Activating transcription factor 4 (ATF4) is a critical mediator of metabolic and oxidative homeostasis and cell survival. ATF4 is elevated in response to diverse microenvironmental stresses, ...including starvation, ER stress damages and exposure to toxic factors. Here we show that ATF4 expression fosters the malignancy of primary brain tumors (WHO grade III and IV gliomas) and increases proliferation and tumor angiogenesis. Hence, ATF4 expression promotes cell migration and anchorage-independent cell growth, whereas siRNA-mediated knockdown of ATF4 attenuates these features of malignancy in human gliomas. Further experiments revealed that ATF4-dependent tumor promoting effects are mediated by transcriptional targeting the glutamate antiporter xCT/SCL7A11 (also known as system Xc
). Thus, xCT is elevated as a consequence of ATF4 activation. We further found evidence that ATF4-induced proliferation can be attenuated by pharmacological or genetic xCT inhibition and ferroptosis inducers such as sorafenib, erastin and GPx4 inhibitor RSL3. Further, fostered xCT expression promotes cell survival and growth in ATF4 knockdown cells. Moreover, increased xCT levels ameliorate sorafenib and erastin-induced ferroptosis. Conversely, ATF4 knockdown renders cells susceptible for erastin, sorafenib and RSL3-induced ferroptosis. We further identified that ATF4 promotes tumor-mediated neuronal cell death which can be alleviated by xCT inhibition. Moreover, elevated ATF4 expression in gliomas promotes tumor angiogenesis. Noteworthy, ATF4-induced angiogenesis could be diminished by ferroptosis inducers erastin and by GPx4 inhibitor RSL3. Our data provide proof-of-principle evidence that ATF4 fosters proliferation and induces a toxic microenvironmental niche. Furthermore, ATF4 increases tumor angiogenesis and shapes the vascular architecture in a xCT-dependent manner. Thus, inhibition of ATF4 is a valid target for diminishing tumor growth and vasculature via sensitizing tumor cells for ferroptosis.
Isolation of circulating tumor cells (CTCs) from peripheral blood or cancer cells from bone marrow has significant applications in cancer diagnosis, therapy monitoring, and drug development. CTCs are ...cancer cells shed from primary tumors; they circulate in the bloodstream, leading to metastasis. The extraordinary rarity of CTCs in the bloodstream makes their isolation a significant technological challenge. Herein, we report the development of a platform combining multivalent DNA aptamer nanospheres with microfluidic devices for efficient isolation of cancer cells from blood. Gold nanoparticles (AuNPs) were used as an efficient platform for assembling a number of aptamers for high-efficiency cell capture. Up to 95 aptamers were attached onto each AuNP, resulting in enhanced molecular recognition capability. An increase of 39-fold in binding affinity was confirmed by flow cytometry for AuNP–aptamer conjugates (AuNP–aptamer) when compared with aptamer alone. With a laminar flow flat channel microfluidic device, the capture efficiency of human acute leukemia cells from a cell mixture in buffer increased from 49% using aptamer alone to 92% using AuNP–aptamer. We also employed AuNP–aptamer in a microfluidic device with herringbone mixing microstructures for isolation of leukemia cells in whole blood. The cell capture efficiency was also significantly increased with the AuNP–aptamer over aptamer alone, especially at high flow rates. Our results show that the platform combining DNA nanostructures with microfluidics has a great potential for sensitive isolation of CTCs and is promising for cancer diagnosis and prognosis.
Despite advances in earlier diagnosis and available aggressive treatments for vascular risk factors, stroke remains a leading cause of death and long-term disability worldwide. Disparities exist in ...stroke risk, rates of stroke, and treatment. Stroke is a heterogeneous disease with multiple additive risk factors and causes. Primary prevention of stroke focusing on risk factor modification plays an important role in reducing the burden of stroke in an aging population. Secondary prevention of recurrent strokes relies on the workup and a tailored treatment targeted at the mechanisms responsible for the incident stroke or transient ischemic attack.
Protein kinases transduce signals to regulate a wide array of cellular functions in eukaryotes. A generalizable method for optical control of kinases would enable fine spatiotemporal interrogation or ...manipulation of these various functions. We report the design and application of single-chain cofactor-free kinases with photoswitchable activity. We engineered a dimeric protein, pdDronpa, that dissociates in cyan light and reassociates in violet light. Attaching two pdDronpa domains at rationally selected locations in the kinase domain, we created the photoswitchable kinases psRaf1, psMEK1, psMEK2, and psCDK5. Using these photoswitchable kinases, we established an all-optical cell-based assay for screening inhibitors, uncovered a direct and rapid inhibitory feedback loop from ERK to MEK1, and mediated developmental changes and synaptic vesicle transport in vivo using light.
Planar perovskite solar cells (PSCs) made entirely via solution processing at low temperatures (<150°C) offer promise for simple manufacturing, compatibility with flexible substrates, and ...perovskite-based tandem devices. However, these PSCs require an electron-selective layer that performs well with similar processing. We report a contact-passivation strategy using chlorine-capped TiO₂ colloidal nanocrystal film that mitigates interfacial recombination and improves interface binding in low-temperature planar solar cells. We fabricated solar cells with certified efficiencies of 20.1 and 19.5% for active areas of 0.049 and 1.1 square centimeters, respectively, achieved via low-temperature solution processing. Solar cells with efficiency greater than 20% retained 90% (97% after dark recovery) of their initial performance after 500 hours of continuous room-temperature operation at their maximum power point under 1-sun illumination (where 1 sun is defined as the standard illumination at AM1.5, or 1 kilowatt/square meter).
Effect of solutes on grain refinement Fan, Z.; Gao, F.; Wang, Y. ...
Progress in Materials Science/Progress in materials science,
January 2022, 2022-01-00, 20220101, Letnik:
123
Journal Article
Recenzirano
Odprti dostop
Grain refinement not only enhances the mechanical performance of as-cast metallic materials but also provides an effective mechanism for controlling cast defects, such as macro-segregation, porosity ...and coarse second phase particles. Therefore, understanding grain refinement of alloys with different solute additions is of both theoretical and practical importance. Although extensive research has been carried out over many decades and significant progress has been made on the subject, such historical research has not delivered the desirable scientific understanding, and many critical questions remain open. Adopting a hybrid approach between review and overview, in this paper, we firstly provide a brief review on the historical research on the solute effect on grain refinement in the literature, then present the recent advances in the understanding of the subject in a holistic manner, and finally offer a summary of the factors that hindered progress in the past, key advances made in recent years and some suggestions for future research directions.
Perioperative use of dexmedetomidine is associated with reduction in postoperative analgesic requirements. This study examined whether dexmedetomidine added to i.v. patient-controlled analgesia (PCA) ...morphine could improve analgesia while reducing opioid-related side-effects.
In this double-blinded, randomized, controlled study, 100 women undergoing abdominal total hysterectomy were allocated to receive either morphine 1 mg ml−1 alone (Group M) or morphine 1 mg ml−1 plus dexmedetomidine 5 μg ml−1 (Group D) for postoperative i.v. PCA, which was programmed to deliver 1 ml per demand with a 5 min lockout interval and no background infusion. Cumulative PCA requirements, pain intensities, cardiovascular and respiratory variables, and PCA-related adverse events were recorded for 24 h after operation.
Compared with Group M, patients in Group D required 29% less morphine during the 0–24 h postoperative period and reported significantly lower pain levels from the second postoperative hour onwards and throughout the study. Whereas levels of sedation were similar between the groups at each observational time point, decreases in heart rate and mean blood pressure from presurgery baseline at 1, 2, and 4 h after operation were significantly greater in Group D (by a range of 5–7 beats min−1 and 10–13%, respectively). The 4–24 h incidence of nausea was significantly lower in Group D (34% vs 56.3%, P<0.05). There was no bradycardia, hypotension, oversedation, or respiratory depression.
The addition of dexmedetomidine to i.v. PCA morphine resulted in superior analgesia, significant morphine sparing, less morphine-induced nausea, and was devoid of additional sedation and untoward haemodynamic changes.
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