•The stratigraphic Mg isotopic profiles and the depositional cycles are coupled in the massive dolostone succession.•Mg isotope could be used to sequence the dolomitization events.•Massive dolostone ...could be generated by the temporal and spatial stacking of multiple dolomitization events.•Sea level fluctuation results in the stacking of multiple dolomitization events.
The origin of ancient massive dolostones, i.e. continuous dolostone sequence with a thickness >100 m and a platform-wide distribution, is the key issue of the ‘Dolomite Problem’ that cannot be clearly demonstrated by any existing dolomitization model individually or sequentially. It has been proposed that the massive dolostone could be generated by the stacking of multistage dolomitization events linked to the sea-level fluctuation, which results in repeatedly occurring of limestone precipitation-dolomitization cycles. However, the sequence of dolomitization events cannot be differentiated by any sedimentological or traditional geochemical techniques. Here we report Mg isotopic compositions of the massive dolostone (δ26Mgdol) from the middle Cambrian Qinjiamiao Formation (QJM) in the Yangtze Platform, South China, which consists of cyclic depositions of shoaling upward sequences. The stratigraphic variation of δ26Mgdol is coincident with the depositional cycles, suggesting the dolomitization might be periodic and be coupled with the sea-level oscillation. As dolomitization fluids experience changes in δ26Mg values during dolomitization processes, the intra-cycle stratigraphic δ26Mgdol profile reflects the processes of dolomitization. Our study indicates that the massive dolostone could be generated by the temporal and spatial stacking of multiple dolomitization events that are associated with sea-level fluctuation. If this model can be verified by other massive dolostone successions, the origin of massive dolostone may be resolved.
Receptor-interacting protein kinase 2 (RIPK2, also known as RIP2) was reported to be associated with bacterial infections as well as inflammatory responses. However, the role of RIPK2 in prognosis ...and immunotherapy response is yet to be elucidated in human pan-cancer.
In this study, we investigated the expression, gene alteration landscape and prognostic value of RIPK2 in 33 cancers through various databases including Ualcan, cBioportal and Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Then, the correlation between RIPK2 and immune infiltration, immune score, stromal score, and ESTIMATE score was investigated in the Cancer Genome Atlas (TCGA) and tumor immune estimation resource (TIMER) databases. Independent cohorts were utilized to explore the role of RIPK2 in tumor immunotherapy response. Furthermore, Gene set enrichment analysis (GSEA) was conducted to explore the mechanisms by which RIPK2 regulates immune therapy resistance. Single-cell RNA-seq datasets were used to analyze the expression level of RIPK2 on different immune cells. Moreover, CellMiner database was used to explore the relationship between RIPK2 expression with drug response.
Compared with normal tissue, tumor tissue had a higher expression level of RIPK2 in various cancers. Survival analysis showed that high expression of RIPK2 associated with poor prognosis in numerous cancers. RIPK2 was found to promote a series of immune cell infiltration and B cells, macrophages, and neutrophils were significantly positively correlated with the expression of RIPK2. Moreover, RIPK2 affected immune score, stromal score and ESTIMATE score for a wide range of cancers. In the vast majority of 33 cancers, gene co-expression analysis showed that RIPK2 was positively correlated with the expression of immune checkpoint markers, such as PDCD1 (PD-1), CD274 (PD-L1), CTLA4 and TIGIT. RIPK2 aggravated cytotoxic T lymphocyte (CTL) dysfunction and related to the poor efficacy of immune checkpoint blockade in skin cutaneous melanoma (SKCM) and kidney renal clear cell carcinoma (KIRC). High expression of RIPK2 promoted innate immunotherapy resistance and adaptive immunotherapy resistance through IL-6/JAK/STAT3 signaling, interferon-gamma response, and interferon-alpha response pathway.
These results confirmed that RIPK2 could serve as a prognostic biomarker and promoted immune therapy resistance via triggering cytotoxic T lymphocytes dysfunction.
Granulation is a key operation unit in preparation of iron ore raw materials. This work presented an experimental study on the iron ore granulation and sintering using a novel horizontal high-shear ...granulator and a traditional drum granulator. The mixing and granulation performance and the effect of granulation on sintering indicators were analyzed. The results showed that the optimal filling level of the shear granulator was about 9%, which was slightly lower than that of the drum granulator (12%). However, the uniformity, bed permeability and the fracture strength of the granules from the shear granulator were significantly better than those from the drum granulator. Compared with the drum granulator, the shear granulator had better mixing ability in the axial direction, more even distributions of water and calcium and less segregation. For the thick-bed sintering with a height of 900 mm, the sintering indicators in terms of sintering speed, sinter yield, strength and flue composition showed the shear granulator was significantly better than that of the drum granulator.
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•A novel horizontal high-shear granulator was used for iron ore granulation.•Granulation and sintering processes were coupled to evaluate granulation performance.•The optimal filling level of high-shear granulator was obtained and compared with the drum granulator.•The sinter indicators corresponding to high-shear granulator were better than that of drum granulator.
As the world's first oral nuclear export inhibitor, selinexor is increasingly being used in clinical applications for malignant tumors. However, there is no extensive exploration on selinexor's ...adverse events (ADEs), necessitating a real-word assessment of its clinical medication safety. FAERS data (July 2019-June 2023) were searched for selinexor ADE reports across all indications. Use the system organ class (SOC) and preferred terms (PT) from the medical dictionary for regulatory activities (MedDRA) to describe, categorize, and statistic ADEs. Disproportionality analysis was employed through calculation of reporting odds ratio (ROR) and proportional reporting ratio (PRR). Based on total of 4392 selinexor related ADE reports as the primary suspect (PS), of which 2595 instances were severe outcomes. The predominant ADEs included gastrointestinal disorders, myelosuppression symptoms, and various nonspecific manifestations. 124 signals associated with selinexor ADE were detected, and 10 of these top 15 signals were not included into the instructions. Our study provides real-world evidence regarding the drug safety of selinexor, which is crucial for clinicians to safeguard patients' health.
The earliest unambiguous evidence for animals is represented by various trace fossils in the latest Ediacaran Period (550-541 Ma), suggesting that the earliest animals lived on or even penetrated ...into the seafloor. Yet, the O
fugacity at the sediment-water interface (SWI) for the earliest animal proliferation is poorly defined. The preferential colonization of seafloor as a first step in animal evolution is also unusual. In order to understand the environmental background, we employed a new proxy, carbonate associated ferrous iron (Fe
), to quantify the seafloor oxygenation. Fe
of the latest Ediacaran Shibantan limestone in South China, which yields abundant animal traces, ranges from 2.27 to 85.43 ppm, corresponding to the seafloor O
fugacity of 162 μmol/L to 297 μmol/L. These values are significantly higher than the oxygen saturation in seawater at the contemporary atmospheric pO
levels. The highly oxygenated seafloor might be attributed to O
production of the microbial mats. Despite the moderate atmospheric pO
level, microbial mats possibly provided highly oxygenated niches for the evolution of benthic metazoans. Our model suggests that the O
barrier could be locally overcome in the mat ground, questioning the long-held belief that atmospheric oxygenation was the key control of animal evolution.
Introduction
OAS1(2’-5’-oligoadenylate synthetase 1) is a member of the Interferon-Stimulated Genes which plays an important role in the antiviral process. In recent years, the role of OAS1 in tumors ...has attracted attention, and it was found to be associated with prognosis in several tumors. However, the mechanism by which OAS1 affects tumors is unclear and pan-cancer study of OAS1 is necessary to better understand its implication in cancers.
Methods
The expression, prognostic value, genetic alteration, alternative splicing events of OAS1 in pan-cancers were analyzed using TCGA, GTEx, HPA, GEPIA and OncoSplicing databases. OAS1 associated immune cell infiltration was evaluated using the ESTIMATE, xCell, CIBERSORT and QUANTISEQ algorithm. Single cell transcriptome data download using TISH database. Finally, the roles of the OAS1 on apoptosis, migration and invasion were investigated in two pancreatic cancer cells.
Results
Our results revealed significant differences in OAS1 expression among various tumors, which had prognostic implications. In addition, we investigated the impact of OAS1 on genomic stability, methylation status, and other factors across different types of cancer, and the effects of these factors on prognosis. Notably, our study also demonstrated that OAS1 overexpression can contribute to CTL dysfunction and macrophage M2 polarization. In addition, cell experiments showed that the knockdown of OAS1 could reduce the invasive ability and increased the apoptosis rate of PAAD cells.
Discussion
These results confirmed that OAS1 could be a prognostic biomarker and therapeutic target for its potential role in CTL dysfunction and macrophage M2 polarization.
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•NK relieved DSS-induced chronic colitis.•NK maintained mucosal integrity by inhibiting apoptosis.•NK regulated gut microbiota of DSS-induced chronic colitis.•NK suppressed Trp ...metabolism via inhibiting IDO-1 in DSS-induced chronic colitis.
In this study, we investigated the protective effect of Nattokinase (NK), the most active ingredient in natto used for healthcare, on dextran sulfate sodium (DSS)-induced chronic colitis and unraveled the potential mechanisms. NK dramatically attenuated clinical symptoms and pathological damage of DSS-induced chronic colitis. NK also inhibited proinflammatory cytokines production in DSS-induced colonic tissues. Mucosal integrity was maintained by NK. Moreover, nattokinase reversed DSS-induced decline of bacteria community diversity and intestinal microbial imbalance by decreasing levels of Firmicutes and increasing levels of Bacteroidetes. Tryptophan (Trp) metabolism analysis demonstrated that NK suppressed Trp catabolism especially the Kynurenine (Kyn) pathway in chronic colitis. Furthermore, NK strikingly down-regulated the protein expression of IDO-1 in chronic colitis mice. Taken together, the study demonstrated that NK relieved DSS-induced chronic colitis by regulating gut microbiota and suppressing Trp metabolism via inhibiting IDO-1. This study indicated that NK might be a promising and effective agent for IBD.
The melter gasifier (MG) is the core unit in the COREX process for the final melting and reduction of iron. This work performed an experimental study to investigate the effects of charging pattern, ...burden bed height and burden material type on the burden distribution in a MG. The ore and coal (coke) were discharged intermittently to a 7.5:1 scaled-down model of a typical COREX MG. After the burden surface reached to a steady state, the burden was analysed in terms of ore-to-coal (coke) ratio, voidage distribution and particle size segregation. With different charging patterns, the ore and coal were not distributed uniformly but significant variation. The ore-to-coal (coke) ratio reached a maximum at the radius position of 0.6R where the thickness of ore was significantly larger than that of coal. The voidage distribution along the radial direction shows a U-shape with a minimum at the middle region. In addition, particle size segregation was observed along the radial direction of the burden pile: the smaller particles tended to accumulate in the centre while the larger ones segregated more evidently near the wall. The results showed that the charging pattern was the major factor affecting the burden distribution, followed by burden material type while the burden bed height had a minimum effect.
Acoustic emission (AE) or vibration signal has been applied in detecting operations of grinding mills in many industries. This paper proposes an approach to generate AE signals based on the ...particle-wall impacts. Through a combination of multi-mode vibrations and the calibration of the key parameters, the model was able to reproduce experimental data. The AE model was then implemented into a discrete element method (DEM) modelling of particle flow in a rotating mill. The AE signals of the mill under different filling levels and rotation speeds were generated and analysed, mainly focusing on the frequency and magnitude of each vibration mode. The link between the AE signals and the particle-wall impact energy was explored.
Discrepancies in the utilization of reactive oxygen species (ROS) between cancer cells and their normal counterparts constitute a pivotal juncture for the precise treatment of cancer, delineating a ...noteworthy trajectory in the field of targeted therapies. This phenomenon is particularly conspicuous in the domain of nano-drug precision treatment. Despite substantial strides in employing nanoparticles to disrupt ROS for cancer therapy, current strategies continue to grapple with challenges pertaining to efficacy and specificity. One of the primary hurdles lies in the elevated levels of intracellular glutathione (GSH). Presently, predominant methods to mitigate intracellular GSH involve inhibiting its synthesis or promoting GSH efflux. However, a conspicuous gap remains in the absence of a strategy capable of directly and efficiently clearing GSH.
We initially elucidated the chemical mechanism underpinning oridonin, a diminutive pharmacological agent demonstrated to perturb reactive oxygen species, through its covalent interaction with glutathione. Subsequently, we employed the incorporation of maleimide-liposomes, renowned for their capacity to disrupt the ROS delivery system, to ameliorate the drug's water solubility and pharmacokinetics, thereby enhancing its ROS-disruptive efficacy. In a pursuit to further refine the targeting for acute myeloid leukemia (AML), we harnessed the maleic imide and thiol reaction mechanism, facilitating the coupling of Toll-like receptor 2 (TLR2) peptides to the liposomes' surface via maleic imide. This strategic approach offers a novel method for the precise removal of GSH, and its enhancement endeavors are directed towards fortifying the precision and efficacy of the drug's impact on AML targets.
We demonstrated that this peptide-liposome-small molecule machinery targets AML and consequently induces cell apoptosis both in vitro and in vivo through three disparate mechanisms: (I) Oridonin, as a Michael acceptor molecule, inhibits GSH function through covalent bonding, triggering an initial imbalance of oxidative stress. (II) Maleimide further induces GSH exhaustion, aggravating redox imbalance as a complementary augment with oridonin. (III) Peptide targets TLR2, enhances the directivity and enrichment of oridonin within AML cells.
The rationally designed nanocomplex provides a ROS drug enhancement and targeted delivery platform, representing a potential solution by disrupting redox balance for AML therapy.
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