Organic aerosols (OAs) account for a large fraction of tropospheric fine particulate matter, but the hygroscopicity of OA is poorly understood. Here, we show remarkably‐enhanced water uptake capacity ...of OA due to formation of highly‐oxidized oxygenated OA on new particle formation (NPF) events in Beijing. While non‐nucleation processes also produce oxidized OA, their hygroscopicity exhibits little enhancement. As a result, a correlation between the hygroscopicity and oxidation state is absent for OA on non‐NPF days. Further analysis reveals that the highly‐oxidized oxygenated OA is 2.5 and 5‐fold as hygroscopic as the oxidized primary OA and less‐oxidized oxygenated OA, respectively. Our results suggest that nucleation‐initiated photooxidation of volatile organic compounds to produce water‐soluble organic acids may dominate on NPF days, and the aqueous oligomerization to yield less water‐soluble products might occur on non‐NPF days.
Plain Language Summary
While organic aerosols (OAs) account for a large proportion of tropospheric fine particles, the water uptake capacity of OA is poorly understood. Here, we show distinct effects of different atmospheric processes on its hygroscopicity in polluted urban atmosphere. Remarkably‐enhanced hygroscopicity is identified for OA formed from nucleation. Our results reveal that it is critical to account for the formation mechanisms in evaluating the impacts of OA on air quality and climate.
Key Points
Remarkably‐enhanced water uptake capacity of organic aerosol (OA) occurs on nucleation days
A correlation between the hygroscopicity and oxidation state of OA is presented on new particle formation (NPF) days, and the correlation is absent on non‐NPF days
The photooxidation of volatile organic compounds to produce organic acids may dominate on NPF days, and the aqueous oligomerization might occur on non‐NPF days
Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple ...prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed
by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth
and
. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. SIGNIFICANCE: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to second-generation antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.
Background Associated with enzyme deficiencies causing glycosaminoglycans (GAGs) accumulation, mucopolysaccharidosis type VI (MPS VI) is lysosomal storage disorder. In the treatment of MPS VI, ...galsulfase (Naglazyme) is commonly used as an enzyme replacement therapy (ERT). There remains a need for comprehensive real-world data on its safety and associated adverse events (AEs). Objective An analysis of the FDA Adverse Event Reporting System (FAERS) database will be conducted to identify potential risks and adverse reactions associated with galsulfase in real-life settings. Methods The FAERS database was used to extract data from Q2 2005 to Q4 2023. A total of 20,281,876 reports were analyzed after duplicate elimination, with 3,195 AE reports related to galsulfase identified. The association between galsulfase and AEs was investigated by utilizing four algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS). The analysis focused on the timing of onset, signs of AEs, and clinical significance. Results Twenty seven organ systems were involved, and significant system organ classes (SOCs) included respiratory, thoracic and mediastinal disorders, and infections and infestations. At the PT level, 72 PTs corresponding to 15 SOCs were identified, with some AEs not previously mentioned in the product label. AEs associated with galsulfase had a median onset time of 1,471 days, with over half of the cases occurred within the first 5 years of treatment initiation. Conclusion This investigation delivers an exhaustive and indicative assessment of galsulfase’s safety profile, grounded in authentic, real-world evidence. The findings emphasis the importance of continuous safety surveillance and the emergence of new AEs. The identification of previously unreported urologic adverse events, such as glomerulonephritis membranous and nephritic syndrome, warrants further investigation. The study emphasizes the need for enhanced pharmacovigilance to ensure patient safety and the effectiveness of galsulfase treatment.
A series of new quinoline derivatives was designed, synthesized and evaluated as potential antitumor agents. The results indicated that most compounds exhibited potent antiproliferative activity, and ...7-(4-fluorobenzyloxy)N-(2-(dimethylamino)- ethyl)quinolin-4-amine 10g was found to be the most potent antiproliferative agent against human tumor cell lines with an IC50 value of less than 1.0 μM. Preliminary structure-activity relationships analysis suggested that (1) the large and bulky alkoxy substituent in position-7 might be a beneficial pharmacophoric group for antiproliferative activity; (2) the amino side chain substituents in position-4 facilitated the antiproliferative activity of this class of compounds; and (3) the length of the alkylamino side chain moiety affected the antiproliferative potency, with two CH2 units being the most favorable. Further investigation of the mechanism of action of this class of compounds demonstrated that the representative compound 10g triggered p53/Bax-dependent colorectal cancer cell apoptosis by activating p53 transcriptional activity. Moreover, the results showed that compound 10g effectively inhibited tumor growth in a colorectal cancer xenograft model in nude mice. Thus, these quinoline derivatives might serve as candidates for the development of new antitumor drugs.
A series of new quinoline derivatives was designed, synthesized and evaluated as promising antitumor agents. The representative compound 10g could trigger p53/Bax-dependent colorectal cancer cell apoptosis by activating p53 transcriptional activity. Display omitted
•A series of new quinolines derivatives was synthesized and evaluated as antitumor agent.•Compound 10g was found to be the most potent antiproliferative agent.•Compound 10g triggered p53/Bax-dependent colorectal cancer cell apoptosis by activating p53 transcriptional activity.•Compound 10g effectively inhibited tumor growth in a colorectal cancer xenograft model in nude mice.
As energy metabolism regulation factor, peroxisome proliferator-activated receptor (PPAR) is thought to be a potential target for the treatment of depression. The present study was performed to ...evaluate the effects of activating PPARβ/δ, the most highly expressed subtype in the brain, in depressive in vivo and in vitro models. We observed that PPARβ/δ agonist GW0742 significantly alleviated depressive behaviors in mice and promoted the formation of autophagosomes around the damaged mitochondria in hippocampal astrocytes. Our in vitro experiments showed that GW0742 could reduce mitochondrial oxidative stress, and thereby attenuate endoplasmic reticulum (ER) stress-mediated apoptosis pathway via inhibiting IRE1α phosphorylation, subsequently protect against astrocytic apoptosis and loss. Furthermore, we found that PPARβ/δ agonist induces astrocytic mitophagy companied with the upregulated UCP2 expressions. Knocking down UCP2 in astrocytes could block the anti-apoptosis and pro-mitophagy effects of GW0742. In conclusion, our findings reveal PPARβ/δ activation protects against ER stress-induced astrocytic apoptosis via enhancing UCP2-mediated mitophagy, which contribute to the anti-depressive action. The present study provides a new insight for depression therapy.
Histone H2A ubiquitination plays critical roles in transcriptional repression and deoxyribonucleic acid (DNA) damage response. More attention has been focused on ubiquitin E3 ligases of H2A, however, ...less is known about the negative regulators of H2A ubiquitination. Here we identified HSCARG as a new negative regulatory protein for H2A ubiquitination and found a possible link between regulator of H2A ubiquitination and cell cycle. Mechanistically, HSCARG interacts with polycomb repressive complex 1 (PRC1) and deubiquitinase USP7 and inhibits PRC1 ubiquitination in a USP7-dependent manner. As ubiquitination of PRC1 is critical for its E3 ligase activity toward H2A, HSCARG and USP7 are further shown to decrease the level of H2A ubiquitination. Moreover, we demonstrated that HSCARG is involved in DNA damage response through affecting the level of H2A ubiquitination and localization of RAP80 at lesion points. Knockout of HSCARG results in persistent activation of checkpoint signaling and leads to cell cycle arrest. This study unravels a novel mechanism for the regulation of H2A ubiquitination and elucidates how regulators of H2A ubiquitination affect cell cycle.
The H3 histone variant CENP-A is an epigenetic marker critical for the centromere identity and function. However, the precise regulation of the spatiotemporal deposition and propagation of CENP-A at ...centromeres during the cell cycle is still poorly understood. Here, we show that CENP-A is phosphorylated at Ser68 during early mitosis by Cdk1. Our results demonstrate that phosphorylation of Ser68 eliminates the binding of CENP-A to the assembly factor HJURP, thus preventing the premature loading of CENP-A to the centromere prior to mitotic exit. Because Cdk1 activity is at its minimum at the mitotic exit, the ratio of Cdk1/PP1α activity changes in favor of Ser68 dephosphorylation, thus making CENP-A available for centromeric deposition by HJURP. Thus, we reveal that dynamic phosphorylation of CENP-A Ser68 orchestrates the spatiotemporal assembly of newly synthesized CENP-A at active centromeres during the cell cycle.
Display omitted
•Ser68 is critical for the in vivo function of CENP-A•Ser68 phosphorylation prevents binding of CENP-A to HJURP•Cdk1 and PP1α control the phosphorylation status of CENP-A Ser68•Ser68 phosphorylation orchestrates the spatiotemporal deposition of CENP-A
CENP-A Ser68 is a critical regulatory site for CENP-A recognition of its chaperone, HJURP. The dynamic phosphoregulation of Ser68 is controlled by Cdk1/PP1α, allowing cell-cycle-dependent orchestration of centromeric CENP-A deposition.
We collected paired samples of tumor and adjacent normal colorectal tissues from 22 patients with colorectal carcinoma to compare the differences in the expression of lysine specific demethylase 1 ...(LSD1) in these two tissues. The results showed that in 19 paired samples (86.4%), LSD1 is more highly expressed in tumor tissue than in normal tissue. To explore the role of LSD1 in colorectal tumorigenesis, we used somatic cell gene targeting to generate an LSD1 knockout (KO) HCT 116 human colorectal cancer cell line as a research model. The analysis of phenotypic changes showed that LSD1 KO colorectal cancer cells are less tumorigenic, both in vivo and in vitro. The differential expression analysis of the cells by mRNA sequencing (RNA-Seq) yielded 2,663 differentially expressed genes, and 28 of these genes had highly significant differences (Q <0.01). We then selected the 4 colorectal cancer-related genes ADM, DKK1, HAS3 and SMURF2 for quantitative real-time PCR verification. The results showed that the differences in the expression of ADM, DKK1 and HAS3 were consistent with those measured using the RNA-Seq data. As DKK1 was the gene with the most significant differential expression, we analyzed the key proteins of the DKK1-related Wnt/β-catenin signaling pathway and found that, after knocking out LSD1, the amount of free β-catenin translocated to the nucleus was significantly reduced and that the transcription of the signaling pathway target gene c-Myc was down-regulated. Our studies show that LSD1 activates the Wnt/β-catenin signaling pathway by down-regulating the pathway antagonist DKK1, which may be one of the mechanisms leading to colorectal tumorigenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hepatitis B virus (HBV) infection is the main risk factor for the development of hepatocellular carcinoma (HCC), the most common type of liver cancer, with high incidence and mortality worldwide. ...Surgery, liver transplantation, and ablation therapies have been used to treat early HBV-caused HCC (HBV-HCC); meanwhile, in the advanced stage, chemoradiotherapy and drug-targeted therapy are regularly considered, but with limited efficacy. Recently, immunotherapies, such as tumor vaccine therapy, adoptive cell transfer therapy, and immune checkpoint inhibitor therapy, have demonstrated promising efficacy in cancer treatment. In particular, immune checkpoint inhibitors can successfully prevent tumors from achieving immune escape and promote an anti-tumor response, thereby boosting the therapeutic effect in HBV-HCC. However, the advantages of immune checkpoint inhibitors in the treatment of HBV-HCC remain to be exploited. Here, we describe the basic characteristics and development of HBV-HCC and introduce current treatment strategies for HBV-HCC. Of note, we review the principles of immune checkpoint molecules, such as programmed cell death protein 1(PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in HBV-HCC, as well as related inhibitors being considered in the clinic. We also discuss the benefits of immune checkpoint inhibitors in the treatment of HBV-HCC and the efficacy of those inhibitors in HCC with various etiologies, aiming to provide insights into the use of immune checkpoint inhibitors for the treatment of HBV-HCC.
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