Abstract
Zinc finger E-box binding homeobox 1 (Zeb1) has been demonstrated to participate in the acquisition of the properties of cancer stem cells (CSCs). However, it is largely unknown how signals ...from the tumor microenvironment (TME) contribute to aberrant Zeb1 expression. Here, we show that Zeb1 depletion suppresses stemness, colonization and the phenotypic plasticity of breast cancer. Moreover, we demonstrate that, with direct cell-cell contact, TME-derived endothelial cells provide the Notch ligand Jagged1 (Jag1) to neighboring breast CSCs, leading to Notch1-dependent upregulation of Zeb1. In turn, ectopic Zeb1 in tumor cells increases VEGFA production and reciprocally induces endothelial Jag1 in a paracrine manner. Depletion of Zeb1 disrupts this positive feedback loop in the tumor perivascular niche, which eventually lessens tumor initiation and progression in vivo and in vitro. In this work, we highlight that targeting the angiocrine Jag1-Notch1-Zeb1-VEGFA loop decreases breast cancer aggressiveness and thus enhances the efficacy of antiangiogenic therapy.
Aerobic glycolysis (the Warburg effect) has been demonstrated to facilitate tumor progression by producing lactate, which has important roles as a proinflammatory and immunosuppressive mediator. ...However, how aerobic glycolysis is directly regulated is largely unknown. Here, we show that ectopic Zeb1 directly increases the transcriptional expression of HK2, PFKP, and PKM2, which are glycolytic rate-determining enzymes, thus promoting the Warburg effect and breast cancer proliferation, migration, and chemoresistance in vitro and in vivo. In addition, Zeb1 exerts its biological effects to induce glycolytic activity in response to hypoxia via the PI3K/Akt/HIF-1α signaling axis, which contributes to fostering an immunosuppressive tumor microenvironment (TME). Mechanistically, breast cancer cells with ectopic Zeb1 expression produce lactate in the acidic tumor milieu to induce the alternatively activated (M2) macrophage phenotype through stimulation of the PKA/CREB signaling pathway. Clinically, the expression of Zeb1 is positively correlated with dysregulation of aerobic glycolysis, accumulation of M2-like tumor-associated macrophages (TAMs) and a poor prognosis in breast cancer patients. In conclusion, these findings identify a Zeb1-dependent mechanism as a driver of breast cancer progression that acts by stimulating tumor-macrophage interplay, which could be a viable therapeutic target for the treatment of advanced human cancers.
A coordination-assisted synthetic approach is reported here for the synthesis of highly active and stable gold nanoparticle catalysts in ordered mesoporous carbon materials using triblock copolymer ...F127 as a structure-directing agent, thiol-containing silane as a coordination agent, HAuCl4 as a gold source, and phenolic resin as a carbon source. Upon carbonization, the gold precursor becomes reduced to form monodispersed Au nanoparticles of ca. 9.0 nm, which are entrapped or confined by the “rigid” mesoporous carbonaceous framework. Nanoparticle aggregation is inhibited even at a high temperature of 600 °C. After removal of the silica component, the materials possess the ordered mesostructure, high surface area (∼1800 m2/g), large pore volume (∼1.19 cm3/g), and uniform bimodal mesopore size (<2.0 and 4.0 nm). The monodispersed gold nanoparticles are highly exposed because of the interpenetrated bimodal pores in the carbon framework, which exhibit excellent catalytic performance. A completely selective conversion of benzyl alcohol in water to benzoic acid can be achieved at 90 °C and 1 MPa oxygen. Benzyl alcohol can also be quantitatively converted to benzoic acid at 60 °C even under an atmospheric pressure, showing great advantages in green chemistry. The catalysts are stable, poison resistant, and reusable with little activity loss due to metal leaching. The silane coupling agent played several functions in this approach: (1) coordinating with gold species by the thiol group to benefit formation of monodispersed Au nanoparticles; (2) reacting with phenolic resins by silanol groups to form relatively “rigid” composite framework; (3) pore-forming agent to generate secondary pores in carbon pore walls, which lead to higher surface area, larger pore volumes, and higher accessibility to to the gold nanoparticles. Complete removal of the silica component proves to have little effect on the catalytic performance of entrapped Au nanoparticles.
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Ischemic stroke is associated with increasing morbidity and has become the main cause of death and disability worldwide. Cerebral edema is a serious complication arising from ischemic stroke. It ...causes an increase in intracranial pressure, rapid deterioration of neurological symptoms, and formation of cerebral hernia, and is an important risk factor for adverse outcomes after stroke. To date, the detailed mechanism of cerebral edema after stroke remains unclear. This limits advances in prevention and treatment strategies as well as drug development. This review discusses the classification and pathological characteristics of cerebral edema, the possible relationship of the development of cerebral edema after ischemic stroke with aquaporin 4, the SUR1-TRPM4 channel, matrix metalloproteinase 9, microRNA, cerebral venous reflux, inflammatory reactions, and cerebral ischemia/reperfusion injury. It also summarizes research on new therapeutic drugs for post-stroke cerebral edema. Thus, this review provides a reference for further studies and for clinical treatment of cerebral edema after ischemic stroke.
Reserve sites for coastal nuclear power plants are gradually being depleted, prompting a shift towards the development of inland nuclear power stations. A new cooling system based on the integration ...of multiple cooling sources using a hybrid dry–wet cycle is proposed to achieve a balance between energy and water consumption for inland nuclear power stations. Comparative studies among all the available cooling systems were further conducted to analyze the cooling performance and economic viability. The case study results indicate that, in comparison to relative humidity, the cooling performance and circulating water consumption of cooling systems are more susceptible to changes in dry-bulb temperature. In arid and water-scarce regions, a Combined Natural Draft Hybrid Cooling System generally exhibits a monthly average circulating water consumption rate that is more than 270 kg/s lower than that of the natural draft wet cooling system, with an average monthly back pressure reduction of 0.11 kPa. When the dry-bulb temperature exceeds 13 °C, the net profit of wet cooling surpasses that of hybrid cooling. However, this scenario undergoes a reversal as the dry-bulb temperature decreases and local water prices rise. It is emphasized that hybrid cooling demonstrates minimal impact when subjected to changes in environmental conditions, offering extensive regional applicability.
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Based on the etiology, stroke can be classified into ischemic or hemorrhagic subtypes, which ranks second among the leading causes of death. Stroke is caused not only by arterial thrombosis but also ...by cerebral venous thrombosis. Arterial stroke is currently the main subtype of stroke, and research on this type has gradually improved. Venous thrombosis, the particular type, accounts for 0.5–1% of all strokes. Due to the lack of a full understanding of venous thrombosis, as well as its diverse clinical manifestations and neuroimaging features, there are often delays in admission for it, and it is easy to misdiagnose. The purpose of this study was to review the pathophysiology mechanisms and clinical features of arterial and venous thrombosis and to provide guidance for further research on the pathophysiological mechanism, clinical diagnosis, and treatment of venous thrombosis. This review summarizes the pathophysiological mechanisms, etiology, epidemiology, symptomatology, diagnosis, and treatment heterogeneity of venous thrombosis and compares it with arterial stroke. The aim is to provide a reference for a comprehensive understanding of venous thrombosis and a scientific understanding of various pathophysiological mechanisms and clinical features related to venous thrombosis, which will contribute to understanding the pathogenesis of intravenous stroke and provide insight into diagnosis, treatment, and prevention.
In the aging process and central nervous system (CNS) diseases, the functions of the meningeal lymphatic vessels (MLVs) are impaired. Alterations in MLVs have been observed in aging-related ...neurodegenerative diseases, brain tumors, and even cerebrovascular disease. These findings reveal a new perspective on aging and CNS disorders and provide a promising therapeutic target. Additionally, recent neuropathological studies have shown that MLVs exchange soluble components between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) and drain metabolites, cellular debris, misfolded proteins, and immune cells from the CSF into the deep cervical lymph nodes (dCLNs), directly connecting the brain with the peripheral circulation. Impairment and dysfunction of meningeal lymphatics can lead to the accumulation of toxic proteins in the brain, exacerbating the progression of neurological disorders. However, for many CNS diseases, the causal relationship between MLVs and neuropathological changes is not fully clear. Here, after a brief historical retrospection, we review recent discoveries about the hallmarks of MLVs and their roles in the aging and CNS diseases, as well as potential therapeutic targets for the treatment of neurologic diseases.
One of the most critical steps in cereal threshing is the ease with which seeds are detached from sticky glumes. Naked grains with low glume coverage have dramatically increased threshing efficiency ...and seed quality. Here, we demonstrate that GC1 (Glume Coverage 1), encoding an atypical G protein γ subunit, negatively regulates sorghum glume coverage. Naturally truncated variations of GC1 C-terminus accumulate at higher protein levels and affect the stability of a patatin-related phospholipase SbpPLAII-1. A strong positive selection signature around the GC1 genic region is found in the naked sorghum cultivars. Our findings reveal a crucial event during sorghum domestication through a subtle regulation of glume development by GC1 C-terminus variation, and establish a strategy for future breeding of naked grains.
Brain function and neuronal activity depend on a constant supply of blood from the cerebral circulation. The cerebral venous system (CVS) contains approximately 70% of the total cerebral blood ...volume; similar to the cerebral arterial system, the CVS plays a prominent role in the maintenance of central nervous system (CNS) homeostasis. Impaired venous autoregulation, which can appear in forms such as cerebral venous congestion, may lead to metabolic abnormalities in the brain, causing severe cerebral functional defects and even chronic tinnitus. However, the role of cerebral venous congestion in the progression of tinnitus is underrecognized, and its pathophysiology is still incompletely understood. This study elucidated the specific pathogenetic role of cerebral venous congestion in the onset and persistence of tinnitus and the possible neurophysiological mechanisms.
We found that a rat model of cerebral venous congestion exhibited tinnitus-like behavioral manifestations at 14 days postoperatively; from that point onward, they showed signs of persistent tinnitus without significant hearing impairment. Subsequent neuroimaging and neurochemical findings showed CNS homeostatic plasticity disturbance in rats with cerebral venous congestion, reflected in increased neural metabolic activity, ultrastructural synaptic changes, upregulated synaptic efficacy, reduced inhibitory synaptic transmission (due to GABA deficiency), and elevated expression of neuroplasticity-related proteins in central auditory and extra-auditory pathways.
Collectively, our data suggest that alternations in CNS homeostatic plasticity may play a vital role in tinnitus pathology caused by cerebral venous congestion. These findings provide a new perspective on tinnitus related to cerebral venous congestion and may facilitate the development of precise interventions to interrupt its pathogenesis.
Crosswind has an adverse impact on the performance of an indirect dry cooling system. In order to mitigate the adverse influence, this study redistributed the circulating cooling water among ...air-cooled heat exchanger sectors so that the performance of the indirect dry cooling system could be improved. An evolution strategies algorithm combined with numerical effectiveness-based heat exchanger model was established to minimize the operation costs of the whole system. Based on a 660 MW practical power plant, optimal circulating cooling water operation strategies under varied crosswind speeds and ambient temperatures were calculated to show its application. According to the calculated results, the performance of the indirect dry cooling system could be enhanced by optimizing circulating cooling water distribution under any crosswind speed, especially under high ambient wind speeds. There is a slight promotion of the coal savings with a rise in ambient temperature: improvements of about 5%. The standard coal consumption rate could save as much as 2.50 g/kWh under crosswind speed of 10 m s−1 and ambient temperature of 32 °C, compared to the 0.1 g/kWh under crosswind speed of 2 m s−1 and ambient temperature of 32 °C.
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