586 research outputs found
Combined antiproliferative activity of imatinib mesylate (STI-571) with radiation or cisplatin in vitro
Little is known about the interaction of novel anticancer drugs with other treatment modalities. The aim of this study was to examine the effect of combining imatinib mesylate (STI-571) with radiation or cisplatin on the survival of two human solid tumor cell lines β SKNMC cells derived from Ewing sarcoma and breast cancer MCF-7 cells. Methods: Cell proliferation was determined using the sulphorodamine B cytotoxicity assay. Cell cycle analysis was performed with flow cytometry. Apoptosis was determined using a commercial cell death ELISA plus kit. Phosphorylated AKT, which has been suggested to be involved in radiation resistance, was detected by Western blot analysis. Results: Exposure of SKNMC cells to STI-571 resulted in a dose-dependent antiproliferative effect and a decrease in phosphorylated AKT expression. There was no evidence of apoptosis. The combination of STI-571 with radiation or cisplatin had an additive antiproliferative effect in SKNMC cells (60% reduction in cell number). A similar effect was observed in human MCF-7 breast cancer cells. Conclusion: STI-571 improves the outcome of cisplatin or irradiation treatment in vitro. AKT pathway may play a role in the additive effect of STI-571 and irradiation.Π¦Π΅Π»Ρ: ΠΎΡΠ΅Π½ΠΈΡΡ Π°Π½ΡΠΈΠΏΡΠΎΠ»ΠΈΡΠ΅ΡΠ°ΡΠΈΠ²Π½ΡΠΉ ΡΡΡΠ΅ΠΊΡ ΠΈΠΌΠ°ΡΠΈΠ½ΠΈΠ±Π° (STI-571) Π² ΠΊΠΎΠΌΠ±ΠΈΠ½Π°ΡΠΈΠΈ Ρ ΠΎΠ±Π»ΡΡΠ΅Π½ΠΈΠ΅ΠΌ ΠΈΠ»ΠΈ ΡΠΈΡΠΏΠ»Π°ΡΠΈΠ½ΠΎΠΉ ΠΏΠΎ ΠΎΡΠ½ΠΎΡΠ΅Π½ΠΈΡ
ΠΊ Π΄Π²ΡΠΌ ΠΊΠ»Π΅ΡΠΎΡΠ½ΡΠΌ Π»ΠΈΠ½ΠΈΡΠΌ β ΠΊΠ»Π΅ΡΠΊΠ°ΠΌ Π»ΠΈΠ½ΠΈΠΈ SKNMC, ΠΏΠΎΠ»ΡΡΠ΅Π½Π½ΡΠΌ ΠΈΠ· ΡΠ°ΡΠΊΠΎΠΌΡ ΠΠ²ΠΈΠ½Π³Π°, ΠΈ ΠΊΠ»Π΅ΡΠΊΠ°ΠΌ ΡΠ°ΠΊΠ° ΠΌΠΎΠ»ΠΎΡΠ½ΠΎΠΉ ΠΆΠ΅Π»Π΅Π·Ρ
ΡΠ΅Π»ΠΎΠ²Π΅ΠΊΠ° Π»ΠΈΠ½ΠΈΠΈ MCF-7. ΠΠ΅ΡΠΎΠ΄Ρ: Π΄Π»Ρ ΠΎΡΠ΅Π½ΠΊΠΈ ΠΏΡΠΎΠ»ΠΈΡΠ΅ΡΠ°ΡΠΈΠΈ ΠΊΠ»Π΅ΡΠΎΠΊ ΠΏΡΠΈΠΌΠ΅Π½ΡΠ»ΠΈ ΠΌΠ΅ΡΠΎΠ΄ Π°Π½Π°Π»ΠΈΠ·Π° ΡΠΈΡΠΎΡΠΎΠΊΡΠΈΡΠ½ΠΎΡΡΠΈ Ρ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ
ΡΡΠ»ΡΡΠΎΡΠΎΠ΄Π°ΠΌΠΈΠ½Π° B. ΠΠ»Ρ Π°Π½Π°Π»ΠΈΠ·Π° ΡΠ°ΡΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΡ ΠΊΠ»Π΅ΡΠΎΠΊ ΠΏΠΎ ΡΠ°Π·Π°ΠΌ ΠΊΠ»Π΅ΡΠΎΡΠ½ΠΎΠ³ΠΎ ΡΠΈΠΊΠ»Π° ΠΏΡΠΈΠΌΠ΅Π½ΡΠ»ΠΈ ΠΌΠ΅ΡΠΎΠ΄ ΠΏΡΠΎΡΠΎΡΠ½ΠΎΠΉ ΡΠΈΡΠΎΠΌΠ΅ΡΡΠΈΠΈ,
Π°ΠΏΠΎΠΏΡΠΎΠ·Π° β Ρ ΠΏΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ΠΌ ΠΊΠΎΠΌΠΌΠ΅ΡΡΠ΅ΡΠΊΠΎΠ³ΠΎ Π½Π°Π±ΠΎΡΠ° Π΄Π»Ρ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΈΡ ΠΠ€Π. Π£ΡΠΎΠ²Π΅Π½Ρ ΡΠΎΡΡΠΎΡΠΈΠ»ΠΈΡΠΎΠ²Π°Π½Π½ΠΎΠΉ ΠΊΠΈΠ½Π°Π·Ρ ΠΠΠ’,
ΠΏΡΠ΅Π΄ΠΏΠΎΠ»ΠΎΠΆΠΈΡΠ΅Π»ΡΠ½ΠΎ ΡΠ²ΡΠ·Π°Π½Π½ΠΎΠΉ Ρ ΡΠ°Π΄ΠΈΠΎΡΠ΅Π·ΠΈΡΡΠ΅Π½ΡΠ½ΠΎΡΡΡΡ, ΠΎΠΏΡΠ΅Π΄Π΅Π»ΡΠ»ΠΈ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ ΠΠ΅ΡΡΠ΅ΡΠ½-Π±Π»ΠΎΡ Π°Π½Π°Π»ΠΈΠ·Π°. Π Π΅Π·ΡΠ»ΡΡΠ°ΡΡ: ΠΈΠ½ΠΊΡΠ±Π°ΡΠΈΡ
ΠΊΠ»Π΅ΡΠΎΠΊ SKNMC STI-571 ΠΏΡΠΈΠ²ΠΎΠ΄ΠΈΠ»Π° ΠΊ Π΄ΠΎΠ·ΠΎΠ·Π°Π²ΠΈΡΠΈΠΌΠΎΠΌΡ Π°Π½ΡΠΈΠΏΡΠΎΠ»ΠΈΡΠ΅ΡΠ°ΡΠΈΠ²Π½ΠΎΠΌΡ ΡΡΡΠ΅ΠΊΡΡ ΠΈ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΡ ΡΠΎΡΡΠΎΡΠΈΠ»ΠΈΡΠΎΠ²Π°Π½ΠΈΡ
AKT, Π½ΠΎ Π½Π΅ Π°ΠΏΠΎΠΏΡΠΎΠ·Ρ ΠΊΠ»Π΅ΡΠΎΠΊ. ΠΠΎΠΌΠ±ΠΈΠ½ΠΈΡΠΎΠ²Π°Π½Π½ΠΎΠ΅ ΠΏΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ STI-571 ΠΈ ΠΎΠ±Π»Π΅Π½ΠΈΡ ΠΈΠ»ΠΈ ΡΠΈΡΠΏΠ»Π°ΡΠΈΠ½Ρ ΠΎΠΊΠ°Π·ΡΠ²Π°Π»ΠΎ Π΄ΠΎΠΏΠΎΠ»Π½ΠΈΡΠ΅Π»ΡΠ½ΠΎΠ΅
Π°Π½ΡΠΈΠΏΡΠΎΠ»ΠΈΡΠ΅ΡΠ°ΡΠΈΠ²Π½ΠΎΠ΅ Π²ΠΎΠ·Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ Π½Π° ΠΊΠ»Π΅ΡΠΊΠΈ Π»ΠΈΠ½ΠΈΠΈ SKNMC (60% ΡΠΌΠ΅Π½ΡΡΠ΅Π½ΠΈΡ ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²Π° ΠΊΠ»Π΅ΡΠΎΠΊ). ΠΠ½Π°Π»ΠΎΠ³ΠΈΡΠ½ΡΠ΅ ΡΡΡΠ΅ΠΊΡΡ
ΠΎΡΠΌΠ΅ΡΠ°Π»ΠΈ Π½Π° ΠΊΠ»Π΅ΡΠΊΠ°Ρ
Π»ΠΈΠ½ΠΈΠΈ MCF-7. ΠΡΠ²ΠΎΠ΄Ρ: ΠΎΠ±ΡΠ°Π±ΠΎΡΠΊΠ° ΠΎΠΏΡΡ
ΠΎΠ»Π΅Π²ΡΡ
ΠΊΠ»Π΅ΡΠΎΠΊ STI-571 ΡΡΠΈΠ»ΠΈΠ²Π°Π΅Ρ ΡΡΡΠ΅ΠΊΡ ΠΎΠ±Π»Π΅Π½ΠΈΡ ΠΈ ΡΠΈΡΠΏΠ»Π°ΡΠΈΠ½Ρ
in, ΠΏΡΠΈΡΠ΅ΠΌ ΡΠ°ΠΊΠΎΠ²ΠΎΠΉ ΠΌΠΎΠΆΠ΅Ρ Π±ΡΡΡ ΠΎΠΏΠΎΡΡΠ΅Π΄ΠΎΠ²Π°Π½ ΡΠΈΠ³Π½Π°Π»ΡΠ½ΡΠΌ ΠΊΠ°ΡΠΊΠ°Π΄ΠΎΠΌ AK
Asymmetric protonation of EmrE
The small multidrug resistance transporter EmrE is a homodimer that uses energy provided by the proton motive force to drive the efflux of drug substrates. The pKa values of its βactive-siteβ residuesβglutamate 14 (Glu14) from each subunitβmust be poised around physiological pH values to efficiently couple proton import to drug export in vivo. To assess the protonation of EmrE, pH titrations were conducted with (1)H-(15)N TROSY-HSQC nuclear magnetic resonance (NMR) spectra. Analysis of these spectra indicates that the Glu14 residues have asymmetric pKa values of 7.0 Β± 0.1 and 8.2 Β± 0.3 at 45Β°C and 6.8 Β± 0.1 and 8.5 Β± 0.2 at 25Β°C. These pKa values are substantially increased compared with typical pKa values for solvent-exposed glutamates but are within the range of published Glu14 pKa values inferred from the pH dependence of substrate binding and transport assays. The active-site mutant, E14D-EmrE, has pKa values below the physiological pH range, consistent with its impaired transport activity. The NMR spectra demonstrate that the protonation states of the active-site Glu14 residues determine both the global structure and the rate of conformational exchange between inward- and outward-facing EmrE. Thus, the pKa values of the asymmetric active-site Glu14 residues are key for proper coupling of proton import to multidrug efflux. However, the results raise new questions regarding the coupling mechanism because they show that EmrE exists in a mixture of protonation states near neutral pH and can interconvert between inward- and outward-facing forms in multiple different protonation states
The effect of cold acclimation on active ion transport in cricket ionoregulatory tissues.
Cold-acclimated insects defend ion and water transport function during cold exposure. We hypothesized that this is achieved via enhanced active transport. The Malpighian tubules and rectum are likely targets for such transport modifications, and recent transcriptomic studies indicate shifts in Na+-K+ ATPase (NKA) and V-ATPase expression in these tissues following cold acclimation. Here we quantify the effect of cold acclimation (one week at 12 Β°C) on active transport in the ionoregulatory organs of adult Gryllus pennsylvanicus field crickets. We compared primary urine production of warm- and cold-acclimated crickets in excised Malpighian tubules via Ramsay assay at a range of temperatures between 4 and 25 Β°C. We then compared NKA and V-ATPase activities in Malpighian tubule and rectal homogenates from warm- and cold-acclimated crickets via NADH-linked photometric assays. Malpighian tubules of cold-acclimated crickets excreted fluid at lower rates at all temperatures compared to warm-acclimated crickets. This reduction in Malpighian tubule excretion rates may be attributed to increased NKA activity that we observed for cold-acclimated crickets, but V-ATPase activity was unchanged. Cold acclimation had no effect on rectal NKA activity at either 21 Β°C or 6 Β°C, and did not modify rectal V-ATPase activity. Our results suggest that an overall reduction, rather than enhancement of active transport in the Malpighian tubules allows crickets to maintain hemolymph water balance during cold exposure, and increased Malpighian tubule NKA activity may help to defend and/or re-establish ion homeostasis
The Cost of (Un)regulation: Shrinking Earthβs Orbits and the Need for Sustainable Space Governance
Steph Paladini: ORCID: 0000-0002-1526-3589 https://orcid.org/0000-0002-1526-3589Outer space is infinite, useable planetary orbits are not. This makes the Earth's orbit a unique case of an Area Beyond National Jurisdiction (ABNJ) complex to address, difficult to use in a sustainable and equitable way and almost intractable to regulate at an international level. As of 2023, we remain far from attaining a sustainable orbital environment, and future uses of the Earth's orbits for new satellites constellations appear now increasingly at risk. Adopting a probability-based empirical model to project the growth trajectory of objects in space, this article argues that the sector will cross a 'critical density' threshold within the upcoming years unless strong remedial actions to clear up the orbits are implemented and estimates the potential costs of active debris removal measures. Our findings suggest that orbital sustainability is unlikely to come from technology alone, no matter how advanced or ground-breaking. A long-term solution will necessarily require a radical rewriting of the outdated, often conflicting international regulatory framework, which contributed to creating this debris crisis in the first place, shrinking the Earth's orbit to (almost) the point of no return.pubpu
Inevitable Evolutionary Temporal Elements in Neural Processing: A Study Based on Evolutionary Simulations
Recent studies have suggested that some neural computational mechanisms are based on the fine temporal structure of spiking activity. However, less effort has been devoted to investigating the evolutionary aspects of such mechanisms. In this paper we explore the issue of temporal neural computation from an evolutionary point of view, using a genetic simulation of the evolutionary development of neural systems. We evolve neural systems in an environment with selective pressure based on mate finding, and examine the temporal aspects of the evolved systems. In repeating evolutionary sessions, there was a significant increase during evolution in the mutual information between the evolved agent's temporal neural representation and the external environment. In ten different simulated evolutionary sessions, there was an increased effect of time -related neural ablations on the agents' fitness. These results suggest that in some fitness landscapes the emergence of temporal elements in neural computation is almost inevitable. Future research using similar evolutionary simulations may shed new light on various biological mechanisms
Evolving Synaptic Plasticity with an Evolutionary Cellular Development Model
Since synaptic plasticity is regarded as a potential mechanism for memory formation and learning, there is growing interest in the study of its underlying mechanisms. Recently several evolutionary models of cellular development have been presented, but none have been shown to be able to evolve a range of biological synaptic plasticity regimes. In this paper we present a biologically plausible evolutionary cellular development model and test its ability to evolve different biological synaptic plasticity regimes. The core of the model is a genomic and proteomic regulation network which controls cells and their neurites in a 2D environment. The model has previously been shown to successfully evolve behaving organisms, enable gene related phenomena, and produce biological neural mechanisms such as temporal representations. Several experiments are described in which the model evolves different synaptic plasticity regimes using a direct fitness function. Other experiments examine the ability of the model to evolve simple plasticity regimes in a task -based fitness function environment. These results suggest that such evolutionary cellular development models have the potential to be used as a research tool for investigating the evolutionary aspects of synaptic plasticity and at the same time can serve as the basis for novel artificial computational systems
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