A combination of a TLR7/8 agonist and an epigenetic inhibitor suppresses triple-negative breast cancer through triggering anti-tumor immune.

BACKGROUND: Combination therapy involving immune checkpoint blockade (ICB) and other drugs is a potential strategy for converting immune-cold tumors into immune-hot tumors to benefit from immunotherapy. To achieve drug synergy, we developed a homologous cancer cell membrane vesicle (CM)-coated metal-organic framework (MOF) nanodelivery platform for the codelivery of a TLR7/8 agonist with an epigenetic inhibitor. METHODS: A novel biomimetic codelivery system (MCM@UN) was constructed by MOF nanoparticles UiO-66 loading with a bromodomain-containing protein 4 (BRD4) inhibitor and then coated with the membrane vesicles of homologous cancer cells that embedding the 18 C lipid tail of 3M-052 (M). The antitumor immune ability and tumor suppressive effect of MCM@UN were evaluated in a mouse model of triple-negative breast cancer (TNBC) and in vitro. The tumor immune microenvironment was analyzed by multicolor immunofluorescence staining. RESULTS: In vitro and in vivo data showed that MCM@UN specifically targeted to TNBC cells and was superior to the free drug in terms of tumor growth inhibition and antitumor immune activity. In terms of mechanism, MCM@UN blocked BRD4 and PD-L1 to prompt dying tumor cells to disintegrate and expose tumor antigens. The disintegrated tumor cells released damage-associated molecular patterns (DAMPs), recruited dendritic cells (DCs) to efficiently activate CD8+ T cells to mediate effective and long-lasting antitumor immunity. In addition, TLR7/8 agonist on MCM@UN enhanced lymphocytes infiltration and immunogenic cell death and decreased regulatory T-cells (Tregs). On clinical specimens, we found that mature DCs infiltrating tumor tissues of TNBC patients were negatively correlated with the expression of BRD4, which was consistent with the result in animal model. CONCLUSION: MCM@UN specifically targeted to TNBC cells and remodeled tumor immune microenvironment to inhibit malignant behaviors of TNBC.

Association between prenatal perfluorinated compounds exposure and risk of pregnancy complications: A meta-analysis.

BACKGROUND AND OBJECTIVE: Per- and polyfluoroalkyl substances (PFASs) have been shown to be persistent and bioaccumulative. An elevated danger of pregnancy complications perhaps connected with exposure to PFASs, but the potential effects remain elusive. The objective of this study is to investigate the possible association between PFASs exposure and pregnancy complications, drawing upon existing evidence. METHODS: Electronic databases of PubMed, Qvid Medline, Embase, and Web of Science were searched thoroughly to identify eligible research published prior to November 28, 2023, examining the relationship between PFASs and pregnancy-related complications. To evaluate the quality of observational studies incorporated into the article, the Strengthening Reporting of Observational Studies in Epidemiology (STROBE) tool was utilized. The main outcomes assessed in this study included gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), gestational hypertension (GH), and preeclampsia (PE). RESULTS: Twenty-five relevant studies involving 30079 participants were finally selected from four databases. The combined estimates indicate that prenatal exposure to perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorobutane sulfonic acid (PFBS), and perfluoroenanthic acid (PFHpA) is associated with gestational diabetes mellitus (GDM) (PFOA: OR = 1.45, 95%CI: 1.07-1.94, P = 0.015; PFHxS: OR = 1.16, 95%CI: 1.00-1.36, P = 0.055; PFBS: OR = 1.44, 95%CI: 1.16-1.79, P = 0.001; PFHpA: OR = 1.41, 95%CI: 1.10-1.82, P = 0.008). The exposure to PFBS is positively associated with HDP (OR = 1.27, 95%CI: 1.14-1.41, P < 0.001), while both PFOA and PFHpA demonstrate statistically significant positive correlations with GH (PFOA: OR = 1.09, 95%CI: 1.00-1.19, P = 0.049; PFHpA: OR = 1.43, 95%CI: 1.15-1.78, P = 0.001). Negative correlations were observed for prenatal perfluorododecanoic acid (PFDoA) exposure and GH (OR = 0.71, 95%CI: 0.57-0.87, P = 0.001). However, no compelling evidence was identified to link PFASs exposure with the risk of PE. CONCLUSION: According to the meta-analysis findings, exposure to PFASs may be linked to GDM, HDP, and GH, but it does not significantly raise the risk of PE alone. Further research with larger sample size is required to verify this potential association and explore the biological mechanisms.

Reversal of H2O2-induced cell death by knockdown of HOTAIR in HTR-8/SVneo cells by mediation of miR-106b-5p/ACSL4 axis.

Preeclampsia is a serious threat to the health of pregnant women. Injury of trophoblasts could contribute to the progression of preeclampsia, and H2O2 was able to induce apoptosis in trophoblasts. LncRNAs have been reported to be involved in the progression of preeclampsia. Additionally, lncRNA HOTAIR is upregulated in patients with preeclampsia. However, the function of HOTAIR in H2O2-treated trophoblasts remains unclear. To explore the function of HOTAIR in preeclampsia, HTR-8/SVneo cells were stimulated with H2O2. RT-qPCR was performed to measure HOTAIR expression in HTR-8/SVneo cells. The apoptosis of HTR-8/SVneo cells was measured using TUNEL staining. The mitochondrial membrane potential was measured using JC-1 staining. Western blotting was performed to detect the expression of ACSL4, GPX4, and FTH1 in HTR-8/SVneo cells. The level of HOTAIR in HTR-8/SVneo cells was upregulated by H2O2. In addition, H2O2 notably inhibited the proliferation of HTR-8/SVneo cells, whereas knockdown of HOTAIR reversed this phenomenon. The mitochondrial membrane potential in HTR-8/SVneo cells was significantly inhibited by H2O2 and partially abolished by HOTAIR silencing. Moreover, HOTAIR could bind to miR-106b-5p; ACSL4 was identified as the downstream target of miR-106b-5p. Furthermore, HOTAIR knockdown reversed H2O2-induced ferroptosis in HTR-8/SVneo cells by regulating miR-106b-5p/ACSL4. Collectively, the knockdown of HOTAIR reversed H2O2-induced ferroptosis in HTR-8/SVneo cells by mediating miR-106b-5p/ACSL4. Thus, HOTAIR may serve as a new therapeutic target against preeclampsia.

qPrimerDB: a thermodynamics-based gene-specific qPCR primer database for 147 organisms.

Real-time quantitative polymerase chain reaction (qPCR) is one of the most important methods for analyzing the expression patterns of target genes. However, successful qPCR experiments rely heavily on the use of high-quality primers. Various qPCR primer databases have been developed to address this issue, but these databases target only a few important organisms. Here, we developed the qPrimerDB database, founded on an automatic gene-specific qPCR primer design and thermodynamics-based validation workflow. The qPrimerDB database is the most comprehensive qPCR primer database available to date, with a web front-end providing gene-specific and pre-computed primer pairs across 147 important organisms, including human, mouse, zebrafish, yeast, thale cress, rice and maize. In this database, we provide 3331426 of the best primer pairs for each gene, based on primer pair coverage, as well as 47760359 alternative gene-specific primer pairs, which can be conveniently batch downloaded. The specificity and efficiency was validated for qPCR primer pairs for 66 randomly selected genes, in six different organisms, through qPCR assays and gel electrophoresis. The qPrimerDB database represents a valuable, timesaving resource for gene expression analysis. This resource, which will be routinely updated, is publically accessible at http://biodb.swu.edu.cn/qprimerdb.

Joint QTL mapping and transcriptome sequencing analysis reveal candidate flowering time genes in Brassica napus L.

BACKGROUND: Optimum flowering time is a key agronomic trait in Brassica napus. To investigate the genetic architecture and genetic regulation of flowering time in this important crop, we conducted quantitative trait loci (QTL) analysis of flowering time in a recombinant inbred line (RIL) population, including lines with extreme differences in flowering time, in six environments, along with RNA-Seq analysis. RESULTS: We detected 27 QTLs distributed on eight chromosomes among six environments, including one major QTL on chromosome C02 that explained 11-25% of the phenotypic variation and was stably detected in all six environments. RNA-Seq analysis revealed 105 flowering time-related differentially expressed genes (DEGs) that play roles in the circadian clock/photoperiod, autonomous pathway, and hormone and vernalization pathways. We focused on DEGs related to the regulation of flowering time, especially DEGs in QTL regions. CONCLUSIONS: We identified 45 flowering time-related genes in these QTL regions, eight of which are DEGs, including key flowering time genes PSEUDO RESPONSE REGULATOR 7 (PRR7) and FY (located in a major QTL region on C02). These findings provide insights into the genetic architecture of flowering time in B. napus.

Genome-wide identification and characterization of Gretchen Hagen3 (GH3) family genes in Brassica napus.

The hormone auxin is involved in many biological processes throughout a plant's lifecycle. However, genes in the GH3 (Gretchen Hagen3) family, one of the three major auxin-responsive gene families, have not yet been identified in oilseed rape (Brassica napus). In this study, we identified 63 BnaGH3 genes in oilseed rape using homology searches. We analyzed the chromosome locations, gene structures, and phylogenetic relationships of the BnaGH3 genes, as well as the cis-elements in their promoters. Most BnaGH3 genes are located on chromosomes A03, A09, C02, C03, and C09, each with 4-7 members. In addition, we analyzed the expression patterns of BnaGH3 genes in seven tissues by transcriptome sequencing and quantitative RT-PCR analysis of plants under exogenous IAA treatment. The BnaGH3 genes showed different expression patterns in various tissues. BnaA.GH3.2-1 and BnaC.GH3.2-1 were expressed in the seed and seed coat during development and in response to IAA treatment. These results shed light on the possible roles of the GH3 gene family in oilseed rape.

Genome-Wide Identification of MicroRNAs in Response to Cadmium Stress in Oilseed Rape (Brassica napus L.) Using High-Throughput Sequencing.

MicroRNAs (miRNAs) have important roles in regulating stress-response genes in plants. However, identification of miRNAs and the corresponding target genes that are induced in response to cadmium (Cd) stress in Brassica napus remains limited. In the current study, we sequenced three small-RNA libraries from B. napus after 0 days, 1 days, and 3 days of Cd treatment. In total, 44 known miRNAs (belonging to 27 families) and 103 novel miRNAs were identified. A comprehensive analysis of miRNA expression profiles found 39 differentially expressed miRNAs between control and Cd-treated plants; 13 differentially expressed miRNAs were confirmed by qRT-PCR. Characterization of the corresponding target genes indicated functions in processes including transcription factor regulation, biotic stress response, ion homeostasis, and secondary metabolism. Furthermore, we propose a hypothetical model of the Cd-response mechanism in B. napus. Combined with qRT-PCR confirmation, our data suggested that miRNAs were involved in the regulations of TFs, biotic stress defense, ion homeostasis and secondary metabolism synthesis to respond Cd stress in B. napus.

Meropenem-induced immune thrombocytopenia and the diagnostic process of laboratory testing.

BACKGROUND: Drug-induced immune thrombocytopenia (DITP) is a serious, life-threatening clinical syndrome, the diagnosis of which is consistently difficult. In this report, we present a case of DITP caused by meropenem that was confirmed by laboratory tests. CASE REPORT: A 59-year-old male patient developed severe thrombocytopenia 8 days after the administration of meropenem and cefoperazone-sulbactam. After other causes were ruled out, DITP was suspected. Drug-induced platelet (PLT) antibodies were detected by enzyme immunoassay, flow cytometry, and monoclonal antibody immobilization of PLT antigens (MAIPA). All these tests were performed in the presence and absence of the associated drugs. RESULTS: PLT antibodies were detected in the patient's serum only in the presence of meropenem. MAIPA experiments demonstrated that glycoprotein IIb/IIIa was the binding site of the meropenem-induced PLT antibodies. CONCLUSIONS: Drug-induced immune thrombocytopenia should be considered in cases of acute thrombocytopenia in patients undergoing meropenem treatment. Clinicians should be cognizant of DITP, and a definitive diagnosis should be pursued, if feasible.

Genome-Wide Identification, Evolutionary and Expression Analyses of the GALACTINOL SYNTHASE Gene Family in Rapeseed and Tobacco.

Galactinol synthase (GolS) is a key enzyme in raffinose family oligosaccharide (RFO) biosynthesis. The finding that GolS accumulates in plants exposed to abiotic stresses indicates RFOs function in environmental adaptation. However, the evolutionary relationships and biological functions of GolS family in rapeseed (Brassica napus) and tobacco (Nicotiana tabacum) remain unclear. In this study, we identified 20 BnGolS and 9 NtGolS genes. Subcellular localization predictions showed that most of the proteins are localized to the cytoplasm. Phylogenetic analysis identified a lost event of an ancient GolS copy in the Solanaceae and an ancient duplication event leading to evolution of GolS4/7 in the Brassicaceae. The three-dimensional structures of two GolS proteins were conserved, with an important DxD motif for binding to UDP-galactose (uridine diphosphate-galactose) and inositol. Expression profile analysis indicated that BnGolS and NtGolS genes were expressed in most tissues and highly expressed in one or two specific tissues. Hormone treatments strongly induced the expression of most BnGolS genes and homologous genes in the same subfamilies exhibited divergent-induced expression. Our study provides a comprehensive evolutionary analysis of GolS genes among the Brassicaceae and Solanaceae as well as an insight into the biological function of GolS genes in hormone response in plants.

Impact of perioperative blood transfusion on survival of patients undergoing laparoscopic gastrectomy for gastric cancer.

PURPOSE: Previous studies have suggested that perioperative blood transfusion is associated with poor prognosis in patients undergoing radical gastrectomy for gastric cancer. The purpose of this study was to evaluate the impact of blood transfusion on the long-term survival of such patients. METHODS: Short- and long-term outcomes were retrieved from a prospectively collected database of patients who underwent laparoscopic gastrectomy with radical intent for gastric cancer. RESULTS: A total of 309 patients who underwent laparoscopic radical gastrectomy were evaluated. Sixty-one (19.7%) received blood transfusions during or within 30 days after gastrectomy. These patients were typically older, had lower preoperative hemoglobin levels, had a more advanced cancer stage, had more than two comorbidities, had a higher rate of postoperative 30-day complications, and had a higher conversion rate. The overall survival (OS) (p=0.040) and disease-free survival (DFS) (p=0.004) were significantly decreased in patients who received blood transfusions. Multivariate analysis revealed that perioperative blood transfusion was not independently associated with decreased OS and DFS but that cancer stage and having more than two comorbidities were independent risk factors. CONCLUSION: Perioperative blood transfusion was associated with decreased OS and DFS in this patient series, but this apparently reflected the relatively poor medical condition of these patients requiring gastrectomy and was not a causative relationship.

N6-methyladenosine-mediated feedback regulation of abscisic acid perception via phase-separated ECT8 condensates in Arabidopsis.

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNAs, yet how plants recognize this chemical modification to swiftly adjust developmental plasticity under environmental stresses remains unclear. Here we show that m6A mRNA modification and its reader protein EVOLUTIONARILY CONSERVED C-TERMINAL REGION 8 (ECT8) act together as a key checkpoint for negative feedback regulation of abscisic acid (ABA) signalling by sequestering the m6A-modified ABA receptor gene PYRABACTIN RESISTANCE 1-LIKE 7 (PYL7) via phase-separated ECT8 condensates in stress granules in response to ABA. This partially depletes PYL7 mRNA from its translation in the cytoplasm, thus reducing PYL7 protein levels and compromising ABA perception. The loss of ECT8 results in defective sequestration of m6A-modified PYL7 in stress granules and permits more PYL7 transcripts for translation. This causes overactivation of ABA-responsive genes and the consequent ABA-hypersensitive phenotypes, including drought tolerance. Overall, our findings reveal that m6A-mediated sequestration of PYL7 by ECT8 in stress granules negatively regulates ABA perception, thereby enabling prompt feedback regulation of ABA signalling to prevent plant cell overreaction to environmental stresses.

Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy.

The high potential of siRNAs to silence oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, divalent lipid-conjugated siRNAs are optimized for in situ binding to albumin to improve pharmacokinetics and tumor delivery. Systematic variation of the siRNA conjugate structure reveals that the location of the linker branching site dictates tendency toward albumin association versus self-assembly, while the lipid hydrophobicity and reversibility of albumin binding also contribute to siRNA intracellular delivery. The lead structure increases tumor siRNA accumulation 12-fold in orthotopic triple negative breast cancer (TNBC) tumors over the parent siRNA. This structure achieves approximately 80% silencing of the anti-apoptotic oncogene MCL1 and yields better survival outcomes in three TNBC models than an MCL-1 small molecule inhibitor. These studies provide new structure-function insights on siRNA-lipid conjugate structures that are intravenously injected, associate in situ with serum albumin, and improve pharmacokinetics and tumor treatment efficacy.

Polypeptide N-Acetylgalactosaminyltransferase 14 (GALNT14) as a Chemosensitivity-Related Biomarker for Osteosarcoma.

Purpose: Osteosarcoma is the most common primary bone tumor. Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14), a member of the N-acetylgalactosaminyltransferase family, has been considered to be associated with various cancers. However, its role in osteosarcoma remains unknown. Here, we aimed to explore the expression and potential mechanism of GALNT14 in osteosarcoma through bioinformatics analysis and in vitro experiments. Methods: We investigated GALNT14 expression in osteosarcoma using GEO, the TIMER database, and clinical samples. Protein-protein interaction (PPI) network analysis on GALNT14 was performed by STRING. TARGET was used to identify differentially expressed genes (DEGs) between high and low GALNT14 expression. The correlation between GALNT14 and cuproptosis-related genes in osteosarcoma was analyzed by R language. The prognostic significance of GALNT14 was examined by Kaplan-Meier survival analysis. Additionally, we inhibited GALNT14 function in an osteosarcoma cell line by transfecting siRNA and subsequently explored the effect on drug sensitivity by CCK-8, clonogenic assay, and flow cytometry. Results: GALNT14 was significantly elevated in osteosarcoma tissue, osteosarcoma cell lines, and metastatic osteosarcoma. PPI analysis revealed that GALNT14 was associated with MUC7, MUC13, MUC5AC, C1GALT1, MUC15, MUC16, MUC1, MUC4, MUC21, and MUC17. In the high GALNT14 expression group, we discovered 81 upregulated DEGs and 73 downregulated DEGs. Functional enrichment analysis of DEGs showed significant enrichment in the Wnt, TGF-ß, Hippo, PI3K signaling pathways and cell adhesion molecules. Expression of cuproptosis-related genes was closely related in osteosarcoma, and GALNT14 expression was significantly positively correlated with FDX1, a key regulator of cuproptosis. Kaplan-Meier survival showed that GALNT14 was linked to poor overall survival and disease-free survival in osteosarcoma. In vitro experiments suggested that GALNT14 was associated with chemotherapy resistance in osteosarcoma. Conclusion: We identified a GALNT family gene, GALNT14, that was highly expressed in osteosarcoma. This gene was closely associated with metastasis, progression, cuproptosis-related genes, and chemosensitivity of osteosarcoma, and showed correlation with poor overall survival and disease-free survival in osteosarcoma.

The landscape of mitophagy in sepsis reveals PHB1 as an NLRP3 inflammasome inhibitor.

Mitophagy is a selective autophagy targeting damaged and potential cytotoxic mitochondria, which can effectively prevent excessive cytotoxic production from damaged mitochondria and alleviate the inflammatory response. However, the potential role of mitophagy in sepsis remains poorly explored. Here, we studied the role of mitophagy in sepsis and its immune heterogeneity. By performing mitophagy-related typing on 348 sepsis samples, three clusters (A, B, and C) were obtained. Cluster A had the highest degree of mitophagy accompanied by lowest disease severity, while cluster C had the lowest degree of mitophagy with the highest disease severity. The three clusters had unique immune characteristics. We further revealed that the expression of PHB1 in these three clusters was significantly different and negatively correlated with the severity of sepsis, suggesting that PHB1 was involved in the development of sepsis. It has been reported that impaired mitophagy leads to the over-activation of inflammasomes, which promotes sepsis development. Further analysis showed that the expressions of NLRP3 inflammasomes core genes in cluster C were significantly up-regulated and negatively correlated with PHB1. Next, we verified whether PHB1 downregulation caused the activation of inflammasomes and found that the PHB1 knockdown increased the levels of mtDNA in the cytoplasm and enhanced the activation of NLRP3 inflammasomes. In addition, mitophagy inhibitor treatment abolished PHB1 knockdown-mediated activation of NLRP3 inflammasomes, suggesting that PHB1 inhibited the activation of inflammasomes through mitophagy. In conclusion, this study reveals that a high degree of mitophagy may predict a good outcome of sepsis, and PHB1 is a key NLRP3 inflammasome regulator via mitophagy in inflammatory diseases such as sepsis.

Recent advances in the plant epitranscriptome.

Chemical modifications of RNAs, known as the epitranscriptome, are emerging as widespread regulatory mechanisms underlying gene regulation. The field of epitranscriptomics advances recently due to improved transcriptome-wide sequencing strategies for mapping RNA modifications and intensive characterization of writers, erasers, and readers that deposit, remove, and recognize RNA modifications, respectively. Herein, we review recent advances in characterizing plant epitranscriptome and its regulatory mechanisms in post-transcriptional gene regulation and diverse physiological processes, with main emphasis on N6-methyladenosine (m6A) and 5-methylcytosine (m5C). We also discuss the potential and challenges for utilization of epitranscriptome editing in crop improvement.

Risk factors for brain injury in premature infants with twin-to-twin transfusion syndrome: a retrospective cohort study.

Background: Brain injury (BI) is prevalent in premature infants with twin-to-twin transfusion syndrome (TTTS), while risk factors of BI in these patients remains unknown. Our study aims to discern potential risk factors that contribute to BI in premature infants with TTTS. Methods: We conducted a retrospective cohort and analyzed clinical data of premature infants diagnosed with TTTS at the Northwest Women's and Children's Hospital between January 1, 2015 and January 1, 2020. Data included the infants' perinatal information, key postnatal examinations, laboratory tests, and treatments. Results: Of the 84 patients enrolled in the study, 22 (26.2%) were categorized in the BI group and 62 (73.8%) in the non-BI group, based on cranial imaging. No significant differences were found at baseline between the groups in relation to the proportion of males (40.9% vs. 35.5%, P=0.845), median gestational age (weeks) [31.9 (31.5, 33.4) vs. 34.2 (31.6, 35.4), P=0.061], average weight (g) (1,676.4±567.5 vs. 1,845.2±511.7, P=0.200), maternal age (years) [29.5 (26.0, 31.0) vs. 28.5 (27.8, 31.0), P=0.656], the proportion of in-vitro fertilization (9.1% vs. 16.1%, P=0.648), cesarean sections (86.4% vs. 93.5%, P=0.549) or TTTS donor infants (50.0% vs. 51.6%, P=0.897). Multivariate logistic regression analysis indicated that invasive mechanical ventilation [invasive mechanical ventilation (IMV); odds ratio (OR) =4.365; 95% confidence interval (CI): 1.066-17.870; P=0.040], [necrotizing enterocolitis (NEC); OR =8.632; 95% CI: 1.542-48.318; P=0.014], [single intrauterine fetal demise (sIUFD); OR =14.067; 95% CI: 1.298-224.421; P=0.031], and a 5-minute Apgar score <9 (OR =4.663; 95% CI: 1.015-21.419; P=0.048) were strongly associated with BI in TTTS premature infants. Conclusions: Our study identifies IMV, NEC, sIUFD, and a 5-minute Apgar score <9 as independent risk factors for BI in premature infants with TTTS.

Degradation of 1-alkyl-3-methylimidazolium tetrafluoroborate in an ultrasonic zero-valent zinc and activated carbon micro-electrolysis system.

Increased attention has been given to the removal of ionic liquids (ILs) from natural water environments. In this work, 5 kinds of 1-alkyl-3-methylimidazoliumtetrafluoroborate ([Cnmim][BF4] (n = 2, 4, 6, 8, 10)) ILs were degraded in an ultrasonic zero-valent zinc (ZVZ) and activated carbon (AC) micro-electrolysis system. Optimization of degradation conditions and the degradation levels were studied by high performance liquid chromatography, the surface morphology of the ZVZ and AC changed before and after the reaction were observed by scanning electron microscope. The degradation intermediates were detected by gas chromatography- mass spectrometry and ion chromatography, and inferred the degradation pathway. The degradation effect of [C4mim][BF4] was best with ultrasonic assistance, pH 3 and an AC/ZVZ ratio of 1:1. The degradation of [Cnmim][BF4] in aqueous solution exceeded 91.7% in 120 min, and the mineralization level exceeded 88.9%. The surface of smooth and dense ZVZ particles became loose flocculent and the porous surface of AC became larger and rougher after reaction. The degradation pathway suggested that the imidazolium ring was sulfurized or oxidized, and then the ring was opened to form N-alkyl formamide and N-methyl formamide. ZVZ/AC micro-electrolysis combined with ultrasonic irradiation is an effective method to remove ILs, which provides new insight into IL degradation.

Serum levels of polychlorinated biphenyls and polybrominated diphenyl ethers in early pregnancy and their associations with gestational diabetes mellitus.

Polychlorinated Biphenyls (PCBs) and Polybrominated Diphenyl Ethers (PBDEs) are extensively present in humans and may disturb glucose metabolism during pregnancy. However, previous reports on the associations between PCBs/PBDEs levels and gestational diabetes mellitus (GDM) have been inconsistent. We performed a nested case-control study to measure the serum levels of 6 PCB and 7 PBDE congeners in early pregnancy, and to assess their associations with GDM risk and blood glucose levels. Totally, 208 serum samples (104 GDM cases and 104 controls) were included based on a prospective cohort which was carried out in Jiangsu province, China, from 2020 to 2022. The results showed that PCB-153 was the major PCB congener, whereas PBDE-47 was the predominant PBDE congener. The continuous concentrations of PCB-153, PBDE-28, and total PCB were significantly related to an increased risk of GDM, with adjusted ORs (95%CI) of 1.25 (1.04-1.50), 1.19 (1.02-1.39), and 1.37 (1.05-1.79), respectively. Potential dose-response relationships were also observed between serum levels of PCB-153 (P = 0.011), PBDE-28 (P = 0.028), total PCB (P = 0.048), and total PCB/PBDE (P = 0.010) and GDM risk. Moreover, PCB-153, PBDE-28 and total PCB levels were positively related to 1-h OGTT blood glucose (adjusted ßPCB-153: 0.14, 95%CI: 0.00-0.28; adjusted ßPBDE-28: 0.20, 95%CI: 0.08-0.32; adjusted ßtotal PCB: 0.30, 95%CI: 0.09-0.50), whereas none of the PCBs/PBDEs were statistically related to fasting blood glucose and 2-h OGTT blood glucose (all P > 0.05). Further meta-analysis also supported the association of PCBs exposure with GDM risk. Our study provides further evidence that PCBs/PBDEs exposure may increase GDM risk during pregnancy.

Study on the Role of an Erythrocyte Membrane-Coated Nanotheranostic System in Targeted Immune Regulation of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in the elderly population. Despite significant advances in studies of the pathobiology on AD, there is still no effective treatment. Here, an erythrocyte membrane-camouflaged nanodrug delivery system (TR-ZRA) modified with transferrin receptor aptamers that can be targeted across the blood-brain barrier to ameliorate AD immune environment is established. Based on metal-organic framework (Zn-CA), TR-ZRA is loaded with CD22shRNA plasmid to silence the abnormally high expression molecule CD22 in aging microglia. Most importantly, TR-ZRA can enhance the ability of microglia to phagocytose Aß and alleviate complement activation, which can promote neuronal activity and decrease inflammation level in the AD brain. Moreover, TR-ZRA is also loaded with Aß aptamers, which allow rapid and low-cost monitoring of Aß plaques in vitro. After treatment with TR-ZRA, learning, and memory abilities are enhanced in AD mice. In conclusion, the biomimetic delivery nanosystem TR-ZRA in this study provides a promising strategy and novel immune targets for AD therapy.

Structural Optimization of siRNA Conjugates for Albumin Binding Achieves Effective MCL1-Targeted Cancer Therapy.

The high potential for therapeutic application of siRNAs to silence traditionally undruggable oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, siRNAs were optimized for in situ binding to albumin through C18 lipid modifications to improve pharmacokinetics and tumor delivery. Systematic variation of siRNA conjugates revealed a lead structure with divalent C18 lipids each linked through three repeats of hexaethylene glycol connected by phosphorothioate bonds. Importantly, we discovered that locating the branch site of the divalent lipid structure proximally (adjacent to the RNA) rather than at a more distal site (after the linker segment) promotes association with albumin, while minimizing self-assembly and lipoprotein association. Comparison to higher albumin affinity (diacid) lipid variants and siRNA directly conjugated to albumin underscored the importance of conjugate hydrophobicity and reversibility of albumin binding for siRNA delivery and bioactivity in tumors. The lead conjugate increased tumor siRNA accumulation 12-fold in orthotopic mouse models of triple negative breast cancer over the parent siRNA. When applied for silencing of the anti-apoptotic oncogene MCL-1, this structure achieved approximately 80% MCL1 silencing in orthotopic breast tumors. Furthermore, application of the lead conjugate structure to target MCL1 yielded better survival outcomes in three independent, orthotopic, triple negative breast cancer models than an MCL1 small molecule inhibitor. These studies provide new structure-function insights on optimally leveraging siRNA-lipid conjugate structures that associate in situ with plasma albumin for molecular-targeted cancer therapy.