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Arabidopsis RESISTANCE TO POWDERY MILDEW 8.2 (RPW8.2) is specifically induced by the powdery mildew (PM) fungus (Golovinomyces cichoracearum) in the infected epidermal cells to activate immunity. However, the mechanism of RPW8.2-induction is not well understood. Here, we identify a G. cichoracearum effector that interacts with RPW8.2, named Gc-RPW8.2 interacting protein 1 (GcR8IP1), by a yeast two-hybrid screen of an Arabidopsis cDNA library. GcR8IP1 physically associated with RPW8.2 with its RING finger domain that is essential and sufficient for the association. GcR8IP1 was secreted and translocated into the nucleus of host cell infected with PM. Association of GcR8IP1 with RPW8.2 led to an increase of RPW8.2 in the nucleus. In turn, the nucleus-localised RPW8.2 promoted the activity of the RPW8.2 promoter, resulting in transcriptional self-amplification of RPW8.2 to boost immunity at infection sites. Additionally, ectopic expression or host-induced gene silencing of GcR8IP1 supported its role as a virulence factor in PM. Altogether, our results reveal a mechanism of RPW8.2-dependent defense strengthening via altered partitioning of RPW8.2 and transcriptional self-amplification triggered by a PM fungal effector, which exemplifies an atypical form of effector-triggered immunity.

Background Lipid metabolic reprogramming in colon cancer shows a potential impact on tumor immune microenvironment and is associated with response to immunotherapy. Therefore, this study aimed to develop a lipid metabolism-related prognostic risk score (LMrisk) to provide new biomarkers and combination therapy strategies for colon cancer immunotherapy. Methods Differentially expressed lipid metabolism-related genes (LMGs) including cytochrome P450 (CYP) 19A1 were screened to construct LMrisk in TCGA colon cancer cohort. The LMrisk was then validated in three GEO datasets. The differences of immune cell infiltration and immunotherapy response between LMrisk subgroups were investigated via bioinformatic analysis. These results were comfirmed by in vitro coculture of colon cancer cells with peripheral blood mononuclear cells, human colon cancer tissue microarray analysis, multiplex immunofluorescence staining and mouse xenograft models of colon cancer. Results Six LMGs including CYP19A1, ALOXE3, FABP4, LRP2, SLCO1A2 and PPARGC1A were selected to establish the LMrisk. The LMrisk was positively correlated with the abundance of macrophages, carcinoma-associated fibroblasts (CAFs), endothelial cells and the levels of biomarkers for immunotherapeutic response including programmed cell death ligand 1 (PD-L1) expression, tumor mutation burden and microsatellite instability, but negatively correlated with CD8+ T cell infiltration levels. CYP19A1 protein expression was an independent prognostic factor, and positively correlated with PD-L1 expression in human colon cancer tissues. Multiplex immunofluorescence analyses revealed that CYP19A1 protein expression was negatively correlated with CD8+ T cell infiltration, but positively correlated with the levels of tumor-associated macrophages, CAFs and endothelial cells. Importantly, CYP19A1 inhibition downregulated PD-L1, IL-6 and TGF-β levels through GPR30-AKT signaling, thereby enhancing CD8+ T cell-mediated antitumor immune response in vitro co-culture studies. CYP19A1 inhibition by letrozole or siRNA strengthened the anti-tumor immune response of CD8+ T cells, induced normalization of tumor blood vessels, and enhanced the efficacy of anti-PD-1 therapy in orthotopic and subcutaneous mouse colon cancer models. Conclusion A risk model based on lipid metabolism-related genes may predict prognosis and immunotherapeutic response in colon cancer. CYP19A1-catalyzed estrogen biosynthesis promotes vascular abnormality and inhibits CD8+ T cell function through the upregulation of PD-L1, IL-6 and TGF-β via GPR30-AKT signaling. CYP19A1 inhibition combined with PD-1 blockade represents a promising therapeutic strategy for colon cancer immunotherapy.

Fatty acid synthesis facilitates tumor cell immune escape and immunotherapy resistance. Cytochrome P450 (CYP) 4A and 4F, the major ω-hydroxylases that convert arachidonic acid (AA) into 20-hydroxyeicosatetraenoic acid (20-HETE), are implicated in inflammation and cancer. However, the role of CYP4 ω-hydroxylases in immune evasion remains unclear. Here, we determined that 20-HETE derived from the CYP4F2 isoenzyme governs immune evasion in non–small cell lung cancer (NSCLC) in a CD8+ T-cell-dependent manner. Mechanistically, CYP4F2 induced expression of immune checkpoint PD-L1 and production of proangiogenic factors IL6 and TGFβ in cancer-associated fibroblasts (CAF) via the 20-HETE-GPR75-STAT3-c-Jun axis. Tumors with high CYP4F2 expression were more resistant to anti-PD-1 treatment, whereas inhibition of CYP4F2 enhanced the efficacy of anti-PD-1 therapy in human NSCLC organoids and mouse models. Collectively, these data delineate that CYP4F2-dependent AA metabolism controls CAF-mediated immune evasion. CYP4F2 inhibition combined with PD-1 antibody represents a promising therapeutic approach for immunotherapy-resistant lung cancer.Significance:The identification of a role for CYP4F2-dependent metabolism in driving immune evasion in non–small cell lung cancer reveals a strategy to improve the efficacy of immunotherapy by inhibiting CYP4F2.See related article by Van Ginderachter, p. 3882

Supplementary Data from CYP4F2-Catalyzed Metabolism of Arachidonic Acid Promotes Stromal Cell-Mediated Immunosuppression in Non–Small Cell Lung Cancer

The yield loss of crops per year in the world is 11%–30% due to crop diseases and pests. A large number of chemical pesticides are used to control the spread of infectious crop diseases and pests every year, which not only pollutes the environment, but also seriously threatens food safety and human health. Therefore, the most economical and effective measure to control crop diseases and insects is to develop the resistant varieties by the utilization of resistance genes ( R ), and it is also the preferable way for sustainable development of future agriculture in China. In recent years, much progress has been made in molecular mechanism of plant innate immunity and isolation of many immune receptors including PRRs and NLRs from crops, molecular mechanism of interactions between insects and crops, and identification and cloning of crop insect resistance genes. We review the recent important breakthroughs in plant immunity and broad-spectrum resistance genes isolated in crops, and trade-off between resistance and other agronomic traits. We point out the bottlenecks in crop breeding for disease and insect resistance, and also propose new insights for plant disease and insect resistance research in China in the future.

To develop a conceptual framework that explores the process of building family resilience among Chinese families with children diagnosed with leukaemia.The diagnosis of childhood leukaemia has a devastating effect on the family. Nonetheless, some families were able to positively respond to the crisis. The process through which Chinese families bounce back has received little attention.Grounded theory.This study used purposive and theoretical sampling to select 16 parents who agreed to participate in semistructured interviews after children were diagnosed with leukaemia. Data collection and analysis occurred simultaneously. Data were analysed through a process of open, axial and selective coding. The COREQ checklist was followed for reporting.A core category of 'finding family resilience in adversity' was generated. The core category was underpinned by a transition process between two fluid stages: (a) Disrupting the family system, informed by subcategories of negative emotional disturbances and challenges of the diagnosis and treatment journey; (b) Cultivating resilience in families, informed by subcategories of increasing positive attitudes; establishing new family routines; activating good support systems; and practising open family communication.The transition process from the disruption of the family system to the cultivation of family resilience is perceived as a complex family dynamic in response to childhood leukaemia. Our findings can form the basis for further research about resilience-based family interventions that promote family well-being during the early stages of a childhood leukaemia diagnosis.It is necessary for healthcare professionals to provide essential support for families to face the challenges of diagnosis and treatment to facilitate the successful transition to family resilience. By understanding the dynamic process of developing family resilience, healthcare professionals are able to focus on these families to provide holistic care that satisfies the specific demands of family members.

ATP-binding cassette (ABC) transporters regulate the efflux of a broad spectrum of substrates to extracellular transporting, which play an important role in the detoxification process in arthropods. Here, we described a comprehensive approach to explore the involvement of ABC transporters in spirotetramat resistance in cotton aphids. In this study, synergism bioassays showed 17.05% and 35.42% increases in the toxicity to spirotetramat with the ABC inhibitor verapamil in adult and 3rd instar nymph aphids of the SR strain, respectively. In a competitive assay based on the microinjection of a fluorescent ABC transporter substrate, verapamil (a general ABC inhibitor) and spirotetramat significantly inhibited the elimination of Texas Red. Based on transcriptome data of midguts of spirotetramat-susceptible (SS) and -resistant (SR) strains, the expression levels of

Field populations of

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and progressive joint destruction in the middle and late stages. Notably, activated rheumatoid arthritis synovial fibroblasts (RASFs) exhibit tumor-like features, including an increased proliferation rate that largely contributes to pannus formation and joint destruction. Our previous studies have demonstrated that acid-sensing ion channel 1a (ASIC1a) was highly expressed in RASFs, and acidic microenvironment of synovial fluid in patients with RA can activate ASIC1a to promote synovial inflammation, leading to the progression of RA. However, the role and possible mechanism of ASIC1a in RASF proliferation remains unclear. The present study aimed to investigate the effect of ASIC1a activation upon acidosis on RASF proliferation and its molecular mechanism in vivo and in vitro. The results of in vitro experiments showed that activation of ASIC1a upon acidosis promoted the proliferation of RASFs, which could be attenuated by the specific ASIC1a inhibitor Psalmotoxin-1 (PcTx-1) or specific siRNA for ASIC1a. Mechanistically, Wnt/β-catenin/c-Myc signaling pathway was involved in ASIC1a-induced RASF proliferation. The results of in vivo experiments indicated that intra-articular injection of PcTx-1 reduced synovial hyperplasia and ameliorated cartilage degradation in rats with adjuvant arthritis (AA). Collectively, these results suggest that activation of ASIC1a upon acidosis promotes RASF proliferation, and the mechanism may be related to Wnt/β-catenin/c-Myc pathway.

Post-harvest processing efficiency and in-field disease resistance are two major traits for crop improvement. Higher grain-processing efficiency saves energy while stronger disease resistance reduces pesticide usage contributing to human health and environmental safety. However, simultaneous improvement on these two traits is exceptionally difficult due to the lack of suitable germplasm/gene resources and technologies. To address this problem in rice, we screened a rice mutant population and identified a rice mutant, improved brown rice processing efficiency 1 (ipe1), which has OsCesA7 mutated leading to improved brown rice processing efficiency. However, ipe1 shows reduced disease resistance. To restore disease resistance in ipe1 but keep its improved grain processing efficiency, we identified a rice intrinsic histone deacetylase 705 (HDA705) gene promoter, which has a similar expression pattern as the OsCesA7 promoter except with little expression in rice glumes, and expressed OsCesA7 with this promoter (proHDA705:OsCesA7). The proHDA705:OsCesA7 lines carry enhanced disease resistance and elevated brown rice processing efficiency with no compromises in other agronomic traits. This engineering strategy greatly saves energy used for brown rice processing and reduces pesticide usage, contributing not only to grain yield but also to human health, environmental safety, and energy saving.

Plant transcription factors (TFs) play important roles in diverse biological processes, including immunity. A recent study by Zhang et al. reported that the rice TF APIP5 regulates immunity through its roles on transcription and mRNA turnover, advancing our conceptual understanding that plant TF may not only function as a TF.

MicroRNA168 (miR168) is a key miRNA that targets Argonaute1 (AGO1), a major component of the RNA-induced silencing complex1,2. Previously, we reported that miR168 expression was responsive to infection by Magnaporthe oryzae, the causal agent of rice blast disease3. However, how miR168 regulates immunity to rice blast and whether it affects rice development remains unclear. Here, we report our discovery that the suppression of miR168 by a target mimic (MIM168) not only improves grain yield and shortens flowering time in rice but also enhances immunity to M. oryzae. These results were validated through repeated tests in rice fields in the absence and presence of rice blast pressure. We found that the miR168–AGO1 module regulates miR535 to improve yield by increasing panicle number, miR164 to reduce flowering time, and miR1320 and miR164 to enhance immunity. Our discovery demonstrates that changes in a single miRNA enhance the expression of multiple agronomically important traits. In rice, it is known that miR168 regulates AGO1. Using a target mimic approach to suppress the microRNA enhances resistance against rice blast disease, increases grain yield and shortens growth period, including in field trials.

Non-coding RNAs appear to be involved in the regulation of the nervous system. However, no competing endogenous RNA (ceRNA) network related to PM2.5 damage in the hippocampal function has yet been constructed. Herein, we used whole-transcriptome sequencing technology to systematically study the ceRNA network in rat hippocampi after PM2.5 exposure. We identified 100 circRNAs, 67 lncRNAs, 28 miRNAs, and 539 mRNAs and constructed the most comprehensive ceRNA network to date, to our knowledge. Gene Ontology and KEGG analyses showed that the network molecules are involved in synapses, neural projections, and neural development and involve signal pathways such as the synaptic vesicle cycle. Finally, the expression of the differentially expressed RNAs confirmed by quantitative real-time PCR was consistent with the sequencing data. This study systematically dissected the ceRNA atlas related to cognitive memory function in the hippocampal tissue of PM2.5-exposed rats for the first time, to our knowledge, and promotes the development of potential new treatments for cognitive impairment.

OBJECTIVE: Many people say they “don’t know” their risk for common diseases (DK responders). Inadequate health literacy and higher disease information avoidance may suppress risk knowledge and thereby increase DK responding. Study goals were to examine two plausible interventions to address the health education needs of DK responders. DESIGN: Participants were identified in a pre-screener as DK responders for either diabetes or colorectal cancer (CRC) risk perception questions (N=1276; 35% non-white; 49% inadequate health literacy). They were randomly assigned to read either standard or low literacy risk information about diabetes or CRC, and to undergo a self-affirmation intervention or not. MAIN OUTCOME MEASURE: DK responding following reading the risk information. RESULTS: Neither intervention reduced DK responding. Multivariable analyses showed that health literacy, information avoidance, and believing the disease is unpredictable – but not risk factor knowledge and need for cognition – best predicted participants’ conversion from a DK response to a non-DK scale point response. CONCLUSION: Results confirm that both inadequate health literacy and higher information avoidance are associated with DK responding. DK responders are also disproportionately underserved and less adherent to health behaviors. Because galvanizing risk perceptions are central to public health, addressing their information needs is a priority.

Trade-offs between plant growth and immunity are a well-known phenomenon in plants that are meant to ensure the best use of limited resources. Recently, many advances have been achieved on molecular regulations of the trade-offs between plant growth and immunity. Here, we provide an overview on molecular understanding of these trade-offs including those regulated at the transcriptional level or post-transcriptional level by transcriptional factors, microRNAs, and post-translational modifications of proteins, respectively The understanding on the molecular regulation of these trade-offs will provide new strategies to breed crops with high yield and enhanced resistance to disease.

bsr‐d1, an allele encoding a transcription factor identified from the rice cultivar Digu, confers durable, broad‐spectrum resistance to infections by strains of Magnaporthe oryzae. bsr‐d1 was predicted to inhibit M. oryzae‐induced expression of Bsr‐d1 RNA and degradation of hydrogen peroxide to achieve resistance to M. oryzae. However, the global effect of biological process and molecular function on blast resistance mediated by Bsr‐d1 remains unknown. In this study, we compared transcriptomic profiling between Bsr‐d1 knockout (Bsr‐d1KO) lines and the wild type, TP309. Our study revealed that bsr‐d1 mainly regulates the redox state of plant cells, but also affects amino acid and unsaturated fatty acid metabolism. We further found that BSR‐D1 indirectly regulates salicylic acid biosynthesis, metabolism, and signal transduction downstream of the activation of H2O2 signalling in the bsr‐d1‐mediated immune response. Furthermore, we identified a novel peroxidase‐encoding gene, Perox3, as a new BSR‐D1 target gene that reduces resistance to M. oryzae when overexpressed in TP309. These results provide new insights into the bsr‐d1‐mediated blast resistance., BSR‐D1 mainly regulates the redox state of plant cells by directly targeting another new gene, Perox3, but indirectly regulates salicylic acid biosynthesis and signal transduction after H2O2 signalling in the bsr‐d1‐mediated immune response.

It is well known that the interactions of insect herbivores and their host plant can be mediated by microbes. Our central hypothesis is that herbivore-associated fungi might directly or indirectly affect plant–insect interactions. In this study, we identified five orally secreted fungi from field-collected black cutworm, Agrotis ipsilon, including Aspergillus parasiticus, Aspergillus niger, Geotrichum candidum, Fusarium subglutinans, and Mucor circinelloides f. lusitanicus. We found that caterpillars inoculated with F. subglutinans or M. circinelloides f. lusitanicus induced higher defense responses in plants, but with different patterns between different plants. These herbivore-induced defense responses reduced the growth of caterpillars. However, direct application of fungi to mechanically wounded tomato did not induce JA-related defense responses. The application of regurgitant from fungi-inoculated or non-inoculated caterpillars, suggested that regurgitant might be responsible for the fungi-mediated defense response in plants against caterpillar attack. Furthermore, both F. subglutinans and M. circinelloides f. lusitanicus benefited caterpillar growth when they fed on detached tomato leaves, but had no influence when caterpillars fed on artificial diet. Our finding suggests that insect-associated fungi could influence plant–insect interactions by indirectly mediating plant defense responses, and directly affecting caterpillar performance on host plants.

A mineral deposit forms because of a combination of complex geologic processes, and this makes it difficult to confirm effectively the presence of ore bodies below the surface. Primary haloes are commonly utilized in mineral exploration as an indicator of the presence of blind ore bodies. Three basic types of zoning occur in primary haloes of mineral deposits, namely axial, longitudinal and transversal. The study of axial zoning is particularly important for deep ore prospecting because it is usually linked to the flow direction of ore-bearing fluids. In this study, multi-element geochemical data were used to analyze the axial variation of primary halos in the Yidinan gold deposit, and a future prospecting target was proposed. A novel method is proposed that combines a correlation matrix and cluster analysis to characterize correlations among various elements. In addition, Gregorian's method was used to calculate the axial zonality series, and the contrast coefficient of the elements on the 14 different elevations of the No. 4 gold-bearing quartz vein was used to study the axial variations of indicator elements. It is proposed that the front halo elements of ore bodies are As, Sb, Bi and Hg, the near-ore halo elements are Au, Ag, Cu, Pb, Zn and Sn, and the tail halo elements are Ti, Co, V, Ni, Mo and W. Finally, based on the zonal concentration of each element and the axial variation of the contrast coefficient of each element with depth, it is speculated that four ore-enrichment regions are present in the No. 4 gold-bearing quartz vein. The study showed that the formation of a primary halo with an ideal element distribution occurred after the establishment of two main metallogenic stages and that other processes that cause strong superimposition of mineralization may occur at depth of the deposit.

Grain formation is fundamental for crop yield but is vulnerable to abiotic and biotic stresses. Rice grain production is threatened by the false smut fungus Ustilaginoidea virens, which specifically infects rice floral organs, disrupting fertilization and seed formation. However, little is known about the molecular mechanisms of the U. virens-rice interaction and the genetic basis of floral resistance. Here, we report that U. virens secretes a cytoplasmic effector, UvCBP1, to facilitate infection of rice flowers. Mechanistically, UvCBP1 interacts with the rice scaffold protein OsRACK1A and competes its interaction with the reduced nicotinamide adenine dinucleotide phosphate oxidase OsRBOHB, leading to inhibition of reactive oxygen species (ROS) production. Although the analysis of natural variation revealed no OsRACK1A variants that could avoid being targeted by UvCBP1, expression levels of OsRACK1A are correlated with field resistance against U. virens in rice germplasm. Overproduction of OsRACK1A restores the OsRACK1A-OsRBOHB association and promotes OsRBOHB phosphorylation to enhance ROS production, conferring rice floral resistance to U. virens without yield penalty. Taken together, our findings reveal a new pathogenic mechanism mediated by an essential effector from a flower-specific pathogen and provide a valuable genetic resource for balancing disease resistance and crop yield.

Previous studies have shown that hydrogen water has antioxidant and anti-inflammatory effects on exercise-induced fatigue; however, its molecular mechanism remains unclear.Adult male Sprague-Dawley rats were randomly divided into a pure water drinking group (NC) and a hydrogen water drinking group (HW) (n = 7), and 2-week treadmill training was used to establish a sports model. Gut bacterial community profiling was performed using 16S rRNA gene sequencing analysis. The expression levels of mitochondrial energy metabolism-related genes and the levels of sugar metabolites and enzymes were measured.The exercise tolerance of rats in the HW group significantly improved, and the distribution and diversity of intestinal microbes were altered. Hydrogen significantly upregulated genes related to mitochondrial biogenesis, possibly via the Pparγ/Pgc-1α/Tfam pathway. In addition, hydrogen effectively mediated the reprogramming of skeletal muscle glucose metabolism.Our findings establish a critical role for hydrogen in improving endurance exercise performance by promoting mitochondrial biogenesis via the Pparγ/Pgc-1α/Tfam pathway.

Plant diseases caused by diverse pathogens lead to a serious reduction in crop yield and threaten food security worldwide. Genetic improvement of plant immunity is considered as the most effective and sustainable approach to control crop diseases. In the last decade, our understanding of plant immunity at both molecular and genomic levels has improved greatly. Combined with advances in biotechnologies, particularly clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-based genome editing, we can now rapidly identify new resistance genes and engineer disease-resistance crop plants like never before. In this review, we summarize the current knowledge of plant immunity and outline existing and new strategies for disease resistance improvement in crop plants. We also discuss existing challenges in this field and suggest directions for future studies.

People’s health information-seeking behaviors differ by their health literacy levels. This study assessed the relationship between health literacy and college students’ levels of trust in and use of a range of health information sources of COVID-19. We collected data from August to December 2020 among college students (n = 763) through an online survey. We used a health literacy measure containing three self-reported survey questions, developed by the CDC. We assessed the extent to which participants trusted and used any of the sixteen different sources of information about COVID-19. Respondents reported high levels of trusting and using COVID-19 information from the CDC, health care providers, the WHO, state/county/city health departments, and official government websites when compared to other sources. After controlling for demographic characteristics (i.e., gender, age, race, ethnicity, and income), those who reported having lower health literacy were significantly less likely to trust and use COVID-19 information from these health authorities when compared to participants who reported having higher health literacy. Students with lower self-reported health literacy indicated not trusting or using official health authority sources for COVID-19 information. Relying on low-quality information sources could create and reinforce people’s misperceptions regarding the virus, leading to low compliance with COVID-19-related public health measures and poor health outcomes.

Chemosensory proteins (CSPs) are a class of transporters in arthropods. Deeper research on CSPs showed that CSPs may be involved in some physiological processes beyond chemoreception, such as insect resistance to pesticides. We identified two upregulated

Spirotetramat is a tetramic acid derivative insecticide with novel modes of action for controlling Aphis gossypii Glover in the field. Previous studies have shown that long noncoding RNAs (lncRNAs) and cytochrome P450 monooxygenases (P450s) are involved in the detoxification process. However, the functions of lncRNAs in regulating P450 gene expression in spirotetramat resistance in A. gossypii are unknown.In this study, we found CYP4CJ1, CYP6CY7 and CYP6CY21 expression levels to be significantly upregulated in a spirotetramat-resistant (SR) strain compared with a susceptible (SS) strain. Furthermore, knockdown of CYP4CJ1, CYP6CY7 and CYP6CY21 increased nymph and adult mortality in the SR strain following exposure to spirotetramat. Drosophila ectopically expressing CYP380C6, CYP4CJ1, CYP6DA2, CYP6CY7 and CYP6CY21 showed significantly decreased mortality after spirotetramat exposure, and CYP380C6, CYP4CJ1 and CYP6CY21 are putative targets of six lncRNAs. Silencing of lncRNAs MSTRG.36649.2/5 and MSTRG.71880.1 changed CYP6CY21 and CYP380C6 expression, altering the sensitivity of the SR strain to spirotetramat. Moreover, MSTRG.36649.2/5 did not compete for microRNA (miRNA) binding to regulate CYP6CY21 expression.Our results confirm that CYP380C6, CYP4CJ1, CYP6DA2, CYP6CY7 and CYP6CY21 are potentially involved in the development of spirotetramat resistance in A. gossypii, and MSTRG.36649.2/5 and MSTRG.71880.1 probably regulate CYP6CY21 and CYP380C6 expression other than through the "sponge effect" of competing for miRNA binding. Our results provide a favorable molecular basis for studying cotton aphid P450 genes and lncRNA functions in spirotetramat resistance development.

BACKGROUND: This study aimed to investigate the correlation of long non‐coding RNA antisense non‐coding RNA in the INK4 locus (lncRNA ANRIL) and its target microRNAs (microRNA‐34a (miR‐34a) and microRNA‐125a (miR‐125a)) with disease risk and severity of Parkinson’s disease (PD). METHODS: Seventy‐eight PD patients and 78 age‐/gender‐matched controls were consecutively enrolled. Their peripheral blood mononuclear cell samples were collected and proposed for the reverse‐transcription quantitative polymerase chain reaction to complete lncRNA ANRIL, miR‐34a, and miR‐125a measurements. RESULTS: LncRNA ANRIL was upregulated, while miR‐34a and miR‐125a were downregulated in PD patients compared to controls (all p

This cross-sectional analysis estimated differences, based on disability status, in college students' (n = 777) experiences during the COVID-19 pandemic. Data were modeled using t-tests and logistic regression. Most participants were white (86.2%), and women (66.4%). The mode age was 23. A third (35.6%) had at least one disability. Students reported high rates of psychosocial distress, like fear of contracting (59.7%) and spreading (74.3%) COVID-19, worry about friends and family (83.7%), and increased anxiety (72.5%), depression (59.9%), and substance use (24.7%). Forty-two percent (42.2%) were scared they would miss out on their education through virtual classes. About a third feared forgetting assignments (34.1%) and making mistakes (33.9%). Fewer students expressed apprehension about (27.9%) and intimidation by (26.3%) virtual learning. Only 17.2% would continue taking virtual classes after the pandemic. Students with disabilities (M = 12.4, SD = 4.1) experienced more psychosocial stressors compared to students without disabilities (M = 9.9, SD = 4.2), [t(775) = 7.86, p < 0.001]. In adjusted models, disabled students were more than twice as likely to experience worry about medical bills (OR = 2.29), loneliness (OR = 2.09), and increased anxiety (OR = 2.31). They were also more than three times as likely to report increased depression (OR = 3.51) and changes in sexual activity (OR = 3.12). However, students with disabilities (M = 1.5, SD = 1.1) also reported receiving more support compared to their non-disabled classmates (M = 1.1, SD = 1.1), [t(775) = 6.06, p < 0.001]. Disabled students were more likely to feel a sense of contributing to society by following precautions (OR = 1.80) and receive support from family and others (emotional support: OR = 2.01, financial support: OR = 2.04). Interestingly, no significant differences were found in students' feelings associated with online or virtual learning [t(526.08) = 0.42, p = 0.68]. Students with disabilities, though, trended toward reporting negative experiences with virtual learning. In conclusion, students with disabilities were disproportionately affected by COVID-19 stressors, but also expressed more support and a sense of contributing to the common good.

Chinese-Americans are one of the largest groups of Asian-Americans in the US with distinctive behavioral and cultural characteristics that influence health service use. Although Chinese-Americans have significantly higher COVID-19-related mortality rates, relative to other racial and ethnic groups, limited literature is available examining their willingness to accept the COVID-19 vaccine. With recent development of the combination influenza-COVID-19 vaccine by biotechnology companies to mitigate COVID-19 infection, we examined factors associated with Chinese-Americans’ acceptance of hypothetical annual doses of COVID-19 vaccination before the vaccine rollout. A total of 241 Chinese-Americans who received at least one dose of the COVID-19 vaccine completed an online questionnaire developed and based on health behavior theories. Our results indicated that Chinese-American participants who were satisfied with their prior COVID-19 vaccination experience, who had more accurate knowledge and perceived higher susceptibility of getting COVID-19, were more willing to receive the annual COVID-19 vaccine in the future. The findings of our current study may be used to guide the development of strategic messages to promote uptake of the annual COVID-19 vaccine by Chinese-Americans in the U.S.

Osteoarthritis (OA) is a complex chronic inflammatory disease characterized by articular degeneration and pain. Recent studies have identified interleukin 6 (IL-6) as a potential mediator leading to OA, but the therapeutic effects of inhibiting IL-6 signaling in intreating OA need to be further clarified. Here, we identified the intracellular signal transduction induced by recombinant IL-6 and focused on the impact of tyrphostin AG490 (a JAK2 inhibitor) on cartilage degeneration and OA pain. We found that IL-6 increased the inflammatory cytokines production and hypertrophic markers expression of primary mouse chondrocytes by activating JAK2/STAT3. Meanwhile, tyrphostin AG490 significantly attenuated articular degeneration and osteophyte formation in experimental mice with anterior cruciate ligament transection (ACLT) surgery. In vivo electrophysiological experiments showed that articular stimulation of IL-6 induced spinal hyperexcitability, which was prevented by coinjection of tyrphostin AG490. Specifically, compared with DMSO-treated ACLT mice, tyrphostin AG490 improved ambulate activity of mice and abolished the enhancement of serum bradykinin induced by IL-6. Together, we suggest that tyrphostin AG490 protected against progression of OA and improved OA prognosis by reducing cartilage degeneration and arthritis pain. Our findings provide further evidence for targeting IL-6 signaling in the treatment of OA.

Fatty acid synthesis facilitates tumor cell immune escape and immunotherapy resistance. Cytochrome P450 (CYP) 4A and 4F, the major ω-hydroxylases that convert arachidonic acid (AA) into 20-hydroxyeicosatetraenoic acid (20-HETE), are implicated in inflammation and cancer. However, the role of CYP4 ω-hydroxylases in immune evasion remains unclear. Here, we determined that 20-HETE derived from the CYP4F2 isoenzyme governs immune evasion in non–small cell lung cancer (NSCLC) in a CD8+ T-cell-dependent manner. Mechanistically, CYP4F2 induced expression of immune checkpoint PD-L1 and production of proangiogenic factors IL6 and TGFβ in cancer-associated fibroblasts (CAF) via the 20-HETE-GPR75-STAT3-c-Jun axis. Tumors with high CYP4F2 expression were more resistant to anti-PD-1 treatment, whereas inhibition of CYP4F2 enhanced the efficacy of anti-PD-1 therapy in human NSCLC organoids and mouse models. Collectively, these data delineate that CYP4F2-dependent AA metabolism controls CAF-mediated immune evasion. CYP4F2 inhibition combined with PD-1 antibody represents a promising therapeutic approach for immunotherapy-resistant lung cancer. Significance: The identification of a role for CYP4F2-dependent metabolism in driving immune evasion in non–small cell lung cancer reveals a strategy to improve the efficacy of immunotherapy by inhibiting CYP4F2. See related article by Van Ginderachter, p. 3882

Purpose Glioblastoma (GBM) is the most common primary brain tumor with a poor therapeutic outcome. Polycomb group factor 1 (PCGF1), a member of the PcG (Polycomb group) family, is highly expressed in the developing nervous system of mice. However, the function and the mechanism of PCGF1 in GBM proliferation still remain unclear. Methods Knockdown of PCGF1 was performed in U87 GBM cell by shRNA strategy via lentivirus vector. MTT assay, colony formation assays, and flow cytometry were used to measure the properties of cell proliferation and cell cycle distribution, respectively. GeneChip analysis was performed to identify the downstream effector molecules. Rescue assay was constructed to verify the screening results. Results We first found that knockdown of PCGF1 led to the inhibition of U87 cells proliferation and decreased colony formation ability. The data from GeneChip expression profiling and Ingenuity Pathway Analysis (IPA) indicated that many of the altered gene cells are associated with the cell proliferation control pathways. We have further confirmed the suppression of AKT/GSK3β/c-Myc/cyclinD1 expressions by Western blotting analysis. The over-expression of c-Myc could partly restore the attenuated proliferation ability caused by knockdown of PCGF1. Conclusion All the above evidences suggested that PCGF1 might be closely associated with tumorigenesis and progression of glioblastoma (GBM), in which process the oncoprotein c-Myc may participate. PCGF1 could thus be a potential therapeutic target for the treatment of glioblastoma (GBM).

Background The cotton aphid Aphis gossypii Glover is one of the most destructive insect pests. It has evolved resistance to numerous insecticides around the world due to the application of insecticides. Uridine diphosphate (UDP)-glycosyltransferases (UGTs) have been reported to potentially facilitate the detoxification process of imidacloprid and thiamethoxam in A. gossypii. Results In this study, the field populations of A. gossypii developed different levels of resistance to multiple insecticides. A UGT inhibitor, 5-nitrouracil, dramatically increased the toxicity of acetamiprid in resistant populations, moderately increased the toxicity of sulfoxaflor in the imidacloprid susceptible (IMI_S) population, and populations from Yuncheng in Shanxi Province (SXYC) and Jingzhou in Hubei Province (HBJZ), and increased the toxicity of bifenthrin in the IMI_S and HBJZ populations, but there was no synergism on omethoate or carbosulfan. Quantitative real-time PCR analysis revealed that UGT344B4 and UGT344C7 were overexpressed in all field populations, and UGT344N4 was overexpressed in the SDBZ and HBZJ populations. Furthermore, the suppression of UGT344B4 or UGT344C7 by RNA interference significantly increased the susceptibility to bifenthrin in the IMI_S population and the susceptibility to sulfoxaflor in the SXYC population. Conclusion These results suggested that UGTs are potentially involved in the detoxification of neonicotinoid, sulfoximine, and pyrethroid insecticides in A. gossypii. Furthermore, the overexpression of UGTs could be associated with insecticide resistance in field populations of A. gossypii. The results might be helpful for the management of insecticide resistance in field populations of A. gossypii. © 2019 Society of Chemical Industry.

In this paper, a numerical model of high-temperature proton exchange membrane fuel cell (HT-PEMFC) was developed, in which the thermal and electrical properties were treated as temperature dependent. Based on the numerical simulation, the needed training data was acquired and used for the development of data-driven model via the artificial neural network (ANN) algorithm. The developed data-driven model was then used to predict the performance of HT-PEMFC. The simulation results indicated that the deviation of ANN prediction was less than 2.48% compared with numerical simulation. The effects of various influential factors, such as the geometry size of the gas flow channel, the thickness of the membrane and the operating temperature, could be predicted easily by using the ANN model. The ANN model prediction results showed that the more compact fuel cell and the higher operating temperature improved the performance of HT-PEMFC. The proposed ANN model and the parameters study will contribute to the further design and operation of HT-PEMFC.

Clinical application of doxorubicin (Dox) is limited due to its undesirable side effects, especially cardiotoxicity. Several microRNAs (miRNAs) such as microRNA-140-5p and miR-23a aggravate Dox-induced cardiotoxicity. Here we demonstrate that upregulation of miRNA let-7f-2-3p by long noncoding RNA (lncRNA) NEAT1 inhibits exportin-1 (XPO1)-mediated nuclear export of hematopoietic-substrate-1 associated protein X-1 (HAX-1) in Dox-induced cardiotoxicity. Treatment of the H9c2 cells with the Dox (1 μM) for 6 h inhibited HAX-1 nuclear export and decreased XPO1 expression. Overexpression of XPO1 significantly attenuated the Dox-induced leakage of myocardial enzymes (creatine phosphokinase, creatine kinase-MB and lactate dehydrogenase) and cardiomyocyte apoptosis with the increased HAX-1 nuclear export. Differentially expressed miRNAs including let-7f-2-3p were selected from the Dox or vehicle-treated cardiomyocytes. TargetScan and luciferase assay showed that let-7f-2-3p targeted XPO1 3' UTR. Inhibition of let-7f-2-3p reduced Dox-induced cardiotoxicity and apoptosis by inhibiting XPO1-mediated HAX-1 nuclear export, whereas let-7f-2-3p overexpression aggravated these effects. In addition, lncRNA NEAT1 was identified as an endogenous sponge RNA to repress let-7f-2-3p expression. Overexpression of lncRNA NEAT1 abolished the increased let-7f-2-3p expression by Dox, and thereby attenuated cardiotoxicity. The loss function of let-7f-2-3p increased XPO1-mediated HAX-1 nuclear export and reduced myocardial injury in Dox (20 mg/kg)-treated rats. Importantly, let-7f-2-3p inhibition in mice alleviated Dox-induced cardiotoxicity and preserved the antitumor efficacy. Together, let-7f-2-3p regulated by lncRNA NEAT1 aggravates Dox-induced cardiotoxicity through inhibiting XPO1-mediated HAX-1 nuclear export, and may serve as a potential therapeutic target against Dox-induced cardiotoxicity.

The cotton aphid, Aphis gossypii Glover, is a destructive global crop pest. Control of A. gossypii has relied heavily on the application of chemical insecticides. The cotton aphid has developed resistance to numerous insecticides, including imidacloprid, which has been widely used to control cotton pests in China since the 1990s. Our objective was to investigate the potential role of UDP-glycosyltransferases (UGTs) in imidacloprid resistance based on transcriptomic and proteomic analyses of field-originated imidacloprid-resistant (IMI_R) and -susceptible (IMI_S) A. gossypii clones. The transcriptomic and proteomic analyses revealed that 12 out of 512 differentially expressed genes and three out of 510 differentially expressed proteins were predicted as UDP-glycosyltransferase (UGT). Based on quantitative real-time PCR analysis, nine UGT genes, UGT343A4, UGT344A15, UGT344A16, UGT344B4, UGT344C7, UGT344C9, UGT344N4, UGT 24541, and UGT7630, were up-regulated in the IMI_R clone compared to the IMI_S clone. Meanwhile, UGT344A16, UGT344B4, UGT344C7, and UGT344N4 were overexpressed at the protein level based on western blot analysis. Furthermore, knockdown of UGT344B4 or UGT344C7 using RNA interference (RNAi) significantly increased sensitivity to imidacloprid in the IMI_R clone. In conclusion, UGTs potentially contributed to imidacloprid resistance in A. gossypii originating from cotton-growing regions of China. These results provide insights into the way we study insecticide resistance in cotton aphids.

The plant cell wall is the first physical and defensive barrier against pathogens. The plant cell wall usually undergoes dynamic remodeling as an immune response to prevent infection by pathogens. In this review, we summarize advances on relationship between cell wall and immunity in plants. In particular, we outline current progresses regarding the regulation of the cell wall components, including cellulose, hemicellulose, pectin and lignin, on plant disease resistance. We also discuss the impacts of cell wall-derived cellodextrin, oligogalacturonic acid and xyloglucan/xylan oligosaccharides as potent elicitors or signal molecules to trigger plant immune response. We further propose future studies on dissecting the molecular regulation of cell wall on plant immunity, which have potentials in practical application of crop breeding aiming at improvement of plant disease resistance.