We report on the first experimental and theoretical investigations of ultrafast intramolecular energy transfer for a novel class of highly luminescent materials – nanostructured organosilicon ...luminophores (NOLs). For this purpose we designed, synthesized and investigated a NOL,
(POPOP)Si2(3Ph-EH)6
, consisting of six
p
-terphenyl (
3Ph
) donor and 1,4-bis(5-phenyloxazol-2-yl)benzene (
POPOP
) acceptor luminophores – well-known laser dyes widely used in plastic scintillators as an activator and a spectral shifter, respectively. The NOL shows excellent optical properties – molar absorption coefficient up to 2.6 × 10
5
L mol
−1
cm
−1
, photoluminescence quantum yield up to 96% and pseudo Stokes shift of 100 nm. Its intramolecular energy transfer efficiency determined from steady-state optical measurements was found to be 93%, while the excitation lifetime was less than 1 ns. For deeper understanding of the processes of intramolecular energy transfer within NOLs, ultrafast spectroscopy investigations of the NOL, model donor and acceptor luminophores were performed for the first time for this class of compounds. It was found that the time constant of the energy transfer from donor to acceptor luminophores within the NOL is
τ
1
= 105 fs, which is significantly faster than the vibrational relaxation within the donor (
ca.
400 fs). Based on these findings, a kinetic scheme of the electronic excitation energy deactivation processes in the NOL was developed. The results obtained not only directly prove that the mechanism of energy transfer within the NOLs is based on Förster resonance energy transfer of the excitation energy from donor to acceptor luminophores, but also highlight the advantages of NOLs and NOL-based materials for future photonics applications – fast and efficient plastic scintillators, scintillating fibers and other spectral shifting optical materials.
Hypoxia-inducible factor-1 (HIF-1) and its most important subunit, HIF-1α, plays a central role in tumor progression by regulating genes involved in cancer cell survival, proliferation and ...metastasis. HIF-1α activity is associated with nuclear accumulation of the transcription factor and regulated by several mechanisms including modulation of protein stability and degradation. Among recent advances are the discoveries that inflammation-induced cytokines and growth factors affect protein accumulation of HIF-1α under normoxia conditions. TNFα, a major pro-inflammatory cytokine that promotes tumorigenesis is known as a stimulator of HIF-1α activity. To improve our understanding of TNFα-mediated regulation of HIF-1α nuclear accumulation we screened a kinase-specific siRNA library using a cell imaging-based HIF-1α-eGFP chimera reporter assay. Interestingly, this systematic analysis determined that depletion of kinases involved in conventional TNFα signaling (IKK/NFκB and JNK pathways) has no detrimental effect on HIF-1α accumulation. On the other hand, depletion of PRKAR2B, ADCK2, TRPM7, and TRIB2 significantly decreases the effect of TNFα on HIF-1α stability in osteosarcoma and prostate cancer cell lines. These newly discovered regulators conveyed their activity through a non-conventional RELB-depended NFκB signaling pathway and regulation of superoxide activity. Taken together our data allow us to conclude that TNFα uses a distinct and complex signaling mechanism to induce accumulation of HIF-1α in cancer cells. In summary, our results illuminate a novel mechanism through which cancer initiation and progression may be promoted by inflammatory cytokines, highlighting new potential avenues for fighting this disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tumor-initiating cells (TICs) contribute to drug resistance and tumor recurrence in cancers, thus experimental approaches to dissect the complexity of TICs are required to design successful TIC ...therapeutic strategies. Here, we show that miRNA-3′ UTR sensor vectors can be used as a pathway-based method to identify, enrich, and analyze TICs from primary solid tumor patient samples. We have found that an miR-181ahigh subpopulation of cells sorted from primary ovarian tumor cells exhibited TIC properties in vivo, were enriched in response to continuous cisplatin treatment, and showed activation of numerous major stem cell regulatory pathways. This miRNA-sensor-based platform enabled high-throughput drug screening leading to identification of BET inhibitors as transcriptional inhibitors of miR-181a. Taken together, we provide a valuable miRNA-sensor-based approach to broaden the understanding of complex TIC regulatory mechanisms in cancers and to identify miRNA-targeting drugs.
•miRNA sensors provide a novel approach to identify TICs in primary human tumors•miR-181a is a driver of tumor initiation in ovarian cancer•miRNA sensors allow discovery of miRNA transcriptional regulators and targeting drugs•BET inhibitors are novel miR-181a-targeting drugs
In this article, DiFeo and colleagues have utilized a miRNA 3′ UTR biosensor to study tumor-initiating cells in ovarian cancer and develop a high-throughput platform to uncover miRNA-targeting drugs. They have identified miR-181a as a potent driver of tumor initiation, which can be regulated by BET inhibitors, thus introducing a previously unknown biomarker for these drugs.
Optical materials doped with manganese ions have attracted interest as a red phosphor for warm white light LEDs. Lead-phosphate glasses are chosen for doping with manganese ions due to high ...refractive index of such material. In this study, new 50 PbO – 50 P2O5 – xMnO2 (x = 0.1, 1, 3, 5, 7, 10, 13 mol%) glasses are synthesized. To determine the optimal manganese ion concentration (to be used as the red phosphor) in those glasses, their spectral and luminescent properties are investigated. Mn2+ ions in lead-phosphate glasses have intense red luminescence in the wavelength range 620–690 nm. The Mn3+ ion to the total Mn ions ratio is found less than 0.1% based on the visible absorption spectroscopy data. Manganese ions in that glass are disposed at non-equivalent positions that results in nonexponential lifetime decay. The maximum absolute quantum yield value of Mn2+ ions is 49% in glass with 2.91 mol% MnO2.
The purpose of this article is to study specific features of the accumulation and distribution of the total content and mobile forms of Heavy Metals (HM) in soils of the estuarine ecosystems of the ...floodplain and deltaic landscapes of the Don River. The results allowed the authors to detect regional specific features in the formation of HM compounds in floodplain soils of the Don River estuarine region and the changes that occur with soil pollution and to detect the influence of different factors on the transformation of metal compounds in the soils and estimate them ecologically. It was shown that the distribution of total HM content in the investigated soils is determined primarily by their content in pedogenic species of the Don river floodplain, as well as by soil factors: The organic matter content and particle-size fractions. The system of chemical element compounds forms a relationship of different compound groups, with strongly bound metal forms predominating.
Regeneration of myelin is mediated by oligodendrocyte progenitor cells-an abundant stem cell population in the central nervous system (CNS) and the principal source of new myelinating ...oligodendrocytes. Loss of myelin-producing oligodendrocytes in the CNS underlies a number of neurological diseases, including multiple sclerosis and diverse genetic diseases
. High-throughput chemical screening approaches have been used to identify small molecules that stimulate the formation of oligodendrocytes from oligodendrocyte progenitor cells and functionally enhance remyelination in vivo
. Here we show that a wide range of these pro-myelinating small molecules function not through their canonical targets but by directly inhibiting CYP51, TM7SF2, or EBP, a narrow range of enzymes within the cholesterol biosynthesis pathway. Subsequent accumulation of the 8,9-unsaturated sterol substrates of these enzymes is a key mechanistic node that promotes oligodendrocyte formation, as 8,9-unsaturated sterols are effective when supplied to oligodendrocyte progenitor cells in purified form whereas analogous sterols that lack this structural feature have no effect. Collectively, our results define a unifying sterol-based mechanism of action for most known small-molecule enhancers of oligodendrocyte formation and highlight specific targets to propel the development of optimal remyelinating therapeutics.
Excessive complement activation contributes significantly to the pathogeneses of various diseases. Currently, significant developmental research efforts aim to identify complement inhibitors with ...therapeutic uses have led to the approval of one inhibitor for clinical use. However, most existing complement inhibitors are based on monoclonal antibodies, which have many drawbacks such as high costs and limited administration options. With this report, we establish an inexpensive, cell imaging-based high-throughput assay for the large-scale screening of potential small molecule complement inhibitors. Using this assay, we screened a library containing 3115 bioactive chemical compounds and identified cisplatin and pyridostatin as two new complement inhibitors in addition to nafamostat mesylate, a compound with known complement inhibitory activity. We further demonstrated that cisplatin and pyridostatin inhibit C5 convertases in the classical pathway of complement activation but have no effects on the alternative pathway of complement activation. In summary, this work has established a simple, large-scale, high-throughput assay for screening novel complement inhibitors and discovered previously unknown complement activation inhibitory activities for cisplatin and pyridostatin.
Ternary phosphate glass doped with different terbium concentration (up to 35 wt.%) is synthesized via standard melt-quenching technique. The effect of terbium content on physical, optical, and ...magneto-optical properties is investigated. Two glass transition regions on DSC curve at 35 wt.% Tb2O3 demonstrate phase-separation process. Transmittance spectra demonstrate maximum 0.2 cm−1 level in optical transmittance window of 400–1600 nm limited by standard absorption bands for terbium-containing materials. Metaphosphate groups in as-synthesized glass structure are predominant over polyphosphate complexes with no ultraphosphate units regardless to composition changes. After the additional heat treatment the partial depolymerization of glass structure occurs resulting in formation of big amount of Q0 and Q1 units. Glass refractive index varies from 1.5872 to 1.5814 with terbium content increase. The concentration dependence of Verdet constant is non-linear due to the presence of Tb4+ ions, which was confirmed by the XPS analysis results. The value of 15 rad/T/m at 1064 nm is reached for 35 wt.% Tb2O3-doped glass. The results indicate the viability of the considered glass series with high terbium oxide concentration to be attractive media for magnetooptical devices working in VIS and near IR ranges.
•Phosphate glass with a high terbium content (up to 35 wt.%) is synthesized.•0.2 cm−1 level in glass optical transmittance window of 400–1600 nm is observed.•Maximum of Verdet constant (15 rad/T/m at 1064 nm) is reached at 35 wt.% Tb2O3.•Considered glass with high terbium content is suitable for magnetooptical devices.
Abstract Proteasomes generate antigenic peptides that are presented on the tumor surface to cytotoxic T-lymphocytes (CTLs). Immunoproteasomes are highly-specialized proteasome variants that are ...expressed at higher levels in antigen-presenting cells and contain replacements of the three constitutive proteasome catalytic subunits to generate peptides with a hydrophobic C-terminus that fit within the groove of MHC class I (MHC-I) molecules. A hallmark of cancer is the ability to evade immunosurveillance by disrupting the antigen presentation machinery and downregulating MHC-I antigen presentation. High-throughput screening was performed to identify Compound A, a novel molecule that selectively increased immunoproteasome activity and expanded the number and diversity of MHC-I-bound peptides presented on multiple myeloma (MM) cells. Compound A increased the presentation of individual MHC-I-bound peptides >100-fold and unmasked tumor-specific neoantigens on myeloma cells. Global proteomic integral stability assays determined that Compound A binds the proteasome structural subunit PSMA1 and promotes association of the proteasome activator PA28α/β (PSME1/PSME2) with immunoproteasomes. CRISPR/Cas9 silencing of PSMA1, PSME1, or PSME2 as well as treatment with immunoproteasome-specific suicide inhibitors abolished the effects of Compound A on antigen presentation. Treatment of MM cell lines and patient bone marrow-derived CD138+ cells with Compound A increased the antimyeloma activity of allogenic and autologous T-cells. Compound A was well-tolerated in vivo and co-treatment with allogeneic T-cells reduced the growth of myeloma xenotransplants in NSG mice. Taken together, our results demonstrate the paradigm-shifting impact of immunoproteasome activators to diversify the antigenic landscape, expand the immunopeptidome, potentiate T-cell-directed therapy, and reveal actionable neoantigens for personalized T-cell immunotherapy.
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