Galectin-7 Induction by EHMT2 Inhibition Enhances Immunity in Microsatellite Stability Colorectal Cancer.

BACKGROUND & AIMS: Although immunotherapy shows substantial advancement in colorectal cancer (CRC) with microsatellite instability high, it has limited efficacy for CRC with microsatellite stability (MSS). Identifying combinations that reverse immune suppression and prime MSS tumors for current immunotherapy approaches remains an urgent need. METHODS: An in vitro CRISPR screen was performed using coculture models of primary tumor cells and autologous immune cells from MSS CRC patients to identify epigenetic targets that could enhance immunotherapy efficacy in MSS tumors. RESULTS: We revealed EHMT2, a histone methyltransferase, as a potential target for MSS CRC. EHMT2 inhibition transformed the immunosuppressive microenvironment of MSS tumors into an immunomodulatory one by altering cytokine expression, leading to T-cell-mediated cytotoxicity activation and improved responsiveness to anti-PD1 treatment. We observed galectin-7 up-regulation upon EHMT2 inhibition, which converted a "cold" MSS tumor environment into a T-cell-inflamed one. Mechanistically, CHD4 repressed galectin-7 expression by recruiting EHMT2 to form a cotranscriptional silencing complex. Galectin-7 administration enhanced anti-PD1 efficacy in MSS CRC, serving as a potent adjunct cytokine therapy. CONCLUSIONS: Our findings suggest that targeting the EHMT2/galectin-7 axis could provide a novel combination strategy for immunotherapy in MSS CRC.

The impact of crowd gatherings on the spread of COVID-19.

Crowd gatherings are an important cause of COVID-19 outbreaks. However, how the scale, scene and other factors of gatherings affect the spread of the epidemic remains unclear. A total of 184 gathering events worldwide were collected to construct a database, and 99 of them with a clear gathering scale were used for statistical analysis of the impact of these factors on the disease incidence among the crowd in the study. The results showed that the impact of small-scale (less than 100 people) gathering events on the spread of COVID-19 in the city is also not to be underestimated due to their characteristics of more frequent occurrence and less detection and control. In our dataset, 22.22% of small-scale events have an incidence of more than 0.8. In contrast, the incidence of most large-scale events is less than 0.4. Gathering scenes such as "Meal" and "Family" occur in densely populated private or small public places have the highest incidence. We further designed a model of epidemic transmission triggered by crowd gathering events and simulated the impact of crowd gathering events on the overall epidemic situation in the city. The simulation results showed that the number of patients will be drastically reduced if the scale and the density of crowds gathering are halved. It indicated that crowd gatherings should be strictly controlled on a small scale. In addition, it showed that the model well reproduce the epidemic spread after crowd gathering events better than does the original SIER model and could be applied to epidemic prediction after sudden gathering events.

Comparison of PM2.5 and CO2 Concentrations in Large Cities of China during the COVID-19 Lockdown.

Estimating the impacts on PM2.5 pollution and CO2 emissions by human activities in different urban regions is important for developing efficient policies. In early 2020, China implemented a lockdown policy to contain the spread of COVID-19, resulting in a significant reduction of human activities. This event presents a convenient opportunity to study the impact of human activities in the transportation and industrial sectors on air pollution. Here, we investigate the variations in air quality attributed to the COVID-19 lockdown policy in the megacities of China by combining in-situ environmental and meteorological datasets, the Suomi-NPP/VIIRS and the CO2 emissions from the Carbon Monitor project. Our study shows that PM2.5 concentrations in the spring of 2020 decreased by 41.87% in the Yangtze River Delta (YRD) and 43.30% in the Pearl River Delta (PRD), respectively, owing to the significant shutdown of traffic and manufacturing industries. However, PM2.5 concentrations in the Beijing-Tianjin-Hebei (BTH) region only decreased by 2.01% because the energy and steel industries were not fully paused. In addition, unfavorable weather conditions contributed to further increases in the PM2.5 concentration. Furthermore, CO2 concentrations were not significantly affected in China during the short-term emission reduction, despite a 19.52% reduction in CO2 emissions compared to the same period in 2019. Our results suggest that concerted efforts from different emission sectors and effective long-term emission reduction strategies are necessary to control air pollution and CO2 emissions.

RNA-binding protein RALY reprogrammes mitochondrial metabolism via mediating miRNA processing in colorectal cancer.

OBJECTIVE: Dysregulated cellular metabolism is a distinct hallmark of human colorectal cancer (CRC). However, metabolic programme rewiring during tumour progression has yet to be fully understood. DESIGN: We analysed altered gene signatures during colorectal tumour progression, and used a complex of molecular and metabolic assays to study the regulation of metabolism in CRC cell lines, human patient-derived xenograft mouse models and tumour organoid models. RESULTS: We identified a novel RNA-binding protein, RALY (also known as hnRNPCL2), that is highly associated with colorectal tumour aggressiveness. RALY acts as a key regulatory component in the Drosha complex, and promotes the post-transcriptional processing of a specific subset of miRNAs (miR-483, miR-676 and miR-877). These miRNAs systematically downregulate the expression of the metabolism-associated genes (ATP5I, ATP5G1, ATP5G3 and CYC1) and thereby reprogramme mitochondrial metabolism in the cancer cell. Analysis of The Cancer Genome Atlas (TCGA) reveals that increased levels of RALY are associated with poor prognosis in the patients with CRC expressing low levels of mitochondrion-associated genes. Mechanistically, induced processing of these miRNAs is facilitated by their N6-methyladenosine switch under reactive oxygen species (ROS) stress. Inhibition of the m6A methylation abolishes the RALY recognition of the terminal loop of the pri-miRNAs. Knockdown of RALY inhibits colorectal tumour growth and progression in vivo and in organoid models. CONCLUSIONS: Collectively, our results reveal a critical metabolism-centric role of RALY in tumour progression, which may lead to cancer therapeutics targeting RALY for treating CRC.

Environmental Indicator for COVID-19 Non-Pharmaceutical Interventions.

A novel coronavirus (COVID-19) has caused viral pneumonia worldwide, posing a major threat to international health. Our study reports that city lockdown is an effective way to reduce the number of new cases and the nitrogen dioxide (NO2) concentration can be used as an environmental lockdown indicator to evaluate the effectiveness of lockdown measures. The airborne NO2 concentration steeply decreased over the vast majority of COVID-19-hit areas since the lockdown. The total number of newly confirmed cases reached an inflection point about two weeks since the lockdown and could be reduced by about 50% within 30 days of the lockdown. The stricter lockdown will help newly confirmed cases to decline earlier and more rapidly, and at the same time, the reduction rate of NO2 concentration will increase. Our research results show that NO2 satellite observations can help decision makers effectively monitor and manage non-pharmaceutical interventions in the epidemic.

Development of the second version of Global Prediction System for Epidemiological Pandemic.

Coronavirus disease 2019 (COVID-19) is a severe global public health emergency that has caused a major crisis in the safety of human life, health, global economy, and social order. Moreover, COVID-19 poses significant challenges to healthcare systems worldwide. The prediction and early warning of infectious diseases on a global scale are the premise and basis for countries to jointly fight epidemics. However, because of the complexity of epidemics, predicting infectious diseases on a global scale faces significant challenges. In this study, we developed the second version of Global Prediction System for Epidemiological Pandemic (GPEP-2), which combines statistical methods with a modified epidemiological model. The GPEP-2 introduces various parameterization schemes for both impacts of natural factors (seasonal variations in weather and environmental impacts) and human social behaviors (government control and isolation, personnel gathered, indoor propagation, virus mutation, and vaccination). The GPEP-2 successfully predicted the COVID-19 pandemic in over 180 countries with an average accuracy rate of 82.7%. It also provided prediction and decision-making bases for several regional-scale COVID-19 pandemic outbreaks in China, with an average accuracy rate of 89.3%. Results showed that both anthropogenic and natural factors can affect virus spread and control measures in the early stages of an epidemic can effectively control the spread. The predicted results could serve as a reference for public health planning and policymaking.

Biological informed graph neural network for tumor mutation burden prediction and immunotherapy-related pathway analysis in gastric cancer.

Tumor mutation burden (TMB) has emerged as an essential biomarker for assessing the efficacy of cancer immunotherapy. However, due to the inherent complexity of tumors, TMB is not always correlated with the responsiveness of immune checkpoint inhibitors (ICIs). Thus, refining the interpretation and contextualization of TMB is a requisite for enhancing clinical outcomes. In this study, we conducted a comprehensive investigation of the relationship between TMB and multi-omics data across 33 human cancer types. Our analysis revealed distinct biological changes associated with varying TMB statuses in STAD, COAD, and UCEC. While multi-omics data offer an opportunity to dissect the intricacies of tumors, extracting meaningful biological insights from such massive information remains a formidable challenge. To address this, we developed and implemented the PGLCN, a biologically informed graph neural network based on pathway interaction information. This model facilitates the stratification of patients into subgroups with distinct TMB statuses and enables the evaluation of driver biological processes through enhanced interpretability. By integrating multi-omics data for TMB prediction, our PGLCN model outperformed previous traditional machine learning methodologies, demonstrating superior TMB status prediction accuracy (STAD AUC: 0.976 ± 0.007; COAD AUC: 0.994 ± 0.007; UCEC AUC: 0.947 ± 0.023) and enhanced interpretability (BA-House: 1.0; BA-Community: 0.999; BA-Grid: 0.994; Tree-Cycles: 0.917; Tree-Grids: 0.867). Furthermore, the biological interpretability inherent to PGLCN identified the Toll-like receptor family and DNA repair pathways as potential combined biomarkers in conjunction with TMB status in gastric cancer. This finding suggests a potential synergistic targeting strategy with immunotherapy for gastric cancer, thus advancing the field of precision oncology.

Paper-supported near-infrared-light-triggered photoelectrochemical platform for monitoring Escherichia coli O157:H7 based on silver nanoparticles-sensitized-upconversion nanophosphors.

Escherichia coli O157:H7 (E. coli O157:H7) is a typical foodborne pathogen that contaminates food and water, leading to lots of infectious diseases. In this study, a near-infrared-responsive photoelectrochemical (PEC) sensing platform for the ultrasensitive detection of E. coli O157:H7 was established by assembling a flexible conductive paper electrode with core-shell-structured upconversion nanophosphors (UCNPs) @SiO2@Ag and carbon self-doped graphitic carbon nitride (C-g-C3N4). In this design, UCNPs act as a self-powered that change near infrared (NIR) excitation into visible emission, while the semiconductor material C-g-C3N4 acts as the energy-conversion center to convert visible illumination to photocurrent. Importantly, silver nanoparticles (AgNPs) significantly enhance the upconversion luminescence of UCNPs and facilitate the separation and transportation of photoelectrons by the localized surface plasmon resonance effect. Using the antimicrobial peptide Magainin I as the recognition element, E. coli O157:H7 was specifically captured and determined directly for its steric hindrance effect on the photoelectrode. As a result, the photocurrent decreased linearly with the increase in E. coli O157:H7 in a wide range from 5 to 5 × 106 colony-forming units per mL (CFU/mL), and the detection limit was as low as 2 CFU/mL. Finally, the proposed NIR PEC sensor was successfully utilized for the determination of E. coli O157:H7 in contaminated pork, cabbage, and milk samples without enrichment of the bacteria in 50 min.

A cognitive evaluation and equity-based perspective of pay for performance on job performance: A meta-analysis and path model.

Pay for performance, as one of the most important means of motivating employees, has attracted the attention of many scholars and managers. However, controversy has continued regarding whether it promotes or undermines job performance. Drawing on a meta-analysis of 108 independent samples (N = 71,438) from 100 articles, we found that pay for performance was positively related to job performance. That pay for performance had a more substantial positive effect on task performance than contextual performance in workplace settings. From the cognitive evaluation perspective, we found that pay for performance enhanced employees' task performance and contextual performance by enhancing intrinsic motivation and weakened task performance and contextual performance by increasing employee pressure. From the equity perspective, our results indicated that the relationship between pay for performance and task performance was partially mediated by employee perceptions of distributive justice and procedural justice, with distributive justice having a more substantial mediating effect than procedural justice. However, the relationship between pay for performance and contextual performance was only partially mediated by procedural justice. Further tests of moderating effects indicated that the varying impacts of pay for performance are contingent on measures of pay for performance and national culture. The findings contributed to understanding the complex mechanisms and boundary conditions of pay-for-performance's effects on job performance, which provided insights for organizations to maximize its positive effects.

Water Transmission Increases the Intensity of COVID-19 Outbreaks.

India suffered from a devastating 2021 spring outbreak of coronavirus disease 2019 (COVID-19), surpassing any other outbreaks before. However, the reason for the acceleration of the outbreak in India is still unknown. We describe the statistical characteristics of infected patients from the first case in India to June 2021, and trace the causes of the two outbreaks in a complete way, combined with data on natural disasters, environmental pollution and population movements etc. We found that water-to-human transmission accelerates COVID-19 spreading. The transmission rate is 382% higher than the human-to-human transmission rate during the 2020 summer outbreak in India. When syndrome coronavirus 2 (SARS-CoV-2) enters the human body directly through the water-oral transmission pathway, virus particles and nitrogen salt in the water accelerate viral infection and mutation rates in the gastrointestinal tract. Based on the results of the attribution analysis, without the current effective interventions, India could have experienced a third outbreak during the monsoon season this year, which would have increased the severity of the disaster and led to a South Asian economic crisis.

The oscillation-outbreaks characteristic of the COVID-19 pandemic.

The evolution of the COVID-19 pandemic features the alternation of oscillations and abrupt rises. The oscillations are attributable to weekly and seasonal modulations, while abrupt rises are stimulated by mass gatherings.

Characteristics of Metabolites by Seed-Specific Inhibition of FAD2 in Brassica napus L.

Fatty acid desaturase-2 (FAD2) is a key enzyme in the production of polyunsaturated fatty acids in plants. RNAi technology can reduce the expression of FAD2 genes in Brassica napus seeds and acquire transgenic B. napus plants with a high oleic acid content, but the effect of seed-specific inhibition of FAD2 expression on B. napus seed metabolites is not clear. Here we use widely targeted metabolomics to investigate the metabolites of normal-oleic-acid rapeseed (OA) and high-oleic-acid rapeseed (HOA) seeds, resulting in a total of 726 metabolites being detected. Among them, 24 differential metabolites were significantly downregulated and 88 differential metabolites were significantly upregulated in HOA rapeseed. In further lipid profile experiments, more lipids in B. napus seeds were accurately quantified. The contents of glycolipids and phospholipids that contain C18:1 increased significantly and C18:2 decreased because FAD2 expression was inhibited. The changes in the expression of key genes in related pathways were also consistent with the changes in metabolites. The insertion site of the ihpRNA plant expression vector was reconfirmed through genomewide resequencing, and the transgenic event did not change the sequence of FAD2 genes. There was no significant difference in the germination rate and germination potential between OA and HOA rapeseed seeds because the seed-specific ihpRNA plant expression vector did not affect other stages of plant growth. This work provides a theoretical and practical guidance for subsequent molecular breeding of high OA B. napus.

Identification of reliable reference genes for quantitative real-time PCR analysis of the Rhus chinensis Mill. leaf response to temperature changes.

Rhus chinensis Mill. (RCM) is the host plant of Galla chinensis, which is valued in traditional medicine. Environmental temperature directly determines the probability of gallnut formation and RCM growth. At present, there is no experiment to systematically analyse the stability of internal reference gene (RG) expression in RCM. In this experiment, leaves that did not form gallnuts were used as the control group, while leaves that formed gallnuts were used as the experimental group. First, we conducted transcriptome experiments on RCM leaves to obtain 45 103 differential genes and functional enrichment annotations between the two groups. On this basis, this experiment established a transcriptional gene change model of leaves in the process of gallnut formation after being bitten by aphids, and RCM reference candidate genes were screened from RNA sequencing (RNA-seq) data. This study is based on RCM transcriptome data and evaluates the stability of 11 potential reference genes under cold stress (4 °C) and heat stress (34 °C), using three statistical algorithms (geNorm, NormFinder, and BestKeeper). The results show that GAPDH1 + PP2A2/UBQ are stable reference genes under heat stress, while GAPDH1 + ACT are the most stable under cold stress. This study is the first to screen candidate reference genes in RCM and could help guide future molecular studies in this genus.

Impact of city lockdown on the air quality of COVID-19-hit of Wuhan city.

A series of strict lockdown measures were implemented in the areas of China worst affected by coronavirus disease 19, including Wuhan, to prevent the disease spreading. The lockdown had a substantial environmental impact, because traffic pollution and industrial emissions are important factors affecting air quality and public health in the region. After the lockdown, the average monthly air quality index (AQI) in Wuhan was 59.7, which is 33.9% lower than that before the lockdown (January 23, 2020) and 47.5% lower than that during the corresponding period (113.6) from 2015 to 2019. Compared with the conditions before the lockdown, fine particulate matter (PM2.5) decreased by 36.9% and remained the main pollutant. Nitrogen dioxide (NO2) showed the largest decrease of approximately 53.3%, and ozone (O3) increased by 116.6%. The proportions of fixed-source emissions and transported external-source emissions in this area increased. After the lockdown, O3 pollution was highly negatively correlated with the NO2 concentration, and the radiation increase caused by the PM2.5 reduction was not the main reason for the increase in O3. This indicates that the generation of secondary pollutants is influenced by multiple factors and is not only governed by emission reduction.

Mindfulness, Life Skills, Resilience, and Emotional and Behavioral Problems for Gifted Low-Income Adolescents in China.

In contrast to emotional and behavioral problems (EBPs), which can disrupt normal adolescent development, resilience can buffer the effects of stress and adverse childhood experiences and can help youth overcome adversity. While research has looked at the relationship between adolescent resilience and EBPs, current literature relatively lack a discussion of a strengths-based approach of resilience framework, nor discuss non-western sociocultural contexts. In this study, we utilized the resilience theory to examine the effects of individual mindfulness and life skills on resilience and consequently on EBPs in a group of low-income and gifted adolescents in China. A secondary data of 152 adolescents from a specialized school for low-income and gifted students in Guangzhou, China was used for the analysis. The findings from structural equation modeling indicated that mindfulness and life skills were associated with heightened resilience and reduced EBPs. In addition, resilience reduced EBPs for this group of adolescents. These findings underscore the promise of mindfulness and life skills training on increasing resilience and reducing EBPs in gifted adolescents.

A versatile UCST-type composite microsphere for image-guided chemoembolization and photothermal therapy against liver cancer.

The development of novel chemoembolization agents to improve the treatment efficacy of transarterial chemoembolization (TACE) against liver cancer remains an urgent need in clinical practice. Herein, a versatile composite microsphere with upper critical solution temperature (UCST) properties was prepared to encapsulate polydopamine coated superparamagnetic iron oxide nanoparticles (SPION@PDA) and doxorubicin for simultaneous chemoembolization and photothermal therapy. The microspheres were spherical with an average diameter of 100-300 µm and exhibited favorable drug loading capability as well as strong photothermal effect. Strikingly, synergistic enhancement of photothermal therapy and chemotherapy against chemoresistant liver cancer cells was achieved. The in vivo therapeutic efficacy and safety evaluations were performed using rabbit VX2 liver tumor models. It was revealed that a single treatment of the combination of TACE and photothermal procedure resulted in 87.5% complete response and 12.5% partial response for the microsphere group, whereas all tumors in the control group progressed rapidly. Contrast-enhanced computed tomography (CT) evaluation indicated that the tumor diameter decreased by 91.5% after treatment, while that in the control group increased by 86.5%. The pathology-proven tumor necrotic rate was 87.2%, which significantly surpassed that of 65.2% in the control group. Furthermore, serum liver enzyme and biochemical studies indicated a temporary liver injury which can be fully recovered. Our findings demonstrated that this microsphere may be advantageous for enhancing therapeutic efficacy of TACE against liver cancer.

Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance.

Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS, NRAS, and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA, PTEN, TP53, MET, HER3, IRS2, FGFR1, and MAP2K1, the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.

Fatty Acid Oxidation Controls CD8+ Tissue-Resident Memory T-cell Survival in Gastric Adenocarcinoma.

The success of checkpoint inhibitors in cancer treatment is associated with the infiltration of tissue-resident memory T (Trm) cells. In this study, we found that about 30% of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment of gastric adenocarcinoma were CD69+CD103+ Trm cells. Trm cells were low in patients with metastasis, and the presence of Trm cells was associated with better prognosis in patients with gastric adenocarcinoma. Trm cells expressed high PD-1, TIGIT, and CD39 and represented tumor-reactive TILs. Instead of utilizing glucose, Trm cells relied on fatty acid oxidation for cell survival. Deprivation of fatty acid resulted in Trm cell death. In a tumor cell-T-cell coculture system, gastric adenocarcinoma cells outcompeted Trm cells for lipid uptake and induced Trm cell death. Targeting PD-L1 decreased fatty acid binding protein (Fabp) 4 and Fabp5 expression in tumor cells of gastric adenocarcinoma. In contrast, the blockade of PD-L1 increased Fabp4/5 expression in Trm cells, promoting lipid uptake by Trm cells and resulting in better survival of Trm cells in vitro and in vivo. PD-L1 blockade unleashed Trm cells specifically in the patient-derived xenograft (PDX) mice. PDX mice that did not respond to PD-L1 blockade had less Trm cells than responders. Together, these data demonstrated that Trm cells represent a subset of TILs in the antitumor immune response and that metabolic reprogramming could be a promising way to prolong the longevity of Trm cells and enhance antitumor immunity in gastric adenocarcinoma.

A polyethylenimine-based diazeniumdiolate nitric oxide donor accelerates wound healing.

Nitric oxide (NO) plays a pivotal role in the cutaneous healing process and a topical supplement of NO is beneficial for wound repair. In this work, a novel polyethylenimine (PEI) based diazeniumdiolate nitric oxide donor was prepared. The obtained polymer (PEI-PO-NONOate) was characterized by Fourier transform infrared (FTIR) spectroscopy, UV-vis absorption spectra, and nuclear magnetic resonance (NMR). The PEI-PO-NONOate polymer was stable under anhydrous conditions at different temperatures. A total of 0.57 µmol gaseous NO was released from 1.0 mg of the PEI-PO-NONOate polymer in PBS of pH 7.4 and it presented a proton-driven release pattern. Furthermore, the PEI-PO-NONOate polymer exhibited a controlled release profile sustained for over 30 hours within the polyethylene glycol (PEG) mixture system. Cytotoxicity evaluation was performed on L929 cells. Full-thickness excisional cutaneous wound models of mice were prepared and the PEI-PO-NONOate polymer was applied to investigate its effects on wound healing. The results revealed that the PEI-PO-NONOates exhibited good biocompatibility. It was also found that the PEI-PO-NONOate polymer promoted cutaneous wound healing and closure with enhanced granulation tissue formation, collagen deposition, and angiogenesis, as compared to the control. In summary, a novel nitric oxide releasing polymer with high loading efficiency and a controlled release profile was developed which presented the potential for application in the acceleration of cutaneous wound healing.