Neuroprotective effects of takinib on an experimental traumatic brain injury rat model via inhibition of transforming growth factor beta-activated kinase 1.

Transforming growth factor ß-activated kinase 1 (TAK1) plays a significant role in controlling several signaling pathways involved with regulating inflammation and apoptosis. As such, it represents an important potential target for developing treatments for traumatic brain injury (TBI). Takinib, a small molecule and selective TAK1 inhibitor, has potent anti-inflammatory activity and has shown promising activity in preclinical studies using rat models to evaluate the potential neuroprotective impact on TBI. The current study used a modified Feeney's weight-drop model to cause TBI in mature Sprague-Dawley male rats. At 30 min post-induction of TBI in the rats, they received an intracerebroventricular (ICV) injection of Takinib followed by assessment of their histopathology and behavior. The results of this study demonstrated how Takinib suppressed TBI progression in the rats by decreasing TAK1, p-TAK1, and nuclear p65 levels while upregulating IκB-α expression. Takinib was also shown to significantly inhibit the production of two pro-inflammatory factors, namely tumor necrosis factor-α and interleukin-1ß. Furthermore, Takinib greatly upregulated the expression of tight junction proteins zonula occludens-1 and claudin-5, reducing cerebral edema. Additionally, Takinib effectively suppressed apoptosis via downregulation of cleaved caspase 3 and Bax and reduction of TUNEL-positive stained cell count. As a result, an enhancement of neuronal function and survival was observed post-TBI. These findings highlight the medicinal value of Takinib in the management of TBI and offer an experimental justification for further investigation of TAK1 as a potential pharmacological target.

Source apportionment of atmospheric ammonia in suburban Beijing revealed through 15N-stable isotopes.

Addressing the urgent issue of atmospheric ammonia (NH3) emissions is crucial in combating poor air quality in megacities. Previous research has highlighted the significant contribution of nonagricultural sources, particularly fossil fuel emissions, to urban NH3 levels. However, there is limited assessment of NH3 dynamics in suburban areas. This study focuses on four suburban sites in Beijing, covering a 16 to 22-month observation period, to investigate spatial and temporal patterns of NH3 concentrations. The δ15N-stable isotope method is employed to identify NH3 sources and their contributions. Our results demonstrate that agricultural sources (53 %) dominate atmospheric NH3 emissions in suburban areas of Beijing, surpassing nonagricultural sources, and primarily emanate from local sources. Notably, fertilizer application (37 ± 11 %) and livestock breeding (32 ± 6 %) emerge as the primary contributors in summer and spring, respectively, leading to significantly elevated NH3 concentrations during these seasons. Even in autumn and winter, both agricultural (49 %) and nonagricultural (51 %) sources contribute almost equally to NH3 emissions. This study emphasizes the need for coordinated efforts to control atmospheric NH3 pollution in Beijing City, with particular attention to addressing both vehicular and agricultural emissions.

Identification of prognostic biomarkers for cervical cancer based on programmed cell death-related genes and assessment of their immune profile and response to drug therapy.

BACKGROUND: Programmed cell death (PCD) has been widely investigated in various human diseases. The present study aimed to identify a novel PCD-related genetic signature in cervical squamous cell carcinoma (CESC) to provide clues for survival, immunotherapy and drug sensitization prediction. METHODS: Single-sample gene set enrichment analysis (ssGSEA) was used to quantify the PCD score and assess the distribution of PCD in clinicopathological characteristics in The Cancer Genome Atlas (TCGA)-CESC samples. Then, the ConsensusClusterPlus method was used to identify molecular subtypes in the TCGA-CESC database. Genomic mutation analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment, as well as tumor microenvironment (TME) infiltration analysis, were performed for each molecular subtype group. Finally, a prognostic model by Uni-Cox and least absolute shrinkage and selection operator-Cox analysis was established based on differentially expressed genes from molecular subtypes. ESTIMATE (i.e. Estimation of STromal and Immune cells in MAlignantTumours using Expression data) and ssGSEA were performed to assess the correlation between the model and TME. Drug sensitization prediction was carried out with the oncoPredict package. RESULTS: Preliminary analysis indicated that PCD had a potential association clinical characteristics of the TCGA-CESC cohort, and PCD-related genes mutated in 289 (70.59%) CESC patients. Next, four groups of CESC molecular typing were clustered based on 63 significantly prognostic PCD-related genes. Among four subtypes, C1 group displayed the worst prognosis combined with over expressed PCD genes and enriched cell cycle-related pathways. C4 group exhibited the best prognosis accompanied with high degree of immune infiltration. Finally, a five-gene (SERPINE1, TNF, CA9, CX3CL1 and JAK3) prognostic model was constructed. Patients in the high-risk group displayed unfavorable survival. Immune infiltration analysis found that the low-risk group had significantly higher levels of immune cell infiltration such as T cells, Macrophages_M1, relative to the high-risk group, and were significantly enriched in apoptosis-associated pathways, which predicted a higher level of immunity. Drug sensitivity correlation analysis revealed that the high-risk group was resistant to conventional chemotherapeutic drugs and sensitive to the Food and Drug Administration-approved drugs BI.2536_1086 and SCH772984_1564. CONCLUSIONS: In the present study, we first found that PCD-related gene expression patterns were correlated with clinical features of CESC patients, which predicts the feasibility of subsequent mining of prognostic features based on these genes. The five-PCD-associated-gene prognostic model showed good assessment ability in predicting patient prognosis, immune response and drug-sensitive response, and provided guidance for the elucidation of the mechanism by which PCD affects CESC, as well as for the clinical targeting of drugs.

Inhibiting the NLRP3 Inflammasome with MCC950 Alleviates Neurological Impairment in the Brain of EAE Mice.

Multiple sclerosis (MS) is a chronic disease that is characterized by demyelination and neuronal damage. Experimental autoimmune encephalomyelitis (EAE) mice are used to model the disease progression of MS and mirror MS-like pathology. Previous researches have confirmed that inhibition of NLRP3 inflammasome significantly alleviated the severity of EAE mice and the demyelination of spinal cord, but its effect on neuronal damage and oligodendrocyte loss in the brain remains unclear. In this study, female C57BL/6 mice were immunized with MOG35-55 and PTX to establish experimental autoimmune encephalomyelitis (EAE) model. MCC950, a selective NLRP3 inflammasome inhibitor, was used to investigate the effect of NLRP3 inflammasome on the pathological changes and glial cell activation in the brain of EAE mice by immunohistochemistry. Our results demonstrated that MCC950 ameliorated the neuronal damage, demyelination, and oligodendrocyte loss in the brain of EAE mice. This protective effect of MCC950 may be attributed to its ability to suppress the activation of glial cells and prevents microglia polarization to M1 phenotype. Our work indicates that inhibition of NLRP3 inflammasome has the therapeutic effects of neuroprotection through immunomodulation and is a promising therapeutic strategy for MS.

WITHDRAWN: Rare plexiform neurofibroma of the scrotum - A case report.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

CEP20 promotes invasion and metastasis of non-small cell lung cancer cells by depolymerizing microtubules.

Worldwide, Lung cancer is the leading cause of cancer-related death and poses a direct health threat, non-small cell lung cancer (NSCLC) is the most common type. In this study, we demonstrated that centrosomal protein 20 (CEP20) is upregulated in NSCLC tissues and associated with cancer invasion metastasis. Notably, CEP20 depletion inhibited NSCLC cell proliferation, migration, and microtubule polymerization. Mechanistically, we discovered that CEP20 is critical in the development of NSCLC by regulating microtubule dynamics and cell adhesion-related signaling pathways. Furthermore, the knockdown or overexpression of CEP20 affects microtubule polymerization in A549 cell lines. Our research provides a promising therapeutic target for the diagnosis and treatment of lung cancer, as well as a theoretical and experimental basis for clinical application.

Ammonia mitigation campaign with smallholder farmers improves air quality while ensuring high cereal production.

Reducing cropland ammonia (NH3) emissions while improving air quality and food supply is a challenge, particularly in China where there are millions of smallholder farmers. We tested the effectiveness of a tailored nitrogen (N) management strategy applied to wheat-maize cropping systems in 'demonstration squares' across Quzhou County in the North China Plain. The N-management techniques included optimal N rates, deep fertilizer placement and application of urease inhibitors, implemented through cooperation between government, researchers, businesses and smallholders. Compared with conventional local smallholder practice, our NH3 mitigation campaign reduced NH3 volatilization from wheat and maize by 49% and 39%, and increased N-use efficiency by 28% and 40% and farmers' profitability by 25% and 19%, respectively, with no detriment to crop yields. County-wide atmospheric NH3 and fine particulate matter (with aerodynamic diameter <2.5 µm) concentrations decreased by 40% and 8%, respectively. County-wide net benefits were estimated at US$7.0 million. Our demonstration-square approach shows that cropland NH3 mitigation and improved air quality and farm profitability can be achieved simultaneously by coordinated actions at the county level.

Serum cytokine analysis in a cohort of advanced non-small cell lung cancer treated with PD-1 inhibitors reveals predictive markers of CXCL12.

Background: The circulating predictive factors for the outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs) remain elusive. We aimed to assess the predictive value of circulating cytokines for outcomes. Methods: Serum samples of 102 advanced-stage NSCLC patients who underwent immunotherapy were collected at baseline. The relative levels of 37 cytokines were detected. PD-L1 expression was also analyzed. Results: Higher serum CXCL12 levels (top 33%) were a poor predictive biomarker for durable clinical benefit (DCB) (23.5% vs. 72.1%, p<0.001), progression-free survival (PFS) (3.76 vs. 14.40 months; p<0.001) and overall survival (OS) (12.20 vs. 44.84 months; p=0.008). Compared with PD-L1-negative patients, PD-L1-positive patients had a significantly higher objective response rate (ORR) (70.0% vs. 28.8%, p<0.001) and a prolonged mPFS (25.35 vs. 4.64 months, p=0.003) and tended to have an increased mOS (44.84 vs. 20.42 months, p=0.087). A signature comprising PD-L1<1% and the top 33% CXCL12 level was associated with the lowest ORR (27.3% vs. 73.7%, p<0.001) and DCB (27.3% vs. 73.7%, p<0.001) and the worst mPFS (2.44 vs. 25.35 months, p<0.001) and mOS (11.97 vs. 44.84 months, p=0.007). Area under the curve (AUC) analyses of PD-L1 expression, CXCL12 level and PD-L1 expression plus CXCL12 level to predict DCB or no durable benefit (NDB) showed AUC values of 0.680, 0.719 and 0.794, respectively. Conclusion: Our findings suggest that serum cytokine CXCL12 levels can predict the outcomes of patients with NSCLC receiving ICI. Moreover, the combination of CXCL12 levels and PD-L1 status can predict outcomes with a significantly improved discriminatory power.

MiR-95-3p acts as a prognostic marker and promotes cervical cancer progression by targeting VCAM1.

Background: Cervical cancer patients have a high risk of metastasis and a poor prognosis with shorter disease-free survival. Thus, novel biomarkers and feasible therapies urgently need to be discovered. Previous studies have shown that miR-95-3p plays crucial roles in several cancer types. However, the roles of miR-95-3p in cervical cancer remain unknown. Methods: The micro ribonucleic acid (miRNA) expression data and clinical characteristics of cervical cancer samples were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate Cox regression analyses were conducted to identify the prognostic-related miRNAs. The potential target genes of miR-95-3p were predicted by the TargetScan database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to explore the target gene of miR-95-3p. The effects of miR-95-3p inhibition and overexpression on cell proliferation were inspected by cell counting kit-8 (CCK-8) assays and cell colony formation assays. Wound-healing assays and transwell assays were also used to examine cell migration ability in HeLa and SiHa cells. Results: MiR-95-3p was the only miRNA significantly associated with the poor prognosis of cervical squamous cell carcinoma. A further analysis suggested that vascular cell adhesion molecule 1 (VCAM1) is a target gene of miR-95-3p in cervical cancer, and miR-95-3p promotes the malignant behavior of cervical cancer cells by inhibiting the expression of VCAM1. The CCK-8 and cell colony assays showed that miR-95-3p downregulation significantly suppressed cell proliferation in the HeLa and SiHa cells. The transwell and wound-healing assays showed that miR-95-3p inhibition suppressed cell migration in the HeLa and SiHa cells. Further the Western blot analysis and the quantitative real-time-polymerase chain reaction (qRT-PCR) showed that the knockdown of miR-95-3p in HeLa cells resulted in increased VCAM1 expression. And VCAM1 was highly expressed in the paired adjacent normal cervical epithelium tissue samples, but lowly expressed in the cervical tumor tissue samples. Conclusions: Our study was the first to show that miR-95-3p could serve as a prognostic biomarker of cervical cancer. Mechanistically, we discovered that miR-95-3p inhibited the expression of the cell adhesion molecule VCAM1 and thus promoted further tumor progression.

Polycyclic and nitro-polycyclic aromatic hydrocarbon pollution characteristics and carcinogenic risk assessment of indoor kitchen air during cooking periods in rural households in North China.

Medium-flow atmospheric samplers were used to collect particulate (PM2.5) and gaseous samples from the indoor kitchen of each of 35 randomly selected rural houses in North China while a meal was being cooked. The concentrations of 16 polycyclic aromatic hydrocarbons (PAHs) and 9 nitro-PAHs (NPAHs) in the samples were quantified by high-performance liquid chromatography (HPLC). This study provided the real PAH and NPAH pollution characteristics and carcinogenic risk produced by cooking in rural indoor kitchens in North China. The mean PAH and NPAH concentrations in air in the indoor kitchens during cooking periods were 4049.1 and 1741.6 ng/m3, respectively. The PAH and NPAH concentrations were lower in the particulate phase than the gaseous phase. The mean PAH and NPAH concentrations were much higher for cooking using coal than for cooking using liquefied petroleum gas (LPG) or electricity. The PAH and NPAH benzo[a]pyrene toxic equivalent (TEQBaP) concentrations for cooking using coal were 1823.3 and 2760.9 ng/m3, respectively. Lower PAH and NPAH concentrations were found in kitchens with than without range hoods. Range hoods decreased the PAH and NPAH TEQBaP concentrations by 68.8% and 61.9%, respectively. Appropriate fuel and ventilation choice will improve air pollution in indoor kitchens during cooking. The results provide important evidence for changing cooking habits and developing policies for cooking in rural China.

The proximity of ideas: An analysis of patent text using machine learning.

This paper introduces a measure of the proximity in ideas using unsupervised machine learning. Knowledge transfers are considered a key driving force of innovation and regional economic growth. I explore knowledge relationships by deriving vector space representations of a patent's abstract text using Document Vectors (Doc2Vec), and using cosine similarity to measure their proximity in ideas space. I illustrate the potential uses of this method with an application to geographic localization in knowledge spillovers. For patents in the same technology field, their normalized text similarity is 0.02-0.05 S.D.s higher if they are located within the same city, compared to patents from other cities. This effect is much smaller than when knowledge transfers are measured using normalized patent citations: local patents receive about 0.23-0.30 S.D.s more local citations than compared to non-local control patents. These findings suggest that the effect of geography on knowledge transfers may be much smaller than the previous literature using citations suggests.

Amino acid-amidated pectin: Preparation and characterization.

There is interest in extending the functionality of natural polymers using simple chemical derivatization methods. In this study, the ability of pectin to react with various amino acids (40 °C) in aqueous solution without a catalyst was investigated, including glutamic acid, glycine, cysteine, lysine, and arginine. Only glycine, lysine, and arginine could form conjugates with pectin under these conditions. Amino acid-amidated pectin (AAAP) conjugates with a degree of amidation of 6.50% were prepared and characterized using elemental analysis, FT-IR, and 1H NMR. Size exclusion chromatography combined with multiangle light scattering and refractive index detection indicated pectin degradation occurred during the reaction. These results were supported by measurements of apparent viscosities. Scanning electron microscopy showed appreciable differences among the surface topographies of samples. Cell culture experiments showed the AAAP conjugates exhibited no cytotoxic effects. Our results suggested the AAAP conjugates may be suitable for use as new functional ingredients in food industry.

Microtubule-binding protein FOR20 promotes microtubule depolymerization and cell migration.

Microtubules are highly dynamic filaments assembled from αß-tubulin heterodimers and play important roles in many cellular processes, including cell division and migration. Microtubule dynamics is tightly regulated by microtubule-associated proteins (MAPs) that function by binding to microtubules or free tubulin dimers. Here, we report that FOR20 (FOP-related protein of 20 kDa), a conserved protein critical for ciliogenesis and cell cycle progression, is a previously uncharacterized MAP that facilitates microtubule depolymerization and promotes cell migration. FOR20 not only directly binds to microtubules but also regulates microtubule dynamics in vitro by decreasing the microtubule growth rate and increasing the depolymerization rate and catastrophe frequency. In the in vitro microtubule dynamics assays, FOR20 appears to preferentially interact with free tubulin dimers over microtubules. Depletion of FOR20 inhibits microtubule depolymerization and promotes microtubule regrowth after the nocodazole treatment in HeLa cells. In addition, FOR20 knockdown significantly inhibits both individual and collective migration of mammalian cells. Taken together, these data suggest that FOR20 functions as a MAP to promote microtubule depolymerization and cell migration.

[Impact of Ammonia and H2O2 on Bromate and Disinfection By-products Control].

A pilot-scale study with conventional water treatment and ozone-biological activated carbon (O3-BAC) treatment was conducted to evaluate the impact of ammonia and hydrogen peroxide (H2O2) addition on the bromate and disinfection by-products formation potential (DBPFP) control, with bromide containing water as raw water. It was found that bromate concentration would exceed 10.00 µg·L-1 as ozone doses were higher than 1.0 mg·L-1 under different water qualities. Ammonia and H2O2could effectively control bromate formation and bromate concentration decreased as ammonia and H2O2 doses increased. Bromate concentration could be controlled below 10.00 µg·L-1 as ammonia dose was 0.10-0.30 mg·L-1 or the m(H2O2)/m(O3) was 0.2-1.0. However, as ammonia-H2O2 was combined for the same purpose, bromate increased firstly and then decreased. Ammonia addition would not significantly affect the THMFP control but H2O2 application would depress the efficiency of THMFP removal.

Characteristics of polycyclic aromatic hydrocarbons in food oils in Beijing catering services.

The concentrations and characteristics of 16 polycyclic aromatic hydrocarbons (PAHs) in 48 oil samples randomly collected from 30 catering services that employ six cooking methods were quantified via high-performance liquid chromatography (HPLC). These 16 PAHs were detected in almost all of the samples. The levels of Σ16PAHs, Σ4PAHs, benzo[a]pyrene (BaP), and total BaP equivalents (ΣBaPeq) for the six cooking methods exceeded the legal limit. The concentrations of Σ4PAHs were approximately 9.5 to 16.4 times the legal limit proposed by the European Commission (Off J Eur Union 215:4-8, 2011), and the level of BaP exceeded the national standard in China by 4.7- to 10.6-fold, particularly in oil from fried foods. Low molecular weight PAHs (LMW PAHs) were predominant in fried food oil from different catering services and accounted for 94.8 % of these oils, and the ΣBaPeq of the high molecular weight PAHs (HMW PAHs) was 11.5-fold higher than that of the LMW PAHs. The concentrations of Σ16PAHs (3751.9-7585.8 µg/kg), Σ4PAHs (144.6-195.7 µg/kg), BaP (79.7-135.8 µg/kg), and ΣBaPeq (231.0-265.4 µg/kg) were highest in the samples from fast food restaurants/buffets (FB), followed by those from fried food stalls (FS) and then cooking restaurants/cafeterias (RC). The results of this study suggest that the government should strengthen control and supervision of PAH contamination in food and edible oils.