with a dynamic non-random control limit and a given sampling strategy for small samples sequence.

This article proposes a performance measure to evaluate the detection performance of a control chart with a given sampling strategy for finite or small samples sequence and prove that the CUSUM control chart with dynamic non-random control limit and a given sampling strategy can be optimal under the measure. Numerical simulations and real data for an earthquake are provided to illustrate that for different sampling strategies, the CUSUM chart will have different monitoring performance in change-point detection. Among the six sampling strategies that take only a part of samples, the numerical comparing results illustrate that the uniform sampling strategy (uniformly dispersed sampling strategy) has the best monitoring effect.

Predictions of Aeroengines' Infrared Radiation Characteristics Based on HKELM Optimized by the Improved Dung Beetle Optimizer.

To solve the problems of high computational cost and the long time required by the simulation and calculation of aeroengines' exhaust systems, a method of predicting the characteristics of infrared radiation based on the hybrid kernel extreme learning machine (HKELM) optimized by the improved dung beetle optimizer (IDBO) was proposed. Firstly, the Levy flight strategy and variable spiral strategy were introduced to improve the optimization performance of the dung beetle optimizer (DBO) algorithm. Secondly, the superiority of IDBO algorithm was verified by using 23 benchmark functions. In addition, the Wilcoxon signed-rank test was applied to evaluate the experimental results, which proved the superiority of the IDBO algorithm over other current prominent metaheuristic algorithms. Finally, the hyperparameters of HKELM were optimized by the IDBO algorithm, and the IDBO-HKELM model was applied to the prediction of characteristics of infrared radiation of a typical axisymmetric nozzle. The results showed that the RMSE and MAE of the IDBO-HKELM model were 20.64 and 8.83, respectively, which verified the high accuracy and feasibility of the proposed method for predictions of aeroengines' infrared radiation characteristics.

RAB5A in triple-negative breast cancer: a critical role in macrophage reshaping in an exosomal miR-21-dependent manner.

Breast cancer is the leading cause of cancer-related deaths in females, and triple-negative breast cancer (TNBC) is characterized as one of the main subtypes of breast cancer, with poor prognosis and limited treatments. Investigating the molecular basis or discovering relevant oncogenes will greatly help in developing effective targeted therapies. In this study, we ascertained that RAB5A depletion in TNBC cells suppresses the secretion of exosomes and blocks the polarization of macrophages toward an M2 phenotype. By scanning miRNAs associated with macrophage polarization, we identified that miR-21 was the pivotal component in tumor cell-derived exosomes and played a key role in RAB5A-mediated macrophage polarization. The enhanced expression of miR-21 in macrophages is able to potentiate the M2 polarization of macrophages in the presence of tumor cells. Pellino-1 (PELI1) was subsequently identified as the target of miR-21, and forced PELI1 expression partially abrogated the M2 polarization of macrophages induced by miR-21 overexpression. Macrophages stimulated with RAB5A-depleted TNBC cells (coculture, conditioned medium or exosomes) impaired their capability to promote the proliferation, migration, and invasion of tumor cells. In vivo xenograft experiments further confirmed that RAB5A knockdown TNBC cells exhibited reduced tumor formation and impaired tumor-associated macrophage recruitment. These studies shed light on the potential underlying mechanism of RAB5A-mediated macrophage polarization in an exosomal miR-21-dependent manner and provide an experimental basis for the development of RAB5A- or exosome-based tumor therapeutic strategies.

IL-6-Driven Autocrine Lactate Promotes Immune Escape of Uveal Melanoma.

Purpose: Early metastasis, in which immune escape plays a crucial role, is the leading cause of death in patients with uveal melanoma (UM); however, the molecular mechanism underlying UM immune escape remains unclear, which greatly limits the clinical application of immunotherapy for metastatic UM. Methods: Transcriptome profiles were revealed by RNA-seq analysis. TALL-104 and NK-92MI-mediated cell killing assays were used to examine the immune resistance of UM cells. The glycolysis rate was measured by extracellular acidification analysis. Protein stability was evaluated by CHX-chase assay. Immunofluorescence histochemistry was performed to detect protein levels in clinical UM specimens. Results: Continuous exposure to IL-6 induced the expression of both PD-L1 and HLA-E in UM cells, which promoted UM immune escape. Transcriptome analysis revealed that the expression of most metabolic enzymes in the glycolysis pathway, especially the rate-limiting enzymes, PFKP and PKM, was upregulated, whereas enzymes involved in the acetyl-CoA synthesis pathway were downregulated after exposure to IL-6. Blocking the glycolytic pathway and lactate production by knocking down PKM and LDHA decreased PD-L1 and HLA-E protein, but not mRNA, levels in UM cells treated with IL-6. Notably, lactate secreted by IL-6-treated UM cells was crucial in influencing PD-L1 and HLA-E stability via the GPR81-cAMP-PKA signaling pathway. Conclusions: Our data reveal a novel mechanism by which UM cells acquire an immune-escape phenotype by metabolic reprogramming and reinforce the importance of the link between inflammation and immune escape.

An activatable fluorescent-photoacoustic dual-modal probe for highly sensitive imaging of nitroxyl in vivo.

Nitroxyl (HNO) plays a vital role in various biological functions and pharmacological activities, so the development of an excellent near-infrared fluorescent (NIRF) and photoacoustic (PA) dual-modality probe is crucial for understanding HNO-related physiological and pathological progression. Herein, we proposed and synthesized a novel NIRF/PA dual probe (QL-HNO) by substituting an indole with quinolinium in hemicyanine for the sensitive detection of exogenous and endogenous HNO in vivo. The designed probe showed the highest sensitivity in NIRF mode and a desirable PA signal-to-noise ratio for HNO detection in vitro and was further applied for NIRF/PA dual-modal imaging of HNO with high contrast in living cells and tumor-bearing animals. Based on the excellent performance of QL-HNO, we believe that this study provides a promising molecular tool for further understanding of HNO-related physiological and pathological progression.

Characterization of OsPIN2 Mutants Reveal Novel Roles for Reactive Oxygen Species in Modulating Not Only Root Gravitropism but Also Hypoxia Tolerance in Rice Seedlings.

Tolerance to submergence-induced hypoxia is an important agronomic trait especially for crops in lowland and flooding-affected areas. Although rice (Oryza sativa) is considered a flood-tolerant crop, only limited cultivars display strong tolerance to prolonged submergence and/or hypoxic stress. Therefore, characterization of hypoxic resistant genes and/or germplasms have important theoretical and practical significance for rice breeding and sustained improvements. Previous investigations have demonstrated that loss-of-function of OsPIN2, a gene encoding an auxin efflux transporter, results in the loss of root gravitropism due to disrupted auxin transport in the root tip. In this study, we revealed a novel connection between OsPIN2 and reactive oxygen species (ROS) in modulating root gravitropism and hypoxia tolerance in rice. It is shown that the OsPIN2 mutant had decreased accumulation of ROS in root tip, due to the downregulation of glycolate oxidase encoding gene OsGOX6, one of the main H2O2 sources. The morphological defects of root including waved rooting and agravitropism in OsPIN2 mutant may be rescued partly by exogenous application of H2O2. The OsPIN2 mutant exhibited increased resistance to ROS toxicity in roots due to treatment with H2O2. Furthermore, it is shown that the OsPIN2 mutant had increased tolerance to hypoxic stress accompanied by lower ROS accumulation in roots, because the hypoxia stress led to over production of ROS in the roots of the wild type but not in that of OsPIN2 mutant. Accordingly, the anoxic resistance-related gene SUB1B showed differential expression in the root of the WT and OsPIN2 mutant in response to hypoxic conditions. Notably, compared with the wild type, the OsPIN2 mutant displayed a different pattern of auxin distribution in the root under hypoxia stress. It was shown that hypoxia stress caused a significant increase in auxin distribution in the root tip of the WT but not in that of the war1 mutant. In summary, these results suggested that OsPIN2 may play a role in regulating ROS accumulation probably via mediating auxin transport and distribution in the root tip, affecting root gravitropism and hypoxic tolerance in rice seedlings. These findings may contribute to the genetic improvement and identification of potential hypoxic tolerant lines in rice.