Hexokinase 3 (HK3) is one of the key enzymes involved in glucose phosphorylation (the first step in most glucose metabolic pathways). Many studies have demonstrated the vital role of dysregulation of ...HK3 in several tumors. However, there is a need for in-depth characterization of the role of HK3 in glioblastoma multiforme (GBM).
All data were sourced from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA). Kaplan-Meier analysis and univariate regression were applied for survival analysis. Gene set enrichment analysis (GSEA) was used for enrichment analysis. Tumor Immune Single Cell Hub (TISCH) database was applied for single-cell analysis. Tumor Immune Dysfunction and Exclusion (TIDE) analysis was applied to evaluate the immune response.
HK3 expression was upregulated in GBM and correlated with poor prognosis. The high HK3 expression group was primarily enriched in adaptive immune response, chemokine signaling pathway, and cytokine-cytokine receptor interaction. The high HK3 expression group showed significantly greater enrichment of the majority of immune cells and immune-related pathways. HK3 showed significant correlation with most immune cells, especially macrophages (
< .001, R = .81). TISCH analysis showed that HK3 was predominantly expressed in macrophages in most cancers. HK3 showed significant correlation with most immune-related genes, such as PD-1 (
< .001, R = .41), PDL-1 (
< .001, R = .27), and CTLA-4 (
< .001, R = .29). TIDE analysis revealed that the low HK3 expression group has a lower TIDE score and may benefit from immunotherapy. Drug sensitivity analysis showed that patients with high HK3 expression frequently showed drug resistance.
HK3 was associated with poor prognosis and may serve as a biomarker of macrophages in GBM. HK3 was also associated with immune response and drug resistance. Our findings may provide novel insights for GBM immunotherapy.
Plasmacytoid dendritic cells (pDCs) play a critical role in antiviral immunity through their ability to produce large amounts of type I IFNs. Activation of pDCs upon viral infection has been shown to ...be dependent on MyD88 and mediated by Toll-like receptors (TLR) 7 and 9, which sense viral ssRNA and CpG DNA, respectively. In this study, we showed that murine pDC recognition of vaccinia virus (VV), a dsDNA virus, was MyD88-dependent but TLR9-independent. Using HEK293 cells transfected with murine TLR7 or TLR8 and a NF-κB luciferase reporter, we demonstrated that stimulation of TLR8-, but not TLR7-, transfected cells with either VV or VV DNA resulted in substantial NF-κB activation, and that siRNA-mediated knockdown of TLR8 expression in pDCs led to a complete ablation of VV-induced type I IFN production. We further identified that the VV genome was rich in poly(A)/T sequences, and synthetic poly(A) and poly T oligodeoxynucleotides were capable of activating pDCs in a TLR8-dependent manner. In vivo, TLR8-MyD88-dependent pDC activation played a critical role in innate immune control of VV infection. Collectively, our data are unique in demonstrating that TLR8 is required for sensing poly(A)/T-rich DNA in pDCs, and that murine TLR8 is functional in the context of a viral infection.
The compositional stratigraphy of Al-rich clays overlying Fe/Mg-rich clays on Mars has been viewed as a window to understanding the atmospheric conditions of early Mars. Compact Reconnaissance ...Imaging Spectrometer for Mars (CRISM) indicates that nontronite is a main component of Fe/Mg-rich clays. However, the role of the ancient climate in the alteration process, which produced and dissolved these phyllosilicates, remains under debate. The present study experimentally modeled the dissolution of nontronite and precipitation of kaolinite in an acidic solution, which enables us to enhance the interpretation of near-infrared remote sensing data from compositional stratigraphy on Mars. The obtained results show that the transformation started from the losses of both tetrahedral Si and interlayer alkali(earth) cations in nontronite, and Fe3+ in the dioctahedral sheet was released and formed hematite with progressive damage of SiO tetrahedral sheets. TG analyses also show that the dissolution of nontronite and precipitation of kaolinite led to an increase in metal-OH (metal = Al, Fe3+ and Mg) content and a simultaneous decrease in H2O content. Accordingly, the gradual increasing trend of visible/near-infrared reflectance (VNIR) spectra ratios of BD1400/BD1900 (BD, band depth) in the kaolinized nontronite can be linked to a gradual upward transition from nontronite to a mixture of nontronite and kaolinite, and finally into kaolinite and hematite, by comparing their spectral features at different evolution stages. Such a trend suggests a weathering process known as ferrallitization, i.e., partial leaching of Si and enrichment of Fe3+ and Al3+. The observed weathering process is consistent with a warm and wet climate capable of sustaining acidic liquid water on its surface over extended geological periods.
•A semi-quantitative investigation was conducted to examine VNIR proxies for characterizing nontronite ferrallitization.•Formation of hematite and kaolinite in the compositional stratigraphy on Mars was resulted from nontronite ferrallitization.•A warm and wet climate capable of sustaining acidic liquid water possibly existed on martian surface.
Introduction
The lungs are extremely vulnerable to ischemia/reperfusion (I/R), which is characterized by intense inflammation, oxidative stress, alveolar damage, and vascular permeability. Parecoxib ...sodium (Pare) has been shown to exert protective effects against multiple I/R‐induced tissue injuries. However, its role in I/R‐induced lung injury remains unknown. This study aimed to reveal the roles and mechanisms of Pare in pulmonary I/R injury.
Methods
Sixty‐six rats were randomly divided into three groups: The sham‐operated group, the pulmonary I/R group, and the Pare‐pretreated I/R group. Pare at 10 mg/kg or saline (vehicle control) were intraperitoneally administered to rats once per day for 5 consecutive days before ischemia. Serum and tissue samples were harvested following 2 h of reperfusion. The oxygenation index (OI) and alveolar‐arterial oxygen partial pressure difference (PA‐aO2) were analyzed. The levels or activities of malondialdehyde, superoxidase dismutase, catalase, glutathione peroxidase, intracellular reactive oxygen species, tumor necrosis factor‐α, interleukin (IL)‐6, and IL‐8 were examined. The mitochondrial membrane potential was measured. The protein expression levels of the extracellular signal‐regulated kinase (ERK), nuclear factor‐κB (NF‐κB) and their phosphorylated forms, and hypoxia‐inducible factor‐1α (HIF‐1α) were detected. Histological changes were observed using hematoxylin and eosin staining. Moreover, the survival rate following pulmonary I/R injury was recorded daily.
Results
Pare significantly increased the OI, decreased the PA‐aO2, increased the levels of antioxidants, while decreasing the levels of oxidants, and alleviated mitochondrial dysfunction and the histopathological damage induced by I/R. Furthermore, Pare inhibited the expression of proinflammatory cytokines, suppressed the activation of ERK and NF‐κB, further increased HIF‐1α expression, and significantly improved the rat survival rate.
Conclusions
Pare pretreatment attenuated lung I/R injury by inhibiting oxidative stress and the inflammatory response possibly via inhibiting the activation of the ERK/NF‐κB pathway and further activating the HIF‐1α pathway.
Parecoxib sodium alleviates ischemia/reperfusion (I/R)‐induced pulmonary injury via inhibiting extracellular signal‐regulated kinase/nuclear factor‐κB and further activating the hypoxia‐inducible factor‐1α pathway
Non-line-of-sight (NLOS) target detection utilizing multipath plays an important role in anti-terrorism, urban warfare, indoor rescue and intelligent driving. In this paper, an imaging method based ...on single-channel ultra-wideband (UWB) radar and dual-view observation is proposed for detecting NLOS targets. First, the cause of producing ghosts from a single view in a previous study is analyzed in detail. On this basis, with focusing on dual-view observation, the ghost problem is handled at two levels. From the level of the radar echo, path partition is conducted with the utilization of dual-view observation, solving the problem of uneven energy among multipaths. After that, two images are generated by multipath imaging, respectively, which reduces the accumulation of ghosts. From the level of the image, owing to the distinct distribution of ghosts between the imaging result, the ghosts at different locations are eliminated by image fusion. Experimental results demonstrate that compared with single view and direct multipath imaging, the approach based on dual-view observation successfully eliminates most ghosts while retaining the targets in both single-target and double-targets scenarios, which verifies the effectiveness of the method.
Abstract
Advances in crystal nucleation and growth over the past three decades have led to the understanding that crystallization proceeds through a variety of pathways, ranging from the conventional ...atom-by-atom model to the particle aggregation- or amorphous transformation-based non-classical modes. Here, we present a novel mineralization mechanism exemplified by a lunar chromite formed via solid-liquid interface reactions, through investigations towards a lunar breccia returned by the Chang'e 5 mission. The chromite occurs in the middle of a whisker-shaped intergrowth structure made by olivine at the bottom and nanospheres of troilite and metallic iron at the top. Morphological observation and size statistics of the nanospheres, including those within the whisker structure and the others dispersed in glass, suggest the nanophases attached to olivine with coherent crystallographic orientations, possibly through an oriented aggregation process. The chromium deficiency in the olivine near the interface between olivine and chromite suggests that Cr in chromite originated from olivine, but the significantly reduced ferrous concentration in the glass surrounding chromite indicates the iron was derived from surrounding impact-induced glass. Based on laboratory observations and simulated calculations of energy and lattice mismatch, we propose that chromite crystallized at the interface between troilite and olivine in the impact melts, during which the nanospheres were lifted up and transported away from olivine surface and form a mushroom-shaped structure. This finding suggests that oriented attachment growth, chiefly confined to homogeneous systems thus far, can also take place in heterogeneous systems far from equilibrium, such as that produced by the impacts. It is conceivable that the studied crystallization pathway occurring on the heterogeneous interfaces may have been a common mineralization mode at highly-nonequilibrium conditions.
The composition and microstructure of phyllosilicates are prone to transformation due to their great sensitivity to surrounding physicochemical changes. Berthierine (R
,R
,□)
(Si,Al)
(OH)8 (□ ...represents octahedral vacancy) is a typical ferromagnesian phyllosilicate that commonly occurs in ferruginous rocks of shallow-marine habitats and has been used as an indicator of local depositional and/or hydrothermal activity in marine environments. However, little is known about the formation and mineralogy of non-marine berthierine, particularly in volcanic systems. Using high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM), we have identified a berthierine twin structure within weakly altered biotite in a rhyolite from Long Valley, California, U.S.A. The presence of nanoscale Fe-rich layers in the host biotite is revealed by energy-dispersive spectroscopy and electron energy loss spectroscopy (EELS). The HAADF-STEM pictures with atomic resolution demonstrate that the Fe-rich layers are composed of twinning berthierine layers rather than a single chlorite layer. The transformation of biotite to berthierine requires the dissolution of a tetrahedral (T) layer and the introduction of a new TO (O represents octahedral sheet) structure into the biotite stacking sequence, resulting in substituting one biotite layer (i.e., TOT) with two twinning berthierine layers (i.e., TO-OT). Observations based on morphology indicate that the transformation began at biotite defect locations (such as screw dislocation, edge dislocation, and microcleavage fracture), concurrent with the rearrangement of metal cations. During the fluid alteration of biotite, berthierine was produced via an interface-coupled dissolution-reprecipitation process. The EELS analyses further demonstrate that the Fe-rich biotite promotes the production of berthierine as the principal alteration product in low-temperature environments. Additionally, this study suggests that the combination of HAADF-STEM and EELS is effective for identifying nanominerals and elucidating their formation and alteration mechanisms.
People with hypertension have a higher risk of developing Parkinson's disease (PD), epidemiological evidence suggests that multiple antihypertensives may affect the occurrence and development of PD ...with inconsistent results. With multisource data, we sought to determine whether specific antihypertensive classes elevated or reduced the risk for PD.
We used a mixed methods approach that combines 4 methodologies. First, we conducted a disproportionality analysis using the reports causing adverse events in the US Food and Drug Administration Adverse Events Reporting System (FAERS) to explore the effect of different classes of antihypertensive medications on the risk of PD; based on the findings from FAERS, a meta-analysis and a UK Biobank cohort analysis were used to further assess the association of drug use with PD; finally, we employed Mendelian randomization (MR) analysis to validate the causal relationship between the drug target and the occurrence of PD.
In the disproportionality analysis using the FAERS (N = 187,266), nonselective beta-adrenoceptor blockers (NBBs) were demonstrated to have a significant association with PD (reporting odds ratio (ROR) = 3.13; 95% CI 2.33-4.22). In the meta-analysis of 12 studies with 12,183,809 participants, PD risk was elevated in NBBs (RR, 1.64; 95% CI, 1.19-2.09) when stratified by subtypes of BBs. Among the 105,763 participants included in the cohort analysis using data from the UK Biobank, individuals who used NBBs had a significantly increased risk of PD compared to nonusers (HR, 1.47; 95% CI 1.04-2.06). The MR analysis revealed a significant association between higher expression of the β2 adrenergic receptor (ADRB2) gene, a drug target blocked by NBBs, and a reduced risk of PD (OR, 0.85; 95% CI 0.73-0.99).
Our comprehensive study indicated that regular NBB use is associated with an increased risk of PD. In light of the detrimental effects of NBBs on PD, some people should choose alternative antihypertensive treatments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Ion-adsorption-type rare earth element (REE) deposits are the source of more than 90% of global heavy REEs (HREEs). Thus, understanding the ore genesis of REEs, particularly the distribution ...characteristics and enrichment mechanisms of HREEs, is vital for efficient exploration and mining of ion-adsorption-type REE deposits worldwide. The characteristics and petrogenesis of bedrock, and the aqueous mobility of REEs, are known to be important factors controlling REE accumulation and fractionation in the weathering crust of REE deposits. However, the effect of REE adsorption on secondary minerals, which is a crucial step in deposit formation, remains poorly understood. This problem was addressed by the study described herein, which involved a systematic analysis of the complete weathering profile (78 m) of the Renju ion-adsorption-type REE deposit in South China and a simulated adsorption experiment. Clay minerals and iron (Fe) (hydr)oxides are the dominant REE adsorbents in the weathering crust and most are micro-to-nanosized particles. Thus, the fine particle fraction (< 2 μm) was separated from field samples, to better disclose their effects on the concentration and redistribution of REEs. Phase compositions and morphologies were characterized by X-ray diffraction, Mössbauer spectrometry, and scanning/transmission electron microscopy (SEM/TEM), which revealed that various clay minerals and Fe (hydr)oxides form composites along the profile of the deposit. Composites of ferrihydrite–kaolinite, goethite–kaolinite/halloysite, and hematite–kaolinite/halloysite were found to be distributed in the semi-weathered, completely weathered, and topsoil layers, respectively, with different sizes and shapes. The concentrations and partition patterns of REEs in different occurrence states were distinguished after sequential extraction. Ion-exchangeable-REEs were the major state and enriched in the upper completely weathered layer. These species were found to be adsorbed onto kaolinite and halloysite via electrostatic attraction, without obvious fractionation. Fe (hydr)oxides were determined to comprise ca. 20% of REEs at most depths and over 50% of REEs in the topsoil and semi-weathered layer. It was found that Fe (hydr)oxides scavenge REEs through complexation and oxidation, resulting in HREE enrichment and a positive cerium (Ce) anomaly, respectively. In addition, compared with crystalline Fe (hydr)oxides, amorphous Fe (hydr)oxides immobilize more REEs but exhibit weaker preferential adsorption of HREEs. The above-described findings are consistent with the results of simulated experiments for REE adsorption onto a clay mineral–Fe (hydr)oxide composite (Bt-60), which was obtained from hydrothermal processing of biotite. Furthermore, the distributions and stabilities of LREEs and HREEs were distinguished by TEM–energy–dispersive spectroscopy (EDS) of Bt-60 before and after REE extraction by ammonium sulfate. The phase transformation pathways of clay minerals and Fe (hydr)oxides, and their different enrichment and fractionation characteristics in REEs, were also discussed in terms of the structure and surface properties of minerals, adsorption mechanisms, and variations in chemical properties across the REE group. The results shed new light on how clay minerals and Fe (hydr)oxides affect the enrichment and fractionation of REEs in ion-adsorption-type deposits.
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