Search Results (18)

Background: Cytokine-induced JAK–STAT signaling becomes dysregulated in chronic human diseases, including cancer and autoimmunity, and contributes to immune cell dysfunction. A cytokine-independent approach to activating STAT proteins could “hardwire” pro-survival and effector programs in immune cells to sustain function within diseased tissues. Engineered variants of the herpesvirus saimiri tyrosine kinase interacting protein (TIP) can recruit the SRC family kinase (SFK) LCK to drive STAT phosphorylation and activation. Here, we evaluated the interactome of a TIP-derived, cytokine-independent STAT5 activator and determined whether it could induce STAT5 activation in immune cell lines and primary human CD8+ T cells. Methods: A STAT5 activator (aSTAT5) was characterized by proteomics using affinity purification mass spectrometry (AP-MS) to define its interactome and STAT5 binding specificity. STAT5 phosphorylation was assessed in hematopoietic cell lines and primary human CD8+ T cells. Results: Proteomic analysis confirmed preferential association of aSTAT5 with STAT5 relative to other proteins. In cell-based assays, aSTAT5 induced robust STAT5 phosphorylation in LCK-expressing NK-92 and Jurkat T cells, whereas phosphorylation was not observed in Raji B cells or RAW 264.7 macrophages despite expression of closely related SFKs and STAT5. Cytokine-independent STAT5 phosphorylation supported the viability of NK-92 cells and primary human CD8+ T cells during cytokine withdrawal and preserved the cytotoxic function of CAR T cells. Conclusions: We defined the interactome of a cytokine-independent STAT5 activator and demonstrated its capacity to maintain survival and function in human CD8+ T cells and NK-92 cells. These findings underscore the translational potential of engineered, cytokine-independent STAT5 activation for immune cell therapies. Full article

Procyanidin B1 (PB1), a polyphenol abundant in Cyperus esculentus stems and leaves extract (CELE), exhibits antioxidant and anti-inflammatory activities, though its mechanisms are not fully understood. This study investigated CELE’s effects in chickens and LPS-stimulated HD11 macrophages. Chickens fed CELE showed increased blood levels of SOD, GSH-Px, TNF-α, IL-1β, IL-6, and IL-10, while MDA decreased. RNA-seq of LPS + PB1 vs. LPS-treated cells identified 696 differentially expressed genes enriched in inflammation and antioxidant pathways. Analysis indicated 120 transcription factors (TFs) may regulate these changes, with FOSL1, HIF1A, and STAT2 significantly downregulated. In HD11 cells, PB1 reduced expression of HIF1A/STAT2-target genes (e.g., HMGA2, EPSTI1), lowered IL-1β, IL-6, and ROS, and shifted macrophage polarization from M1 to M2. PB1’s effects were enhanced by an HIF1A inhibitor but reversed by a STAT2 activator. These findings support PB1 and CELE as potential feed additives for livestock. Full article

Background/Objectives: Doxorubicin (DOXO) is effective against various types of cancer; however, it is associated with hepatotoxicity that may eventually lead to liver fibrosis, limiting its clinical use. Aurora kinase A (AURKA) has emerged as a crucial regulator of essential cellular processes and a promising target to overcome tumors resistant to some anticancer drugs, including DOXO. However, the potential beneficial effect of targeting AURKA on DOXO-induced toxicities has not been explored yet. Therefore, the current study aimed to explore the potential protective effect of the AURKA-selective inhibitor alisertib on DOXO-induced hepatotoxicity in mice and address the possible underlying mechanism. Methods: Mice were treated with alisertib (10 and 20 mg/kg) daily for five consecutive days and challenged with DOXO (20 mg/kg, i.p.) once on day two. Results: Our findings revealed that alisertib significantly reduced biomarkers of liver dysfunction and oxidative stress elevated by the DOXO challenge. Interestingly, alisertib suppressed DOXO-induced IL-17A upsurge along with NF-κB and STAT3 activation. Alisertib also suppressed the upregulated expression of HIF-1α and VEGF-A as well as PERK activation associated with the DOXO challenge. Moreover, alisertib counteracted DOXO-induced TGF-β1 and α-SMA overexpression in the liver. These beneficial effects of alisertib were further reflected in the histopathological findings, which indicated the ability of alisertib to ameliorate DOXO-induced hepatic necroinflammation and fibrosis. Conclusions: Alisertib mitigates DOXO-induced hepatotoxicity in mice via targeting the IL-17A/NF-κB and IL-17A/STAT3/HIF-1α/VEGF-A signaling pathways, attenuating oxidative stress, inflammation, ER stress, and fibrosis. Full article

Background: Parkinson’s disease (PD) involves progressive dopaminergic neuron degeneration and motor deficits. Oligodendrocyte dysfunction contributes to PD pathogenesis through impaired myelination. Methods: Single-nucleus RNA sequencing (snRNA-seq) of PD mice revealed compromised oligodendrocyte differentiation and STAT5B downregulation. Pseudotemporal trajectory analysis via Monocle2 demonstrated impaired oligodendrocyte maturation in PD oligodendrocytes, correlating with reduced myelin-related gene expression (Sox10, Plp1, Mbp, Mog, Mag, Mobp). DoRothEA-predicted regulon activity identified STAT5B as a key transcriptional regulator. Results: Oligodendrocyte-specific STAT5B activation improved myelin integrity, as validated by Luxol Fast Blue staining and transmission electron microscopy; attenuated dopaminergic neuron loss; and improved motor function. Mechanistically, STAT5B binds the MBP promoter to drive transcription, a finding confirmed by the luciferase assay, while the DNMT3A-mediated hypermethylation of the STAT5B promoter epigenetically silences its expression, as verified by MethylTarget sequencing and methylation-specific PCR. Conclusions: DNMT3A inhibited the expression of STAT5B by affecting its methylation, which reduced the transcription of MBP, caused oligodendrocyte myelin damage, and eventually led to dopamine neuron damage and motor dysfunction in an MPTP-induced mouse model. This DNMT3A-STAT5B-MBP axis underlies PD-associated myelin damage, connecting epigenetic dysregulation with oligodendrocyte dysfunction and subsequent PD pathogenesis. Full article

Glioblastoma (GBM), as the most common primary brain tumor, usually results in an extremely poor prognosis, in which glioma stem cells (GSCs) and their immunosuppressive microenvironment prominently intervene in the resistance to radiotherapy and chemotherapy that directly leads to tumor recurrence and shortened survival time. The specific mechanism through which exosomes generated from GSCs support the creation of an immunosuppressive microenvironment remains unknown, while it is acknowledged to be engaged in intercellular communication and the regulation of the glioma immunosuppressive microenvironment. The elevated expression of LncRNA-NEAT1 was found in glioma cells after radiotherapy, chemotherapy, and DNA damage stimulation, and NEAT1 could promote the malignant biological activities of GSCs. Emerging evidence suggests that lncRNAs may reply to external stimuli or DNA damage by playing a role in modulating different aspects of tumor biology. Our study demonstrated a promotive role of the carried NEAT1 by GSC-derived exosomes in the polarization of M2-like macrophages. Further experiments demonstrated the mediative role of miR-125a and its target gene STAT3 in NEAT1-induced polarization of M2-like macrophages that promote glioma progression. Our findings elucidate the mechanism by which GSCs influence the polarization of M2-like macrophages through exosomes, which may contribute to the formation of immunosuppressive microenvironments. Taken together, our study reveals the miR-125a-STAT3 pathway through which exosomal NEAT1 from treatment-resistant GSCs contributes to M2-like macrophage polarization, indicating the potential of exosomal NEAT1 for treating glioma. Full article

Background: Differentiated thyroid cancer (DTC) patients have an outstanding overall long-term survival rate, and certain subsets of DTC patients have a very high likelihood of disease recurrence. Radioactive iodine (RAI) therapy is a cornerstone in DTC management, but cancer cells can eventually develop resistance to RAI. Radioactive iodine-refractory DTC (RAIR-DTC) is a condition defined by ATA 2015 guidelines when DTC cannot concentrate RAI ab initio or loses RAI uptake ability after the initial therapy. The RAIR condition implies that RAI cannot reveal new met-astatic foci, so RAIR-DTC metabolic imaging needs new tracers. ¹⁸F-FDG PET/CT has been widely used and has demonstrated prognostic value, but ¹⁸F-FDG DTC avidity may remain low. Fibroblast activation protein inhibitors (FA-Pi)s, prostatic-specific membrane antigen (PSMA), and somatostatin receptor (SSTR) tracers have been proposed as theragnostic agents in experimental settings and Arg-Gly-Asp (RGD) peptides in the diagnostic trial field. Multi-targeted tyrosine kinase inhibitors are relatively new drugs approved in RAIR-DTC therapy. Despite the promising targeted setting, they relate to frequent adverse-event onset. Sorafenib and trametinib have been included in re-differentiation protocols aimed at re-inducing RAI accumulation in DTC cells. Results appear promising, but not excellent. Conclusions: RAIR-DTC remains a challenging nosological entity. There are still controversies on RAIR-DTC definition and post-RAI therapy evaluation, with post-therapy whole-body scan (PT-WBS) the only validated criterion of response. The recent introduction of multiple diagnostic and therapeutic agents obliges physicians to pursue a multidisciplinary approach aiming to correct drug introduction and timing choice. Full article

The caddisflies (Trichoptera) of calcareous fen habitats, in contrast to those of other peatland types, have been poorly researched. We thus conducted a two-year study in south-eastern Poland encompassing four types of such habitats—drained and undrained fens and water bodies (pools and ditches) located within the fens—in order to define trichopteran reference assemblages (PCoA), indicator species (IndVal analysis), and the drivers (both natural and those associated with landscape management, including area protection) responsible for caddisfly species distribution (CCA). The most important environmental driver was habitat persistence. Distance-based RDA analysis revealed a distinct pattern in the distribution of species with or without diapause along the persistence gradient. Environmental drivers associated with plants were also crucial for both fens and water bodies. The key factor influencing the caddisfly assemblages of pools and ditches was the use and management of the surrounding land, whereas in the fens, it was the level of area protection. Physical and chemical water parameters had no statistically significant impact on the assemblages. Some factors can be modified by humans (e.g., water level regulation, vegetation, and landscape management) to maintain healthy ecosystems for aquatic insects. Full article

Mitochondrial Complex I plays a crucial role in the proliferation, chemoresistance, and metastasis of breast cancer (BC) cells. This highlights it as an attractive target for anti-cancer drugs. Using submitochondrial particles, we identified FRV–1, an ortho-carbonyl quinone, which inhibits NADH:duroquinone activity in D-active conformation and reduces the 3ADP state respiration dependent on Complex I, causing mitochondrial depolarization, ATP drop, increased superoxide levels, and metabolic remodeling towards glycolysis in BC cells. Introducing methyl groups at FRV–1 structure produced analogs that acted as electron acceptors at the Complex I level or increased the inhibitory effect of FCCP-stimulated oxygen consumption rate, which correlated with their redox potential, but increased toxicity on RMF-621 human breast fibroblasts was observed. FRV–1 was inactive in the naphthoquinone oxidoreductase 1 (NOQ1)-positive BC cell line, MCF7, but the sensitivity was recovered by dicoumarol, a NOQ1 inhibitor, suggesting that FRV–1 is a NOQ1 substrate. Importantly, FRV–1 selectively inhibited the proliferation, migration, and invasion of NQO1 negative BC cell, MDA-MB-231, in an OXPHOS- and ROS-dependent manner and sensitized it to the BH3 mimetic drug venetoclax. Overall, FRV–1 is a novel Complex I inhibitor in D-active conformation, blocking possibly the re-activation to A-state, producing selective anti-cancer effects in NQO1-negative BC cell lines. Full article

Bismuth shows outstanding optical properties, including a metal-like response in the ultraviolet-visible range and a dielectric character with a giant refractive index in the infrared range. In recent years, such unique properties have been employed to construct bismuth-based metamaterials with remarkable optical responses in these spectral regions, especially with cost-effective lithography-free methods. Such responses can be manipulated, both in an astatic way by suitable metamaterial design and in a dynamic way by harnessing the solid–liquid transition of bismuth. In this paper, we review the advances in this field and highlight the applications of such metamaterials to information technology production, energy harvesting and sensing. Full article

Hormone receptor-positive and HER2-negative (HR+/HER2−; luminal A) tumors are prevalent in breast cancer. Our past studies demonstrated that “TME Stimulation” (estrogen + TNFα + EGF, representing three arms of the tumor microenvironment, TME) has enriched metastasis-forming cancer stem cells (CSCs) in HR+/HER2− human breast cancer cells. Here, following information obtained by RNAseq analyses of TME-stimulated CSCs and Non-CSCs, we found that TME Stimulation has induced the activation of S727-STAT3, Y705-STAT3, STAT1 and p65. Upon TME Stimulation, stattic (STAT3 inhibitor) usage demonstrated that Y705-STAT3 activation negatively controlled CSC enrichment and epithelial-to-mesenchymal transition (EMT) traits, while inducing CXCL8 (IL-8) and PD-L1 expression. However, STAT3 knock-down (siSTAT3) had no effect on these functions; in terms of CSC enrichment, p65 had down-regulatory roles that compensated for the loss of an entire STAT3 protein. Y705-STAT3 and p65 acted additively in reducing CSC enrichment, and Y705A-STAT3 variant + sip65 has enriched chemo-resistant CSCs. Clinical data analyses revealed an inverse correlation between Y705-STAT3 + p65 phosphorylation and CSC signature in luminal A patients, and connection to improved disease course. Overall, we find regulatory roles for Y705-STAT3 and p65 in TME-stimulated HR+/HER2− tumors, with the ability to limit CSC enrichment. These findings raise concerns about using inhibitors of STAT3 and p65 as therapeutic strategies in the clinic. Full article

River discharge monitoring is an important component of the hydrology objectives of Surface Water and Ocean Topography mission (SWOT). River discharge can be estimated Solely using river widths and At Many-stations Hydraulic Geometry (AMHG), but the accuracy is low due to the parameters of At a-station Hydraulic Geometry (AHG) given by AMHG deviate from the truth. In view of this, a Constrained At-Many-Stations Hydraulic Geometry (CAMHG) is proposed to optimize AHG parameters. The performance of CAMHG is verified in three reaches of the Yangtze River using river widths derived from SWOT. After using CAMHG, the relative root mean square error (RRMSE) of estimated discharge reduce 100.1% to 24.4%, 1137.1% to 49.9% and 48.6% to 45.5% for Hankou, Shashi and Luoshan respectively. In addition, CAMHG can also weaken the accuracy difference of estimated discharge in dry and wet seasons benefited from its more reliable AHG parameters. Thus, the proposed CAMHG can dramatically improves the accuracy of discharge estimations and it is meaningful for the discharge calculation after SWOT data release. Full article

The alpha particle-emitting radionuclide astatine-211 (²¹¹At) is of interest for targeted radiotherapy; however, low in vivo stability of many ²¹¹At-labeled cancer-targeting molecules has limited its potential. As an alternative labeling method, we evaluated whether a specific type of astatinated aryl compound that has the At atom in a higher oxidation state might be stable to in vivo deastatination. In the research effort, para-iodobenzoic acid methyl ester and dPEG₄-amino acid methyl ester derivatives were prepared as HPLC standards. The corresponding para-stannylbenzoic acid derivatives were also prepared and labeled with ¹²⁵I and ²¹¹At. Oxidization of the [¹²⁵I]iodo- and [²¹¹At]astato-benzamidyl-dPEG₄-acid methyl ester derivatives provided materials for in vivo evaluation. A biodistribution was conducted in mice with coinjected oxidized ¹²⁵I- and ²¹¹At-labeled compounds. The oxidized radioiodinated derivative was stable to in vivo deiodination, but unfortunately the oxidized [²¹¹At]astatinated benzamide derivative was found to be unstable under the conditions of isolation by radio-HPLC (post animal injection). Another biodistribution study in mice evaluated the tissue concentrations of coinjected [²¹¹At]NaAtO₃ and [¹²⁵I]NaIO₃. Comparison of the tissue concentrations of the isolated material from the oxidized [²¹¹At]benzamide derivative with those of [²¹¹At]astatate indicated the species obtained after isolation was likely [²¹¹At]astatate. Full article

Fisheries in Cuitzeo, the second largest Mexican lake, used to take place on the permanent freshwater East and Central Basins as opposed to the temporal, saline, and initially thought barren West Basin. The 1980 fisheries collapse forced fishers to look for non-conventional fishing products elsewhere in the lake. The West Basin’s temporal, saline-alkaline, and shallow water provides exceptional habitat for ephydrids to flourish. Locally known as “pupa”, ephydrids are collected in large numbers. Although consumed since pre-Hispanic times, no other commercial fisheries of ephydrids are known worldwide. This study records the species composition and abundance of the “pupa” throughout an annual cycle in the West Basin, where fisheries occur. Two species were found: Ephydra hians and Lamproscatella muria. Ephydrids co-occurred in June and July at the end of the dry season when salinity was highest. L. muria was more abundant (954 ± 2385 ind m⁻²) than E. hians (94 ± 38 ind m⁻²). The relatively low salinity of the West Basin favoured L. muria over E. hians, which prefers higher salinities. This “pupa” fishery is still unpredictable due to the astatic nature of the lake, and hence limited economic importance to the local fishers. Full article

Measuring the viscosity and density of petroleum products is important for their proper production, transportation and application. Viscosity and density are the main parameters determining the composition and structure of petroleum products. Therefore, in the industry, to control the quality of petroleum products during various technological processes, automatic and non-automatic devices are used for their measurement. The accuracy of measuring the viscosity and density of petroleum products is an important factor. The authors analyzed different methods of measuring the viscosity and density of petroleum products and synthesized three versions of throttle bridge transducers. These versions implement differential measurement methods and have different numbers of laminar and turbulent throttles. The authors obtained new equations of static conversion functions by channels of measuring the kinematic viscosity and density of petroleum products of the proposed throttle bridge transducers. The authors developed a block diagram and designed measuring equipment to study experimentally the static characteristics of the throttle bridge transducers. The authors determined that the maximal relative deviations of the results of experimental studies from numerical calculations of a static conversion factor by channels of kinematic viscosity and density were 5.88% and 8.76%, respectively. The authors developed two versions of automatic devices for measuring the kinematic viscosity and density of petroleum products based on the proposed throttle bridge transducers. The first version is an automatic analyzer with tracking astatic balancing. The second version is an automatic analyzer with deployment balancing. The authors developed constructions of both versions of automatic analyzers and obtained the results of experimental measuring of the kinematic viscosity and density of petroleum products in different ranges. Full article

In this study, we examine, identify, and discuss fossil remains of large branchiopod crustaceans collected from six sites across the Beringian region (north-eastern Asia and north-western North America). Eggs and mandibles from Anostraca and Notostraca, as well as a notostracan telson fragment and a possible notostracan second maxilla, were collected from both paleosediment samples and also from large mammal hair. The remains of large branchiopods and other species that are limited to seasonally astatic aquatic habitats (temporary wetlands) could be useful indicator organisms of paleoecological conditions. Different recent large branchiopod species have very different ecological preferences, with each species limited to specific geochemical component tolerance ranges regarding various salinity, cation, and gypsum concentrations. Our purpose is to bring the potential usefulness of these common fossil organisms to the attention of paleoecologists. Full article