Decoding the impact of fiscal decentralization on urban pollution intensity in China: A spatial econometric analysis.

Utilizing city-level data from China, the paper employs a spatial econometric analysis to investigate the impact of fiscal decentralization on urban pollution. Empirical evidence indicates: (1) In the context of the emphasis of ecological civilization construction in China, an increase of fiscal autonomy for local governments is conducive to mitigating urban pollution intensity. Specifically, fiscal decentralization in one city not only promotes a reduction in local pollution intensity but alleviates environmental pollution problems in adjacent cities through spatial spillover effects. (2) Industrial structure upgrading and green technology progress become crucial measures for local governments to realize pollution reduction targets through fiscal expenditure. (3) Heterogeneity analysis reveals that the positive significance of decentralization is most prominent in the eastern China, while local governments with fiscal autonomy in central region tend to transfer pollution to neighboring cities. (4) There is a threshold characteristic for fiscal decentralization to promote a reduction in urban pollution intensity, and its marginal effect becomes more significant accompanied by continuous introduction of sophisticated foreign direct investment. Finally, the paper summarizes the potential significance of fiscal decentralization among Chinese local governments against the background of "Chinese-style decentralization" and proposes corresponding policy recommendations.

Incidence of second primary cancers in patients with retinoblastoma: a systematic review and meta-analysis.

Introduction: This systematic review and meta-analysis aimed to examine the risk of second primary cancers (SPCs) among retinoblastoma (Rb) patients, both hereditary and nonhereditary. Previous studies have reported on the long-term risk of SPCs in these patient populations, but a comprehensive synthesis of the existing evidence is lacking. Methods: A systematic search was conducted in PubMed, EMBASE, and Cochrane Library from inception to 12 March 2023, supplemented by manual screening. Eligible studies were identified, and data were extracted. The primary outcome measure was the standardized incidence ratios (SIRs) of SPCs in Rb patients. Summary estimates were calculated using random or fixed effects models. The quality of included studies was assessed using the Newcastle-Ottawa Scale. Results: Ten studies, including nine high-quality studies, were included in this review. The summary estimate of SIR for SPCs among hereditary Rb patients was 17.55 (95% CI=13.10-23.51), while the pooled estimate of SIR for SPCs among nonhereditary Rb patients was 1.36 (95% CI=0.90-2.04). Significant differences in SIRs for different SPC types were observed (P=0.028), including nasal cavity tumor (SIR=591.06, 95% CI=162.79-2146.01), bone tumor (SIR=442.91, 95% CI=191.63-1023.68), soft tissue sarcoma (SIR=202.93, 95% CI=114.10-360.93), CNS (SIR=12.84, 95% CI=8.80-18.74), and female breast cancer (SIR=3.68, 95% CI=2.52-5.37). Chemotherapy and radiation therapy were associated with an increased risk of SPCs among hereditary Rb patients. Discussion: The findings of this review indicate that hereditary Rb patients have a significantly elevated risk of developing SPCs, whereas nonhereditary Rb patients do not show the same risk. Furthermore, significant differences were observed in the SIRs of different SPC types. Treatment techniques, specifically chemotherapy and radiation therapy, were associated with an increased risk of SPCs among hereditary Rb patients. These findings highlight the importance of radiation protection for Rb patients and the need for further research and tailored management strategies for this high-risk population.

RNF4 prevents genomic instability caused by chronic DNA under-replication.

Eukaryotic genome stability is maintained by a complex and diverse set of molecular processes. One class of enzymes that promotes proper DNA repair, replication and cell cycle progression comprises small ubiquitin-like modifier (SUMO)-targeted E3 ligases, or STUbLs. Previously, we reported a role for the budding yeast STUbL synthetically lethal with sgs1 (Slx) 5/8 in preventing G2/M-phase arrest in a minichromosome maintenance protein 10 (Mcm10)-deficient model of replication stress. Here, we extend these studies to human cells, examining the requirement for the human STUbL RING finger protein 4 (RNF4) in MCM10 mutant cancer cells. We find that MCM10 and RNF4 independently promote origin firing but regulate DNA synthesis epistatically and, unlike in yeast, the negative genetic interaction between RNF4 and MCM10 causes cells to accumulate in G1-phase. When MCM10 is deficient, RNF4 prevents excessive DNA under-replication at hard-to-replicate regions that results in large DNA copy number alterations and severely reduced viability. Overall, our findings highlight that STUbLs participate in species-specific mechanisms to maintain genome stability, and that human RNF4 is required for origin activation in the presence of chronic replication stress.

A critical threshold of MCM10 is required to maintain genome stability during differentiation of induced pluripotent stem cells into natural killer cells.

Natural killer (NK) cell deficiency (NKD) is a rare disease in which NK cell function is reduced, leaving affected individuals susceptible to repeated viral infections and cancer. Recently, a patient with NKD was identified carrying compound heterozygous variants of MCM10 (minichromosome maintenance protein 10), an essential gene required for DNA replication, that caused a significant decrease in the amount of functional MCM10. NKD in this patient presented as loss of functionally mature late-stage NK cells. To understand how MCM10 deficiency affects NK cell development, we generated MCM10 heterozygous (MCM10+/-) induced pluripotent stem cell (iPSC) lines. Analyses of these cell lines demonstrated that MCM10 was haploinsufficient, similar to results in other human cell lines. Reduced levels of MCM10 in mutant iPSCs was associated with impaired clonogenic survival and increased genomic instability, including micronuclei formation and telomere erosion. The severity of these phenotypes correlated with the extent of MCM10 depletion. Significantly, MCM10+/- iPSCs displayed defects in NK cell differentiation, exhibiting reduced yields of hematopoietic stem cells (HSCs). Although MCM10+/- HSCs were able to give rise to lymphoid progenitors, these did not generate mature NK cells. The lack of mature NK cells coincided with telomere erosion, suggesting that NKD caused by these MCM10 variants arose from the accumulation of genomic instability including degradation of chromosome ends.

FANCD2-dependent mitotic DNA synthesis relies on PCNA K164 ubiquitination.

Ubiquitination of proliferating cell nuclear antigen (PCNA) at lysine 164 (K164) activates DNA damage tolerance pathways. Currently, we lack a comprehensive understanding of how PCNA K164 ubiquitination promotes genome stability. To evaluate this, we generated stable cell lines expressing PCNAK164R from the endogenous PCNA locus. Our data reveal that the inability to ubiquitinate K164 causes perturbations in global DNA replication. Persistent replication stress generates under-replicated regions and is exacerbated by the DNA polymerase inhibitor aphidicolin. We show that these phenotypes are due, in part, to impaired Fanconi anemia group D2 protein (FANCD2)-dependent mitotic DNA synthesis (MiDAS) in PCNAK164R cells. FANCD2 mono-ubiquitination is significantly reduced in PCNAK164R mutants, leading to reduced chromatin association and foci formation, both prerequisites for FANCD2-dependent MiDAS. Furthermore, K164 ubiquitination coordinates direct PCNA/FANCD2 colocalization in mitotic nuclei. Here, we show that PCNA K164 ubiquitination maintains human genome stability by promoting FANCD2-dependent MiDAS to prevent the accumulation of under-replicated DNA.

Extraordinarily Time-and Memory-Efficient Large-Scale Canonical Correlation Analysis in Fourier Domain: From Shallow to Deep.

Canonical correlation analysis (CCA) is a correlation analysis technique that is widely used in statistics and the machine-learning community. However, the high complexity involved in the training process lays a heavy burden on the processing units and memory system, making CCA nearly impractical in large-scale data. To overcome this issue, a novel CCA method that tries to carry out analysis on the dataset in the Fourier domain is developed in this article. Appling Fourier transform on the data, we can convert the traditional eigenvector computation of CCA into finding some predefined discriminative Fourier bases that can be learned with only element-wise dot product and sum operations, without complex time-consuming calculations. As the eigenvalues come from the sum of individual sample products, they can be estimated in parallel. Besides, thanks to the data characteristic of pattern repeatability, the eigenvalues can be well estimated with partial samples. Accordingly, a progressive estimate scheme is proposed, in which the eigenvalues are estimated through feeding data batch by batch until the eigenvalues sequence is stable in order. As a result, the proposed method shows its characteristics of extraordinarily fast and memory efficiencies. Furthermore, we extend this idea to the nonlinear kernel and deep models and obtained satisfactory accuracy and extremely fast training time consumption as expected. An extensive discussion on the fast Fourier transform (FFT)-CCA is made in terms of time and memory efficiencies. Experimental results on several large-scale correlation datasets, such as MNIST8M, X-RAY MICROBEAM SPEECH, and Twitter Users Data, demonstrate the superiority of the proposed algorithm over state-of-the-art (SOTA) large-scale CCA methods, as our proposed method achieves almost same accuracy with the training time of our proposed method being 1000 times faster. This makes our proposed models best practice models for dealing with large-scale correlation datasets. The source code is available at https://github.com/Mrxuzhao/FFTCCA.

RNF4 and USP7 cooperate in ubiquitin-regulated steps of DNA replication.

DNA replication requires precise regulation achieved through post-translational modifications, including ubiquitination and SUMOylation. These modifications are linked by the SUMO-targeted E3 ubiquitin ligases (STUbLs). Ring finger protein 4 (RNF4), one of only two mammalian STUbLs, participates in double-strand break repair and resolving DNA-protein cross-links. However, its role in DNA replication has been poorly understood. Using CRISPR/Cas9 genetic screens, we discovered an unexpected dependency of RNF4 mutants on ubiquitin specific peptidase 7 (USP7) for survival in TP53-null retinal pigment epithelial cells. TP53-/-/RNF4-/-/USP7-/- triple knockout (TKO) cells displayed defects in DNA replication that cause genomic instability. These defects were exacerbated by the proteasome inhibitor bortezomib, which limited the nuclear ubiquitin pool. A shortage of free ubiquitin suppressed the ataxia telangiectasia and Rad3-related (ATR)-mediated checkpoint response, leading to increased cell death. In conclusion, RNF4 and USP7 work cooperatively to sustain a functional level of nuclear ubiquitin to maintain the integrity of the genome.

Amsacrine downregulates BCL2L1 expression and triggers apoptosis in human chronic myeloid leukemia cells through the SIDT2/NOX4/ERK/HuR pathway.

Accumulating evidence indicates that the anticancer activity of acridine derivatives is mediated through the regulation of anti-apoptotic and pro-apoptotic BCL2 protein expression. Therefore, we investigated whether the cytotoxicity of amsacrine with an acridine structural scaffold in human chronic myeloid leukemia (CML) K562 cells was mediated by BCL2 family proteins. Amsacrine induced apoptosis, mitochondrial depolarization, and BCL2L1 (also known as BCL-XL) downregulation in K562 cells. BCL2L1 overexpression inhibited amsacrine-induced cell death and mitochondrial depolarization. Amsacrine treatment triggered SIDT2-mediated miR-25 downregulation, leading to increased NOX4-mediated ROS production. ROS-mediated inactivation of ERK triggered miR-22 expression, leading to increased HuR mRNA decay. As HuR is involved in stabilizing BCL2L1 mRNA, downregulation of BCL2L1 was noted in K562 cells after amsacrine treatment. In contrast, amsacrine-induced BCL2L1 downregulation was alleviated by restoring ERK phosphorylation and HuR expression. Altogether, the results of this study suggest that amsacrine triggers apoptosis in K562 cells by inhibiting BCL2L1 expression through the SIDT2/NOX4/ERK-mediated downregulation of HuR. Furthermore, a similar pathway also explains the cytotoxicity of amsacrine in CML MEG-01 and KU812 cells.

Amorphous Transparent Cu(S,I) Thin Films with Very High Hole Conductivity.

Amorphous transparent conductors (a-TCs) are key materials for flexible and transparent electronics but still suffer from poor p-type conductivity. By developing an amorphous Cu(S,I) material system, record high hole conductivities of 103-104 S cm-1 have been achieved in p-type a-TCs. These high conductivities are comparable with commercial n-type TCs made of indium tin oxide and are 100 times greater than any previously reported p-type a-TCs. Responsible for the high hole conduction is the overlap of large p-orbitals of I- and S2- anions, which provide a hole transport pathway insensitive to structural disorder. In addition, the bandgap of amorphous Cu(S,I) can be modulated from 2.6 to 2.9 eV by increasing the iodine content. These unique properties demonstrate that the Cu(S,I) system holds great potential as a promising p-type amorphous transparent electrode material for optoelectronics.

Effects of SIDT2 on the miR-25/NOX4/HuR axis and SIRT3 mRNA stability lead to ROS-mediated TNF-α expression in hydroquinone-treated leukemia cells.

Our previous studies indicated that the benzene metabolite hydroquinone (HQ) evokes the ROS/p38 MAPK/protein phosphatase 2A/tristetraprolin axis, leading to increased TNF-α expression in human acute myeloid leukemia cell lines U937 and HL-60. In this study, we aimed to identify the upstream pathway involved in ROS-mediated TNF-α expression. HQ treatment increased SIDT2 expression, which subsequently decreased miR-25 and SIRT3 expression in U937 cells. Notably, miR-25 downregulation promoted SIDT2 expression in HQ-treated U937 cells. SIDT2 induced lysosomal degradation of SIRT3 mRNA, but inhibited miR-25 expression through a lysosome-independent pathway. MiR-25 inhibition reduced NOX4 mRNA turnover, resulting in increased NOX4 protein levels. NOX4 induces mitochondrial ROS production and HuR downregulation. Restoration of HuR expression increased SIRT3 expression, suggesting that NOX4-mediated HuR downregulation promotes SIDT2-mediated degradation of SIRT3 mRNA. Inhibition of NOX4 or SIRT3 overexpression abolished HQ-induced ROS production, thereby abolishing TNF-α upregulation. Overall, these results indicate that SIDT2 regulates the miR-25/NOX4/HuR axis and SIRT3 mRNA destabilization, leading to ROS-mediated TNF-α upregulation in HQ-treated U937 cells. HQ-induced increase in TNF-α expression in HL-60 cells was also mediated through a similar pathway.

Digital economy and industrial energy efficiency performance: evidence from the city of the Yangtze River Delta in China.

Industry dominates energy consumption and carbon emissions in China, and industrial energy efficiency is critical for the achievement of energy transformation and carbon emission reduction. With the rapid development of the digital economy, its impact on energy efficiency is gradually emerging, and it is necessary to clarify the influencing mechanism on industrial energy efficiency. Based on the panel data of industrial sectors in 41 cities in the Yangtze River Delta from 2011 to 2019, the main objectives of this study are to more accurately measure the industrial total factor energy efficiency in each city by using the Super-Dynamic-SBM model. It analyses the influence mechanism of the digital economy and other influencing factors on industrial total factor energy efficiency with different methods. The research results indicate that, first, the total factor energy efficiency of the industrial sector in the Yangtze River Delta urban agglomeration generally showed a steady upward trend. Second, the digital economy and environmental regulation play a significant role in promoting total factor energy efficiency. In addition, industrial energy efficiency and the digital economy show an inverted "U" shaped relationship. With the improvement of the digital economy, its marginal contribution to total factor energy efficiency gradually weakens. Finally, technological progress is an important transmission channel for the impact of the digital economy on total factor energy efficiency.

Carboxyl Group-Modified Myoglobin Induces TNF-α-Mediated Apoptosis in Leukemia Cells.

Previous studies have shown that chemical modification may increase the activity of proteins or confer novel activity to proteins. Some studies have indicated that myoglobin (Mb) is cytotoxic; however, the underlying mechanisms remain unclear. In this study, we investigated whether chemical modification of the carboxyl group by semicarbazide could promote the Mb cytotoxicity in human leukemia U937 cells and the underlying mechanism of semicarbazide-modified myoglobin (SEM-Mb)-induced U937 cell death. The semicarbazide-modified Mb (SEM-Mb) induced U937 cell apoptosis via the production of cleaved caspase-8 and t-Bid, while silencing of FADD abolished this effect. These findings suggest that SEM-Mb can induce U937 cell death by activating the death receptor-mediated pathway. The SEM-Mb inhibited miR-99a expression, leading to increased NOX4 mRNA and protein expression, which promoted SIRT3 degradation, and, in turn, induced ROS-mediated p38 MAPK phosphorylation. Activated p38 MAPK stimulated miR-29a-dependent tristetraprolin (TTP) mRNA decay. Downregulation of TTP slowed TNF-α mRNA turnover, thereby increasing TNF-α protein expression. The SEM-Mb-induced decrease in cell viability and TNF-α upregulation were alleviated by abrogating the NOX4/SIRT3/ROS/p38 MAPK axis or ectopic expression of TTP. Taken together, our results demonstrated that the NOX4/SIRT3/p38 MAPK/TTP axis induces TNF-α-mediated apoptosis in U937 cells following SEM-Mb treatment. A pathway regulating p38 MAPK-mediated TNF-α expression also explains the cytotoxicity of SEM-Mb in the human leukemia cell lines HL-60, THP-1, K562, Jurkat, and ABT-199-resistant U937. Furthermore, these findings suggest that the carboxyl group-modified Mb is a potential structural template for the generation of tumoricidal proteins.

Carboxyl group-modified myoglobin shows membrane-permeabilizing activity.

In this study, we investigated whether modification of the carboxyl group with semicarbazide-enabled myoglobin (Mb) exhibits membrane-perturbing activity in physiological solutions. Mass spectrometry analysis showed that semicarbazide molecules were coupled to 19 of the 22 carboxyl groups in semicarbazide-modified Mb (SEM-Mb). Measurements of the absorption and circular dichroism spectra indicated that SEM-Mb lost its heme group and reduced the content of the α-helix structure in Mb. The microenvironment surrounding Trp residues in Mb changes after blocking negatively charged residues, as shown by fluorescence quenching studies. The results of the trifluoroethanol-induced structural transition indicated that SEM-Mb had higher structural flexibility than that of Mb. SEM-Mb, but not Mb, induced the permeability of bilayer membranes. Both proteins showed similar lipid-binding affinities. The conformation of SEM-Mb and Mb changed upon binding to lipid vesicles or a membrane-mimicking environment composed of SDS micelles, suggesting that membrane interaction modes differ. Unlike lipid-bound Mb, Trp residues in lipid-bound SEM-Mb are located at the protein-lipid interface. Altogether, our data indicate that modifying negatively charged groups relieves the structural constraints in Mb, consequently switching Mb structure to an active conformation that exhibits membrane-permeabilizing activity.

BCL2 inhibitor ABT-199 and BCL2L1 inhibitor WEHI-539 coordinately promote NOXA-mediated degradation of MCL1 in human leukemia cells.

Human leukemia U937 cells that were continuously treated with hydroquinone (HQ) were transformed into U937/HQ cells with increased MCL1 and BCL2L1 expression. Compared with their parental cells, U937/HQ cells were less sensitive to ABT-263 (BCL2/BCL2L1 inhibitor)/ABT-199 (BCL2 inhibitor) cytotoxicity. The combination of WEHI-539 (BCL2L1 inhibitor) with either ABT-199 or ABT-263 showed synergistic cytotoxicity to U937 and U937/HQ cells. Therefore, we further investigated the cytotoxic mechanism induced by the combination of WEHI-539 and ABT-199. The combined treatment of WEHI-539 and ABT-199 induced NOX4/ROS/p38 MAPK axis-mediated autophagy, which in turn accelerated ß-TrCP mRNA turnover. Downregulation of ß-TrCP increased Sp1 expression, thereby promoting Sp1-mediated NOXA transcription, which in turn induced NOXA-dependent MCL1 degradation. Enforced expression of MCL1 alleviated the cytotoxicity of WEHI-539 plus ABT-199 to induce the loss of mitochondrial membrane potential and cell viability. WEHI-539 alone induced Sp1/NOXA axis-mediated MCL1 downregulation, while ABT-199 significantly decreased the dose of WEHI-539 by approximately 350- and 50-fold to induce MCL1 suppression in parental and HQ-selected cells, respectively. Furthermore, WEHI-539 sensitized ABT-199-resistant U937 cells to ABT-199 cytotoxicity by inducing NOXA-mediated degradation of MCL1. Collectively, the data in this study indicate that ABT-199 and WEHI-539 cooperatively induce NOXA-dependent MCL1 degradation, and the inhibition of MCL1 mainly explains their combined cytotoxicity in parental, HQ-selected, and ABT-199-resistant U937 cells.

Functional and structural properties of cardiotoxin isomers produced by blocking negatively charged groups.

In this study, we investigated the functional roles of Asp40, Asp57, and C-terminal Asn60 in Naja atra cardiotoxin 3 (CTX3) structure and function by modifying these three carboxyl groups with semicarbazide. The conjugation of the carboxyl groups with semicarbazide produced two conformational isomers whose gross and fine structures were different from those of CTX3. The blocking of the carboxyl groups increased the structural flexibility of CTX3 in response to trifluoroethanol-induced effect. Despite presenting modest to no effect on decreasing the induction of permeability in zwitterionic phospholipid vesicles, the carboxyl group-modified CTX3 showed a marked reduction in its permeabilizing effect on anionic phospholipid vesicles in comparison to that of the native protein. Compared with native CTX3, carboxyl group-modified CTX3 exhibited lower activity in inducing membrane leakage in U937 cells. The CD spectra of lipid-bound toxins and the color transition of polydiacetylene/lipid assay showed that the membrane interaction mode of CTX3 was distinctly changed by the modification in the carboxyl groups. Given that the selective modification of Asp40 does not cause the conformational isomerization of CTX3, our data indicate that the carboxyl groups in Asp57 and Asn60 are essential in maintaining the structural topology of CTX3. Furthermore, modification of carboxyl groups changes the interdependence between the infrastructure and the global conformation of CTX3 in modulating membrane permeabilizing activity.

Hydroquinone destabilizes BIM mRNA through upregulation of p62 in chronic myeloid leukemia cells.

Studies have shown that hydroquinone (HQ), a benzene metabolite, induces autophagy and apoptosis in leukemia cells. We found that HQ-induced autophagy was cytotoxic to acute myeloid leukemia U937 cells but had a protective effect against apoptosis in chronic myeloid leukemia (CML) K562 cells. HQ-induced autophagy downregulated p62 expression in U937 cells, whereas it upregulated p62 expression in K562 cells regardless of autophagic flux. We also investigated the mechanism of p62 expression induction by HQ in K562 cells. Increased p62 expression in K562 cells reduced BIM mRNA stability and protein expression, which conferred resistance against the BH3 mimetics ABT-199 (BCL2 inhibitor) and A-1210477 (MCL1 inhibitor). K562/HQ cells, selected by the continuous exposure of K562 cells to HQ, also showed increased p62 expression and decreased BIM expression. HQ-induced SIRT3 expression promoted the upregulation of TET3 expression and JNK-mediated Sp1 phosphorylation, thereby increasing p62 expression in K562 and K562/HQ cells. Chromatin immunoprecipitation assay revealed that TET3-mediated DNA demethylation and JNK-mediated Sp1 phosphorylation promoted Sp1 recruitment to the p62 promoter. In CML KU812 cells, HQ induced p62 expression and downregulated BIM expression via a similar pathway. Collectively, our data indicate that HQ induces the upregulation of p62 expression in K562, KU812, and K562/HQ cells, increasing their resistance to BCL2 and MCL1 inhibition by reducing BIM expression. Thus, our findings propose a mechanism by which HQ induces the malignant progression of CML cells.

CREB/Sp1-mediated MCL1 expression and NFκB-mediated ABCB1 expression modulate the cytotoxicity of daunorubicin in chronic myeloid leukemia cells.

Although some studies have hinted at the therapeutic potential of daunorubicin (DNR) in chronic myeloid leukemia (CML), the mechanism by which DNR induces CML cell death is unclear. Therefore, this study aimed to investigate DNR-induced cell death signaling pathways in CML cell lines K562 and KU812. DNR-triggered apoptosis in K562 cells was characterized by inhibition of MCL1 expression, while restoration of MCL1 expression protected K562 cells from DNR-mediated cytotoxicity. In addition, DNR induced NOX4-dependent ROS production, leading to the activation of p38 MAPK and inactivation of Akt and ERK. Activated p38 MAPK stimulated protein phosphatase 2A-dependent dephosphorylation of CREB. Since Akt-mediated activation of ERK reduced ß-TrCP mRNA stability, the inactivation of Akt-ERK axis increased ß-TrCP expression, which in turn promoted proteasomal degradation of Sp1. Inhibition of CREB phosphorylation and Sp1 expression simultaneously reduced MCL1 transcription and protein expression. DNR-induced MCL1 suppression was not reliant on its ability to induce DNA damage. In addition, DNR induced the expression of drug exporter ABCB1 in K562 cells through the p38 MAPK/NFκB-mediated pathway, while imatinib or ABT-199 inhibited the DNR-induced effect. The combination of imatinib or ABT-199 with DNR showed synergistic cytotoxicity in K562 cells by increasing intracellular DNR retention. Cumulatively, our data indicate that DNR induces MCL1 downregulation in K562 cells by promoting p38 MAPK-mediated dephosphorylation of CREB and inhibiting the Akt-ERK axis-mediated Sp1 protein stabilization. Furthermore, experimental evidence indicates that DNR-induced death of KU812 cells occurs through a similar pathway.

Docetaxel-triggered SIDT2/NOX4/JNK/HuR signaling axis is associated with TNF-α-mediated apoptosis of cancer cells.

Previous studies have confirmed that docetaxel (DTX) treatment increases TNF-α production in cancer cells, but its mechanism of action remains unclear. Therefore, this study aimed to determine the signaling axis by which DTX induced the expression of TNF-α in U937 leukemia and MCF-7 breast carcinoma cells. DTX treatment promoted Ca2+-controlled autophagy and SIDT2 expression, resulting in lysosomal degradation of miR-25 in U937 cells. Downregulation of miR-25 increased NOX4 mRNA stability and protein expression. NOX4-stimulated ROS generation led to JNK-mediated phosphorylation of cytosolic HuR at Ser221, thereby increasing TNF-α protein expression by stabilizing TNF-α mRNA. Consequently, DTX induced TNF-α-dependent death in U937 cells. Depletion of HuR using siRNA or abolishment of JNK activation reduced TNF-α expression and eliminated DTX-mediated cytotoxicity. Knockdown of SIDT2 or pretreatment with chloroquine (a lysosome inhibitor) reduced DTX-induced NOX4 and TNF-α expression and mitigated JNK-mediated HuR phosphorylation. Altogether, our data indicate that DTX triggers HuR-mediated TNF-α mRNA stabilization through the Ca2+/SIDT2/NOX4/ROS/JNK axis, thereby inducing TNF-α-dependent apoptosis in U937 cells. In addition, DTX induces apoptosis in MCF-7 cells through SIDT2/NOX4/JNK/HuR axis-mediated TNF-α expression.

Exposure to air pollutants during pregnancy and after birth increases the risk of neonatal hyperbilirubinemia.

OBJECTIVES: Exposure to air pollution is associated with increased risks of several adverse conditions in newborns, such as preterm birth. Whether air pollution is associated with neonatal hyperbilirubinemia remains unclear. We aimed to develop and validate an air-quality-based model to better predict neonatal hyperbilirubinemia. METHODS: A multicenter, population-based cohort of neonates with a gestational age (GA) ≥35 weeks and birth weight ≥2000 g was enrolled in the study. The study was conducted in Shanghai, China, from July 2017 to December 2018. The daily average concentrations of particulate matter (PM) with aerodynamic diameters≤2.5 µm (PM2.5) and ≤10 µm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2) and carbon monoxide (CO) were measured. Neonatal hyperbilirubinemia was diagnosed according to the American Academy of Pediatrics (AAP) guidelines by trained neonatologists. We used logistic least absolute shrinkage and selection operator (LASSO) regression to screen air pollutant indicators related to neonatal hyperbilirubinemia and build an air-quality signature for each patient. An air-quality-based nomogram was then established to predict the risk of neonatal hyperbilirubinemia. RESULTS: A total of 11196 neonates were evaluated. Prenatal PM10, CO and NO2 exposure and postpartum SO2 exposure were significantly associated with neonatal hyperbilirubinemia. The air-quality score was calculated according to the hyperbilirubinemia-related pollutants. The air-quality score of the hyperbilirubinemia group was significantly higher than that of the nonhyperbilirubinemia group (P < .01, odds ratio = 2.97). An air-quality-based logistic regression model was built and showed good discrimination (C-statistic of 0.675 [95% CI (confidence interval), 0.658 to 0.692]) and good calibration. Decision curve analysis showed that the air-quality-based model was better than the traditional clinical model in predicting neonatal hyperbilirubinemia. CONCLUSIONS: The findings of this study suggest that ambient air pollution exposure is associated with an increased risk of neonatal hyperbilirubinemia. Our results encourage further exploration of this possibility in future studies.

Naja atra Cardiotoxin 1 Induces the FasL/Fas Death Pathway in Human Leukemia Cells.

This study aimed to investigate the mechanistic pathway of Naja atra (Taiwan cobra) cardiotoxin 1 (CTX1)-induced death of leukemia cell lines U937 and HL-60. CTX1 increased cytoplasmic Ca2+ and reactive oxygen species (ROS) production, leading to the death of U937 cells. It was found that Ca2+-induced NOX4 upregulation promoted ROS-mediated p38 MAPK phosphorylation, which consequently induced c-Jun and ATF-2 phosphorylation. Using siRNA knockdown, activated c-Jun and ATF-2 were demonstrated to regulate the expression of Fas and FasL, respectively. Suppression of Ca2+-mediated NOX4 expression or ROS-mediated p38 MAPK activation increased the survival of U937 cells exposed to CTX1. FADD depletion abolished CTX1-induced cell death, caspase-8 activation, and t-Bid production, supporting the correlation between the Fas death pathway and CTX1-mediated cytotoxicity. Among the tested N. atra CTX isotoxins, only CTX1 induced Fas and FasL expression. Chemical modification studies revealed that intact Met residues were essential for the activity of CTX1 to upregulate Fas and FasL expression. Taken together, the data in this study indicate that CTX1 induces c-Jun-mediated Fas and ATF-2-mediated FasL transcription by the Ca2+/NOX4/ROS/p38 MAPK axis, thereby activating the Fas death pathway in U937 cells. Furthermore, CTX1 activates Fas/FasL death signaling in the leukemia cell line HL-60.