The role of m6A-associated membraneless organelles in the RNA metabolism processes and human diseases.

N6-methyladenosine (m6A) is the most abundant post-transcriptional dynamic RNA modification process in eukaryotes, extensively implicated in cellular growth, embryonic development and immune homeostasis. One of the most profound biological functions of m6A is to regulate RNA metabolism, thereby determining the fate of RNA. Notably, the regulation of m6A-mediated organized RNA metabolism critically relies on the assembly of membraneless organelles (MLOs) in both the nucleus and cytoplasm, such as nuclear speckles, stress granules and processing bodies. In addition, m6A-associated MLOs exert a pivotal role in governing diverse RNA metabolic processes encompassing transcription, splicing, transport, decay and translation. However, emerging evidence suggests that dysregulated m6A levels contribute to the formation of pathological condensates in a range of human diseases, including tumorigenesis, reproductive diseases, neurological diseases and respiratory diseases. To date, the molecular mechanism by which m6A regulates the aggregation of biomolecular condensates associated with RNA metabolism is unclear. In this review, we comprehensively summarize the updated biochemical processes of m6A-associated MLOs, particularly focusing on their impact on RNA metabolism and their pivotal role in disease development and related biological mechanisms. Furthermore, we propose that m6A-associated MLOs could serve as predictive markers for disease progression and potential drug targets in the future.

Fowl adenovirus serotype 4 (FAdV-4) infection induces inflammatory responses in chicken embryonic cardiac fibroblasts via PI3K/Akt and IκBα/NF-κB signaling pathways.

Fowl adenovirus serotype 4 (FAdV-4) is the main pathogen of the acute infectious disease hepatitis-hydropericardium syndrome (HHS). Previous studies have focused on the mechanisms of FAdV-4 caused liver injury, while studies revealing potential mechanisms of inflammatory injury in FAdV-4-infected chicken cardiac cells remain scare. Here we found that FAdV-4 successfully infected chicken embryonic cardiac fibroblasts (CECF) cells in vitro and significantly upregulated production of inflammatory cytokines including IL-1ß, IL-6, IL-8, and TNF-α, suggesting induction of a strong inflammatory response. Mechanistically, FAdV-4 infection increased expression of phosphorylated Akt in a time-dependent manner, while phosphorylation of Akt and production of pro-inflammatory cytokines IL-1ß, IL-6, IL-8, and TNF-α were greatly reduced in FAdV-4-infected CECF cells after treatment with LY294002, a potent inhibitor of PI3K, indicating that the inflammatory response induced by FAdV-4 infection is mediated by the PI3K/Akt signaling pathway. Furthermore, FAdV-4 infection increased expression of phosphorylated IκBα, a recognized indicator of NF-κB activation, and treatment with the BAY11-7082, a selective IκBα phosphorylation and NF-κB inhibitor, significantly reduced IκBα phosphorylation and inflammatory cytokines (IL-1ß, IL-6, IL-8, and TNF-α) production in FAdV-4-infected CECF cells, suggesting a critical role of IκBα/NF-κB signaling in FAdV-4-induced inflammatory responses in CECF cells. Taken together, our results suggest that FAdV-4 infection induces inflammatory responses through activation of PI3K/Akt and IκBα/NF-κB signaling pathways in CECF cells. These results reveal potential mechanisms of inflammatory damage in chicken cardiac cells caused by FAdV-4 infection, which sheds new insight into clarification of the pathogenic mechanism of FAdV-4 infection and development of new strategies for HHS prevention and control.

The transcription factor ERF110 promotes cold tolerance by directly regulating sugar and sterol biosynthesis in citrus.

ERFs (ethylene-responsive factors) are known to play a key role in orchestrating cold stress signal transduction. However, the regulatory mechanisms and target genes of most ERFs are far from being well deciphered. In this study, we identified a cold-induced ERF, designated as PtrERF110, from trifoliate orange (Poncirus trifoliata L. Raf., also known as Citrus trifoliata L.), an elite cold-hardy plant. PtrERF110 is a nuclear protein with transcriptional activation activity. Overexpression of PtrERF110 remarkably enhanced cold tolerance in lemon (Citrus limon) and tobacco (Nicotiana tabacum), whereas VIGS (virus-induced gene silencing)-mediated knockdown of PtrERF110 drastically impaired the cold tolerance. RNA sequence analysis revealed that PtrERF110 overexpression resulted in global transcriptional reprogramming of a range of stress-responsive genes. Three of the genes, including PtrERD6L16 (early responsive dehydration 6-like transporters), PtrSPS4 (sucrose phosphate synthase 4), and PtrUGT80B1 (UDP-glucose: sterol glycosyltransferases 80B1), were confirmed as direct targets of PtrERF110. Consistently, PtrERF110-overexpressing plants exhibited higher levels of sugars and sterols compared to their wild type counterparts, whereas the VIGS plants had an opposite trend. Exogenous supply of sucrose restored the cold tolerance of PtrERF110-silencing plants. In addition, knockdown of PtrSPS4, PtrERD6L16, and PtrUGT80B1 substantially impaired the cold tolerance of P. trifoliata. Taken together, our findings indicate that PtrERF110 positively modulates cold tolerance by directly regulating sugar and sterol synthesis through transcriptionally activating PtrERD6L16, PtrSPS4, and PtrUGT80B1. The regulatory modules (ERF110-ERD6L16/SPS4/UGT80B1) unraveled in this study advance our understanding of the molecular mechanisms underlying sugar and sterol accumulation in plants subjected to cold stress.

Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors.

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.

Combination of monensin and erlotinib synergistically inhibited the growth and cancer stem cell properties of triple-negative breast cancer by simultaneously inhibiting EGFR and PI3K signaling pathways.

BACKGROUND: Cancer stem cells (CSCs) in triple-negative breast cancer (TNBC) are recognized as a highly challenging subset of cells, renowned for their heightened propensity for relapse and unfavorable prognosis. Monensin, an ionophoric antibiotic, has been reported to exhibit significant therapeutic efficacy against various cancers, especially CSCs. Erlotinib is classified as one of the EGFR-TKIs and has been previously identified as a promising therapeutic target for TNBC. Our research aims to assess the effectiveness of combination of monensin and erlotinib as a potential treatment strategy for TNBC. METHODS: The combination of monensin and erlotinib was assessed for its potential anticancer activity through various in vitro assays, including cytotoxicity assay, colony formation assay, wound healing assay, transwell assay, mammosphere formation assay, and proportion of CSCs assay. Additionally, an in vivo study using tumor-bearing nude mice was conducted to evaluate the inhibitory effect of the monensin and erlotinib combination on tumor growth. RESULTS: The results indicated that combination of monensin with erlotinib synergistically inhibited cell proliferation, the migration rate, the invasion ability and decreased the CSCs proportion, and CSC markers SOX2 and CD133 in vivo and in vitro. Furthermore, the primary proteins involved in the signaling pathways of the EGFR/ERK and PI3K/AKT are simultaneously inhibited by the combination treatment of monensin and erlotinib in vivo and in vitro. CONCLUSIONS: The simultaneous inhibition of the EGFR/ERK and PI3K/AKT/mTOR signaling pathways by the combination of monensin and erlotinib exhibited a synergistic effect on suppressing tumor proliferation and cancer cell stemness in TNBC.

Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances.

Spinocerebellar ataxia is a phenotypically and genetically heterogeneous group of autosomal dominant-inherited degenerative disorders. The gene mutation spectrum includes dynamic expansions, point mutations, duplications, insertions, and deletions of varying lengths. Dynamic expansion is the most common form of mutation. Mutations often result in indistinguishable clinical phenotypes, thus requiring validation using multiple genetic testing techniques. Depending on the type of mutation, the pathogenesis may involve proteotoxicity, RNA toxicity, or protein loss-of-function. All of which may disrupt a range of cellular processes, such as impaired protein quality control pathways, ion channel dysfunction, mitochondrial dysfunction, transcriptional dysregulation, DNA damage, loss of nuclear integrity, and ultimately, impairment of neuronal function and integrity which causes diseases. Many disease-modifying therapies, such as gene editing technology, RNA interference, antisense oligonucleotides, stem cell technology, and pharmacological therapies are currently under clinical trials. However, the development of curative approaches for genetic diseases remains a global challenge, beset by technical, ethical, and other challenges. Therefore, the study of the pathogenesis of spinocerebellar ataxia is of great importance for the sustained development of disease-modifying molecular therapies.

Transcriptome and metabolome atlas reveals contributions of sphingosine and chlorogenic acid to cold tolerance in Citrus.

Citrus is one of the most important fruit crop genera in the world, but many Citrus species are vulnerable to cold stress. Ichang papeda (Citrus ichangensis), a cold-hardy citrus species, holds great potential for identifying valuable metabolites that are critical for cold tolerance in Citrus. However, the metabolic changes and underlying mechanisms that regulate Ichang papeda cold tolerance remain largely unknown. In this study, we compared the metabolomes and transcriptomes of Ichang papeda and HB pummelo (Citrus grandis "Hirado Buntan", a cold-sensitive species) to explore the critical metabolites and genes responsible for cold tolerance. Metabolomic analyses led to the identification of common and genotype-specific metabolites, consistent with transcriptomic alterations. Compared to HB pummelo under cold stress, Ichang papeda accumulated more sugars, flavonoids, and unsaturated fatty acids, which are well-characterized metabolites involved in stress responses. Interestingly, sphingosine and chlorogenic acid substantially accumulated only in Ichang papeda. Knockdown of CiSPT (C. ichangensis serine palmitoyltransferase) and CiHCT2 (C. ichangensis hydroxycinnamoyl-CoA: shikimate hydroxycinnamoyltransferase2), two genes involved in sphingosine and chlorogenic acid biosynthesis, dramatically decreased endogenous sphingosine and chlorogenic acid levels, respectively. This reduction in sphingosine and chlorogenic acid notably compromised the cold tolerance of Ichang papeda, whereas exogenous application of these metabolites increased plant cold tolerance. Taken together, our findings indicate that greater accumulation of a spectrum of metabolites, particularly sphingosine and chlorogenic acid, promotes cold tolerance in cold-tolerant citrus species. These findings broaden our understanding of plant metabolic alterations in response to cold stress and provide valuable targets that can be manipulated to improve Citrus cold tolerance.

Predicting Outcome of Patients With Cerebral Hemorrhage Using a Computed Tomography-Based Interpretable Radiomics Model: A Multicenter Study.

OBJECTIVE: The aim of this study was to develop and validate an interpretable and highly generalizable multimodal radiomics model for predicting the prognosis of patients with cerebral hemorrhage. METHODS: This retrospective study involved 237 patients with cerebral hemorrhage from 3 medical centers, of which a training cohort of 186 patients (medical center 1) was selected and 51 patients from medical center 2 and medical center 3 were used as an external testing cohort. A total of 1762 radiomics features were extracted from nonenhanced computed tomography using Pyradiomics, and the relevant macroscopic imaging features and clinical factors were evaluated by 2 experienced radiologists. A radiomics model was established based on radiomics features using the random forest algorithm, and a radiomics-clinical model was further trained by combining radiomics features, clinical factors, and macroscopic imaging features. The performance of the models was evaluated using area under the curve (AUC), sensitivity, specificity, and calibration curves. Additionally, a novel SHAP (SHAPley Additive exPlanations) method was used to provide quantitative interpretability analysis for the optimal model. RESULTS: The radiomics-clinical model demonstrated superior predictive performance overall, with an AUC of 0.88 (95% confidence interval, 0.76-0.95; P < 0.01). Compared with the radiomics model (AUC, 0.85; 95% confidence interval, 0.72-0.94; P < 0.01), there was a 0.03 improvement in AUC. Furthermore, SHAP analysis revealed that the fusion features, rad score and clinical rad score, made significant contributions to the model's decision-making process. CONCLUSION: Both proposed prognostic models for cerebral hemorrhage demonstrated high predictive levels, and the addition of macroscopic imaging features effectively improved the prognostic ability of the radiomics-clinical model. The radiomics-clinical model provides a higher level of predictive performance and model decision-making basis for the risk prognosis of cerebral hemorrhage.

Excitotoxic Storms of Ischemic Stroke: A Non-neuronal Perspective.

Numerous neurological disorders share a fatal pathologic process known as glutamate excitotoxicity. Among which, ischemic stroke is the major cause of mortality and disability worldwide. For a long time, the main idea of developing anti-excitotoxic neuroprotective agents was to block glutamate receptors. Despite this, there has been little successful clinical translation to date. After decades of "neuron-centered" views, a growing number of studies have recently revealed the importance of non-neuronal cells. Glial cells, cerebral microvascular endothelial cells, blood cells, and so forth are extensively engaged in glutamate synthesis, release, reuptake, and metabolism. They also express functional glutamate receptors and can listen and respond for fast synaptic transmission. This broadens the thoughts of developing excitotoxicity antagonists. In this review, the critical contribution of non-neuronal cells in glutamate excitotoxicity during ischemic stroke will be emphasized in detail, and the latest research progress as well as corresponding therapeutic strategies will be updated at length, aiming to reconceptualize glutamate excitotoxicity in a non-neuronal perspective.

Influence of blood glucose fluctuations on chemotherapy efficacy and safety in type 2 diabetes mellitus patients complicated with lung carcinoma.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have large fluctuations in blood glucose (BG), abnormal metabolic function and low immunity to varying degrees, which increases the risk of malignant tumor diseases and affects the efficacy of tumor chemotherapy. Controlling hyperglycemia may have important therapeutic implications for cancer patients. AIM: To clarify the influence of BG fluctuations on chemotherapy efficacy and safety in T2DM patients complicated with lung carcinoma (LC). METHODS: The clinical data of 60 T2DM + LC patients who presented to the First Affiliated Hospital of Ningbo University between January 2019 and January 2021 were retrospectively analyzed. All patients underwent chemotherapy and were grouped as a control group (CG; normal BG fluctuation with a mean fluctuation < 3.9 mmol/L) and an observation group (OG; high BG fluctuation with a mean fluctuation ≥ 3.9 mmol/L) based on their BG fluctuations, with 30 cases each. BG-related indices, tumor markers, serum inflammatory cytokines and adverse reactions were comparatively analyzed. Pearson correlation analysis was performed to analyze the correlation between BG fluctuations and tumor markers. RESULTS: The fasting blood glucose and 2-hour postprandial blood glucose levels in the OG were notably elevated compared with those in the CG, together with markedly higher mean amplitude of glycemic excursions (MAGE), mean of daily differences, largest amplitude of glycemic excursions and standard deviation of blood glucose (P < 0.05). In addition, the OG exhibited evidently higher levels of carbohydrate antigen 19-9, carbohydrate antigen 125, carcinoembryonic antigen, neuron-specific enolase, cytokeratin 19, tumor necrosis factor-α, interleukin-6, and high-sensitivity C-reactive protein than the CG (P < 0.05). Pearson analysis revealed a positive association of MAGE with serum tumor markers. The incidence of adverse reactions was significantly higher in the OG than in the CG (P < 0.05). CONCLUSION: The greater the BG fluctuation in LC patients after chemotherapy, the more unfavorable the therapeutic effect of chemotherapy; the higher the level of tumor markers and inflammatory cytokines, the more adverse reactions the patient experiences.

Multi-omics Mendelian randomization integrating GWAS, eQTL, and mQTL data identified genes associated with breast cancer.

Breast cancer (BC) remains a major disease posing a threat to women's health, but the underlying biological interpretation remains largely unknown. Here, we aimed to identify genes associated with breast cancer and analyze their pathophysiological mechanisms based on multi-omics Mendelian randomization (MR). Summary-data-based MR (SMR) was performed to estimate the causal effects of blood and breast mammary tissue expression quantitative trait loci (eQTLs) on BC. External validation analysis was used to validate the identified genes. Integration analyses BC GWAS summaries with eQTLs and DNA methylation QTLs (mQTLs) from the blood were conducted using SMR to prioritize putative blood genes and their regulatory elements associated with BC risk. Finally, two prior genes (ATG10 and RCCD1) from blood tissue reached significant levels in both BCAC (ATG10: ORBRCR = 0.91, PBRCR = 1.29 × 10-11; RCCD1: ORBRCR = 0.90, PBRCR = 3.72 × 10-15) and FinnGen cohorts (ATG10: ORFinnGen = 0.89, PFinnGen = 8.55 × 10-5; RCCD1: ORFinnGen = 0.89, PFinnGen = 2.38 × 10-8). Additionally, those two genes from breast tissues also replicated in both BCAC (ATG10: ORBRCR = 0.95, PBRCR = 1.02 × 10-9; RCCD1: ORBRCR = 0.87, PBRCR = 4.70 × 10-10) and FinnGen cohorts (ATG10: ORFinnGen = 0.93, PFinnGen = 2.38 × 10-4; RCCD1: ORFinnGen = 0.85, PFinnGen = 3.81 × 10-6). Sensitive analysis and external validation analysis validated those two identified genes. Multi-omics MR analysis showed that the SNP signals associated with ATG10 and RCCD1 were significant across the data from BC Genome-wide association study (GWAS), eQTL, and mQTL studies. In conclusion, we identified two priority genes that are potentially associated with BC. These findings improve our limited understanding of the mechanism of BC and shed light on the development of therapeutic agents for treating BC.

Genetically determined telomere length as a risk factor for hematological malignancies: evidence from Mendelian randomization analysis.

BACKGROUND: Over the past years, the exact correlation between telomere length and hematological malignancies was still not fully understood. METHODS: We performed a two-sample Mendelian randomization study to investigate the causal relationship between telomere length and hematological malignancies. We selected genetic instruments associated with telomere length. The genetic associations for lymphoid and hematopoietic malignant neoplasms were obtained from the most recent publicly accessible FinnGen study R9 data. Inverse variant weighted (IVW) analysis was adopted as the primary method, and we also performed the weighted-median method and the MR-Egger, and MRPRESSO methods as sensitive analysis. RESULTS: Significant associations have been observed between telomere length and primary lymphoid (IVW: OR = 1.52, P = 2.11 × 10-6), Hodgkin lymphoma (IVW: OR = 1.64, P = 0.014), non-Hodgkin lymphoma (IVW: OR = 1.70, P = 0.002), B-cell lymphoma (IVW: OR = 1.57, P = 0.015), non-follicular lymphoma (IVW: OR = 1.58, P = 1.7 × 10-3), mantle cell lymphoma (IVW: OR = 3.13, P = 0.003), lymphoid leukemia (IVW: OR = 2.56, P = 5.92E-09), acute lymphocytic leukemia (IVW: OR = 2.65, P = 0.021) and chronic lymphocytic leukemia (IVW: OR = 2.80, P = 8.21 × 10-6), along with multiple myeloma (IVW: OR = 1.85, P = 0.016). CONCLUSION: This MR study found a significant association between telomere length and a wide range of hematopoietic malignancies. But no substantial impact of lymphoma and hematopoietic malignancies on telomere length has been detected.

Maduramicin-guided nanotherapy: A polymeric micelles for targeted drug delivery in canine mammary tumors.

Canine mammary tumors (CMT) can severely compromise the life quality of the affected dogs through local recurrence, distant metastases and ultimately succumb to death. Recently, more attention has been given to the potential antimetastatic effect of maduramicin (MAD) on breast cancer. However, its poor aqueous solubility and toxicity to normal tissues limit its clinical application. Therefore, to address the drawbacks of MAD and enhance its anticancer and antimetastatic effects, MAD-loaded TPGS polymeric micelles (MAD-TPGS) were prepared by a thin-film hydration technique. The optimized MAD-TPGS exhibited excellent size distribution, stability and improved water solubility. Cellular uptake assays showed that TPGS polymer micelles could enhance drug internalization. Moreover, TPGS synergistically improved the cytotoxicity of MAD by targeting mitochondrial organelles, improving reactive oxygen species levels and reducing the mitochondrial transmembrane potential. More importantly, MAD-TPGS significantly impeded the metastasis of tumor cells. In vivo results further confirmed that, in addition to exhibiting excellent biocompatibility, MAD-TPGS exhibited greater antitumor efficacy than free MAD. Interestingly, MAD-TPGS displayed superior suppression of CMT metastasis via tail vein injection compared to oral administration, indicating its suitability for intravenous delivery. Overall, MAD-TPGS could be applied as a potential antimetastatic cancer agent for CMT.

Erythronate utilization activates VdtR regulating its metabolism to promote Brucella proliferation, inducing abortion in mice.

Brucella is a facultative intracellular pathogen that preferentially colonizes reproductive organs and utilizes erythritol as a preferred carbon source for its survival and proliferation. In this study, we identified a virulence-related DeoR-family transcriptional regulator (VdtR) and an erythronate metabolic pathway responsible for four-carbon acid sugar metabolism of D-erythronate and L-threonate in Brucella. We found that VdtR plays an important role in Brucella intracellular survival and trafficking to the endoplasmic reticulum in RAW 264.7 macrophages and in virulence in a mouse model. More importantly, we found that VdtR negatively regulates the erythronate metabolic pathway to promote extracellular proliferation of Brucella, depending on utilization of D-erythronate, an oxidative product of erythritol in the host. In a pregnant mouse model, the erythronate metabolic pathway was shown to cooperate with erythritol metabolism and play a crucial role in Brucella proliferation in the placenta, inducing placentitis and finally resulting in abortion or stillbirth. Our results demonstrate that, in addition to erythritol, erythronate is a preferred carbon source for Brucella utilization to promote its extracellular proliferation. This discovery updates the information on the preferential colonization of reproductive organs by Brucella and provides a novel insight into the Brucella-associated induction of abortion in pregnant animals. IMPORTANCE Brucella is an intracellular parasitic bacterium causing zoonosis, which is distributed worldwide and mainly characterized by reproductive disorders. Erythritol is found in allantoic fluid, chorion, and placenta of aborted animals, preferentially utilized by Brucella to cause infertility and abortion. However, the erythritol metabolism-defected mutant was unable to function as a vaccine strain due to its residual virulence. Here, we found that erythronate, an oxidative product of erythritol in the host, was also preferentially utilized by Brucella relying on the function of a deoxyribonucleoside regulator-family transcriptional regulator VdtR. Erythronate utilization activates VdtR regulation of the erythronate metabolic pathway to promote Brucella extracellular proliferation, inducing placentitis/abortion in mice. Double mutations on Brucella erythritol and D-erythronate metabolisms significantly reduced bacterial virulence. This study revealed a novel mechanism of Brucella infection-induced abortion, thus providing a new clue for the study of safer Brucella attenuated vaccines.

Effect of genetic liability to migraine and its subtypes on breast cancer: a mendelian randomization study.

BACKGROUND: The relationship between migraine and breast cancer risk has generated conflicting findings. We attempted to assess the association between migraine and breast cancer risk using Mendelian randomization (MR) analysis. METHODS: We selected genetic instruments associated with migraine from a recently published genome-wide association studies (GWAS). Inverse variant weighted (IVW) analysis was adopted as the main method, and we also performed the weighted-median method and the MR‒Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR Robust Adjusted Profile Score (MR-RAPS) methods as supplements. RESULTS: Our MR suggested that any migraine (AM) was a risk factor for overall breast cancer (IVW: odds ratio (OR) = 1.072, 95% confidence intervals (CI) = 1.035-1.110, P = 8.78 × 10- 5, false discovery rate (FDR) = 7.36 × 10- 4) and estrogen receptor-positive (ER+) breast cancer (IVW: OR = 1.066, 95% CI = 1.023-1.111, P = 0.0024; FDR = 0.0108) but not estrogen receptor-negative (ER-) breast cancer. In its subtype analysis, women with a history of migraine without aura (MO) had an increased risk of ER- breast cancer (IVW: OR = 1.089, 95% CI = 1.019-1.163, P = 0.0118, FDR = 0.0354), and MO was suggestively associated with the risk of overall breast cancer (FDR > 0.05 and IVW P < 0.05). No significant heterogeneity or horizontal pleiotropy was found in the sensitivity analysis. CONCLUSION: This study suggested that women with AM have an increased risk of overall breast cancer and ER + breast cancer. MO was suggestively associated with the risk of overall breast cancer and ER- breast cancer.

Emissions from international airport and its impact on air quality: A case study of beijing daxing international airport (PKX), China.

The Beijing Daxing International Airport is a newly opened airport, and a comprehensive emission inventory of air pollution sources has not yet been established. The lack of basic inventory data will cause difficulties in controlling the air quality (AQ) in and around the airport. Based on actual flight data, we established a comprehensive emission inventory (carbon monoxide (CO), nitrogen oxides (NOX), hydrocarbons (HC), sulfur dioxide (SO2), particulate matter (PM), and carbon dioxide (CO2)) at Beijing Daxing International Airport. Furthermore, we evaluated the impact of airport emissions on the AQ of the surrounding areas using the ADMS-Airport model. The results showed that Beijing Daxing International Airport emitted 1.15 E+03, 1.76 E+03, 1.38 E+02, 1.16 E+02, 3.53 E+01, and 3.75 E+05 t of CO, NOX, HC, SO2, PM, and CO2, respectively, from July 1, 2020, to June 30, 2021. Engine exhaust emissions (landing and takeoff [LTO] cycles) dominated all airport pollutant emissions except for PM from the power plant. Among all aircraft types, B738 emitted the most CO2, as it accounted for almost half of all the flights. The AQ simulations showed that the air pollutant diffusion range was concentrated within 15 km of the airport and the surrounding areas. The contribution of airport emissions to NOX concentrations was most apparent under the most unfavorable meteorological conditions. Based on the average pollutant concentration during the study period, the Gu'an Li Hu Primary School station was the most affected. In particular, NOX concentrations at this station were approximately 50% higher in winter than in summer. Currently, the airport's contribution to pollution in the surrounding areas is insignificant. However, with the continuous increase in the number of flights at the airport, its impact on the AQ in the surrounding areas must be addressed in the future.

Multifunctional Hollow Porous Fe3O4@N-C Nanocomposites as Anodes of Lithium-Ion Battery, Adsorbents and Surface-Enhanced Raman Scattering Substrates.

At present, it is still a challenge to prepare multifunctional composite nanomaterials with simple composition and favorable structure. Here, multifunctional Fe3O4@nitrogen-doped carbon (N-C) nanocomposites with hollow porous core-shell structure and significant electrochemical, adsorption and sensing performances were successfully synthesized through the hydrothermal method, polymer coating, then thermal annealing process in nitrogen (N2) and lastly etching in hydrochloric acid (HCl). The morphologies and properties of the as-obtained Fe3O4@N-C nanocomposites were markedly affected by the etching time of HCl. When the Fe3O4@N-C nanocomposites after etching for 30 min (Fe3O4@N-C-3) were applied as the anodes for lithium-ion batteries (LIBs), the invertible capacity could reach 1772 mA h g-1 after 100 cycles at the current density of 0.2 A g-1, which is much better than that of Fe3O4@N-C nanocomposites etched, respectively, for 15 min and 45 min (948 mA h g-1 and 1127 mA h g-1). Additionally, the hollow porous Fe3O4@N-C-3 nanocomposites also exhibited superior rate capacity (950 mA h g-1 at 0.6 A g-1). The excellent electrochemical properties of Fe3O4@N-C nanocomposites are attributed to their distinctive hollow porous core-shell structure and appropriate N-doped carbon coating, which could provide high-efficiency transmission channels for ions/electrons, improve the structural stability and accommodate the volume variation in the repeated Li insertion/extraction procedure. In addition, the Fe3O4@N-C nanocomposites etched by HCl for different lengths of time, especially Fe3O4@N-C-3 nanocomposites, also show good performance as adsorbents for the removal of the organic dye (methyl orange, MO) and surface-enhanced Raman scattering (SERS) substrates for the determination of a pesticide (thiram). This work provides reference for the design and preparation of multifunctional materials with peculiar pore structure and uncomplicated composition.

Characterization of Brucella abortus Mutant A19mut2, a Potential DIVA Vaccine Candidate with a Modification on Lipopolysaccharide.

BACKGROUND: Brucella abortus is the main causative agent for bovine brucellosis. B. abortus A19 is a widely used vaccine strain to protect cows from Brucella infection in China. However, A19 has a similar lipopolysaccharide (LPS) antigen to that of the field virulent Brucella strain, whose immunization interferes with the serodiagnosis of vaccinated and infected animals. [Aim] To develop a novel Brucella DIVA vaccine candidate. STUDY DESIGN AND METHODS: The B. abortus mutant A19mut2 with the formyltransferase gene wbkC is replaced by an acetyltransferase gene wbdR from E. coli O157 using the bacterial homologous recombination technique, generating a modified O-polysaccharide that cannot induce antibodies in mice against wild-type Brucella LPS. The biological phenotypes of the A19mut2 were assessed using a growth curve analysis, agglutination tests, Western blotting, and stress resistance assays. Histopathological changes and bacterial colonization in the spleens of vaccinated mice were investigated to assess the residual virulence and protection of the A19mut2. Humoral and cellular immunity was evaluated by measuring the levels of IgG, IgG subtypes, and the release of cytokines IFN-γ and IL10 in the splenocytes of the vaccinated mice. ELISA coated with wild-type LPS can distinguish mouse antibodies induced by A19 and A19mut2 immunization. RESULTS: The A19mut2 showed a decreased residual virulence in mice, compared to the A19 strain, but induced significant humoral and cellular immune responses, as the A19 immunization did. The protection efficacy of A19mut2 immunization against B. abortus S2308 NalR infection was similar to that of A19 immunization. CONCLUSION: The A19mut2 has potential as a novel DIVA vaccine candidate in the future.

A surgical nursing perspective analysis of glucose variability in BCLC stage B-C hepatocellular carcinoma patients with and without T2D within 1 year of hepatectomy: a retrospective cohort study from 2016 to 2020.

Background: Previous research has reported that variability in glucose levels is associated with a variety of patient characteristics in colon cancer. However, relevant research is still lacking in relation to hepatocellular carcinoma (HCC). Methods: A total of 95 HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage B-C who underwent liver resection at the Eastern Hepatobiliary Surgery Hospital and Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were included in this study. The patients were divided into 2 groups with type 2 diabetes (T2D) and without T2D. The primary outcome variable was blood glucose variability at 1 month and within 1 year of HCC surgery. Results: In this study, the age of patients with T2D was greater than that of patients without T2D (mean age: 70.3±8.45 vs. 60.4±11.27 years, P=0.031). Compared to the patients without T2D, those with T2D had higher blood glucose measurements within 1 month (33 vs. 7) and 1 year (46.5 vs. 22.5, P<0.001) of surgery. The T2D patients and non-T2D patients did not differ in terms of chemotherapy medication or other characteristics. Among the 95 patients with BCLC stage B-C HCC, those with T2D had higher variability in glucose levels (P<0.001) than those without T2D within 1 month of surgery [standard deviation (SD) =46.43 mg/dL, coefficient of variation (CV) =23.5% vs. SD =21.56 mg/dL, CV =13.21%], and within 1 year of surgery (SD =42.49 mg/dL, CV =26.14% vs. SD =20.45 mg/dL, CV =17.36%). A correlation was found between a lower body mass index and higher variability in glucose levels within 1 month of surgery among patients with T2D [SD (r=-0.431, P<0.05) and CV (r=-0.464, P<0.01)]. A higher preoperative blood glucose level in T2D patients was correlated with a higher blood glucose variability within 1 year of surgery (r=0.435, P<0.01). Variability in glucose levels was weakly correlated with the demographic and clinical characteristics of patients who do not have T2D. Conclusions: HCC patients with T2D in BCLC stage B-C showed greater variability in glucose levels within 1 month and 1 year of surgery. Preoperative hyperglycemia, insulin use, and a lower cumulative dose of steroids were clinical features correlated with a higher variability in glucose levels in T2D patients.

Multiple sclerosis and breast cancer risk: a meta-analysis of observational and Mendelian randomization studies.

Background: Several observational studies have explored the relationships between multiple sclerosis (MS) and breast cancer; however, whether an association exists remains unknown. Methods: We conducted a meta-analysis of observational studies and Mendelian randomization (MR) based on genetic variants to identify the relationship between MS and breast cancer. The observational studies were searched from PubMed, Embase, Web of Science, and Scopus to assess the relationship between MS and breast cancer from inception to 07 Nov 2022. Moreover, we explored the association between genetically pre-disposed MS and breast cancer risk based on an MR study. The summary analysis for MS from two separate databases [International Multiple Sclerosis Genetics Consortium (IMSGC), FinnGen] and the summary analysis for breast cancer from Breast Cancer Association Consortium. Results: Fifteen cohort studies involving 173,565 female MS patients were included in this meta-analysis. The correlation between MS and breast cancer was not statistically significant [relative ratio (RR) = 1.08, 95% confidence interval (CI) = 0.99-1.17]. In the MR analysis, we did not observe causal associations of genetically determined MS with breast cancer and its subtypes from both the IMSGC and FinnGen datasets. Conclusion: The meta-analysis of observational and MR based on genetic variants does not support the correlation between MS and breast cancer.