Eutectogel Electrolyte Constructs Robust Interfaces for High-Voltage Safe Lithium Metal Battery.

Dramatic growth of lithium dendrite, structural deterioration of LiCoO2 (LCO) cathode at high voltages, and unstable electrode/electrolyte interfaces pose significant obstacles to the practical application of high-energy-density LCO||Li batteries. In this work, a novel eutectogel electrolyte is developed by confining the nonflammable eutectic electrolyte in a polymer matrix. The eutectogel electrolyte can construct a robust solid electrolyte interphase (SEI) with inorganic-rich LiF and Li3N, contributing to a uniform Li deposition. Besides, the severe interface side reactions between LCO cathode and electrolyte can be retarded with an in situ formed protective layer. Correspondingly, Li||Li symmetrical cells achieve highly reversible Li plating/stripping over 1000 h. The LCO||Li full cell can maintain 72.5% capacity after 1500 cycles with a decay rate of only 0.018% per cycle at a high charging voltage of 4.45 V. Moreover, the well-designed eutectogel electrolyte can even enable the stable operation of LCO at an extremely high cutoff voltage of 4.6 V. This work introduces a promising avenue for the advancement of eutectogel electrolytes, the nonflammable nature and well-regulated interphase significantly push forward the future application of lithium metal batteries and high-voltage utilization of LCO cathode.

Astrocyte-derived hepcidin aggravates neuronal iron accumulation after subarachnoid hemorrhage by decreasing neuronal ferroportin1.

Iron accumulation is one of the most essential pathological events after subarachnoid hemorrhage (SAH). Ferroportin1 (FPN1) is the only transmembrane protein responsible for exporting iron. Hepcidin, as the major regulator of FPN1, is responsible for its degradation. Our study investigated how the interaction between FPN1 and hepcidin contributes to iron accumulation after SAH. We found that iron accumulation aggravated after SAH, along with decreased FPN1 in neurons and increased hepcidin in astrocytes. After knocking down hepcidin in astrocytes, the neuronal FPN1 significantly elevated, thus attenuating iron accumulation. After SAH, p-Smad1/5 and Smad4 tended to translocate into the nucleus. Moreover, Smad4 combined more fragments of the promoter region of Hamp after OxyHb stimulation. By knocking down Smad1/5 or Smad4 in astrocytes, FPN1 level restored and iron overload attenuated, leading to alleviated neuronal cell death and improved neurological function. However, the protective role disappeared after recombinant hepcidin administration. Therefore, our study suggests that owing to the nuclear translocation of transcription factors p-Smad1/5 and Smad4, astrocyte-derived hepcidin increased significantly after SAH, leading to a decreased level of neuronal FPN1, aggravation of iron accumulation, and worse neurological outcome.

Increased NOX2 expression in astrocytes leads to eNOS uncoupling through dihydrofolate reductase in endothelial cells after subarachnoid hemorrhage.

Introduction: Endothelial nitric oxide synthase (eNOS) uncoupling plays a significant role in acute vasoconstriction during early brain injury (EBI) after subarachnoid hemorrhage (SAH). Astrocytes in the neurovascular unit extend their foot processes around endothelia. In our study, we tested the hypothesis that increased nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression in astrocytes after SAH leads to eNOS uncoupling. Methods: We utilized laser speckle contrast imaging for monitoring cortical blood flow changes in mice, nitric oxide (NO) kits to measure the level of NO, and a co-culture system to study the effect of astrocytes on endothelial cells. Moreover, the protein levels were assessed by Western blot and immunofluorescence staining. We used CCK-8 to measure the viability of astrocytes and endothelial cells, and we used the H2O2 kit to measure the H2O2 released from astrocytes. We used GSK2795039 as an inhibitor of NOX2, whereas lentivirus and adeno-associated virus were used for dihydrofolate reductase (DHFR) knockdown in vivo and in vitro. Results: The expression of NOX2 and the release of H2O2 in astrocytes are increased, which was accompanied by a decrease in endothelial DHFR 12 h after SAH. Moreover, the eNOS monomer/dimer ratio increased, leading to a decrease in NO and acute cerebral ischemia. All of the above were significantly alleviated after the administration of GSK2795039. However, after knocking down DHFR both in vivo and in vitro, the protective effect of GSK2795039 was greatly reversed. Discussion: The increased level of NOX2 in astrocytes contributes to decreased DHFR in endothelial cells, thus aggravating eNOS uncoupling, which is an essential mechanism underlying acute vasoconstriction after SAH.

Neuroprotective mechanisms of OXCT1 via the SIRT3-SOD2 pathway after traumatic brain injury.

BACKGROUND: Ketones are not only utilized to produce energy but also play a neuroprotective role in many neurodegenerative diseases. However, whether this process has an impact on secondary brain damage after traumatic brain injury (TBI) remains unknown. OXCT1 (3-Oxoacid CoA-Transferase 1) is the rate-limiting enzyme in the intra-neuronal utilization of ketones. In this study, we investigated whether reduced expression of OXCT1 after TBI could impact neuroprotective mechanisms and exacerbate neurological dysfunction. MATERIALS AND METHODS: Experimental TBI was induced by a modified version of the weight drop model, it is a model of severe head trauma. Expression of OXCT1 in the injured hippocampus of mice was measured at different time points using immunoblotting assays. The release of abnormal mitochondrial cytochrome c from neurons of the mouse injured lateral hippocampus was measured 1 week after TBI using immunoblotting assays. Neuronal death was assessed by Nissl staining and the level of reactive oxygen species (ROS) within the neurons of the injured lateral hippocampus was assessed by Dihydroethidium staining. RESULTS: OXCT1 was overexpressed in hippocampal neurons by injection of adeno-associated virus into the lateral ventricle. OXCT1 expression levels decreased significantly 1 week post-TBI. After comparing the data obtained from different groups of mice, OXCT1 was found to significantly increase the expression of SIRT3 and reduce the proportion of acetylated SOD2, thus decreasing the production of ROS in the injured hippocampal neurons, reducing neuronal death, and improving cognitive function. CONCLUSIONS: OXCT1 has a critical previously unappreciated protective role in neurological impairment following TBI via the SIR3-SOD2 pathway. These findings highlight the potential of OXCT1 as a simple treatment for patients with TBI.

Endothelial NOX4 aggravates eNOS uncoupling by decreasing dihydrofolate reductase after subarachnoid hemorrhage.

Endothelial malfunction is a major contributor to early or delayed vasospasm after subarachnoid hemorrhage (SAH). As a representative form of endothelial dysfunction, endothelial nitric oxide synthase (eNOS) uncoupling leads to a reduction in nitric oxide (NO) generated by endothelial cells. In this study, we investigated how the interaction between endothelial NOX4 (nicotinamide adenine dinucleotide phosphate oxidase 4) and DHFR (dihydrofolate reductase) contributes to eNOS uncoupling after SAH. Setanaxib and the adeno-associated virus (AAV) targeting brain vascular endothelia were injected through the tail vein and the expression and localization of proteins were examined by western blot and immunofluorescence staining. The NO content was measured using the NO assay kit, and laser speckle contrast imaging was used to assess cortical perfusion. ROS (reactive oxygen species) level was detected by DHE (dihydroethidium) staining, DCFH-DA (2',7'-dichlorofluorescin diacetate) staining and H2O2 (hydrogen peroxide) measurement. The Garcia score was employed to examine neurological function. Setanaxib is widely used for its preferential inhibition for NOX1/4 over other NOX isoforms. After endothelial NOX4 was inhibited by Setanaxib in a mouse model of SAH, the endothelial DHFR level was significantly elevated, which attenuated eNOS uncoupling, increased cortical perfusion, and improved the neurological function. The protective role of inhibiting endothelial NOX4, however, disappeared after knocking down endothelial DHFR. Our results suggest that endothelial DHFR decreased significantly because of the elevated level of endothelial NOX4, which aggravated eNOS uncoupling after SAH, leading to decreased cortical perfusion and worse neurological outcome.

Facile Synthesis of Ag/Carbon Quantum Dots/Graphene Composites for Highly Conductive Water-Based Inks.

The development of graphene conductive inks with a high conductivity and dispersion stability in water poses considerable challenges. Herein, a highly conductive Ag/carbon quantum dots (CQDs)/graphene (G) composite with good dispersity and stability in water was prepared for the first time through the in situ photoreduction of AgNO3 and deposition of Ag onto graphene nanosheets obtained via CQD-assisted liquid-phase exfoliation. Ag nanoparticles with an average size of ∼1.88 nm were uniformly dispersed on graphene nanosheets. The Ag/CQDs/G composite exhibited good dispersity and stability in water for 30 days. The formation mechanism of the Ag/CQDs/G composites was also discussed. CQDs played a vital role in coordinating with Ag+ and reducing it under visible light conditions. The addition of only 1.58 wt % of Ag NPs to the CQDs/G film resulted in a significant decrease in the electrical resistivity by approximately 89.5%, reaching a value of 0.054 Ω cm for a 40 µm thick Ag/CQDs/G film. A low resistivity of 2.15 × 10-3 Ω cm for the Ag/CQDs/G film was achieved after rolling compression with a compression ratio of 78%. The Ag/CQDs/G film exhibited good conductivity and durability when bent, rolled, or twisted. Moreover, the resistivity of the film displayed a slight deviation after 5000 bending cycles, indicating its outstanding stability. This study provides an efficient strategy for preparing graphene-based conductive composites with good dispersibility and stability in water as well as novel high-performance conductive inks for application in flexible printed electronics.

Tropical volcanism enhanced the East Asian summer monsoon during the last millennium.

Extreme East Asian summer monsoon (EASM) rainfall frequently induces floods that threaten millions of people, and has been generally attributed to internal climate variability. In contrast to the hydrological weakening theory of volcanic eruptions, here we present convergent empirical and modeling evidence for significant intensification of EASM rainfall in response to strong tropical volcanic eruptions. Our multi-proxy analyses show a significantly increased EASM in the first summer after tropical eruptions from 1470 AD to the present, and the more frequent occurrence of El Niños in the first boreal winter after eruptions is necessary for the enhanced EASM. Model simulation ensembles show that a volcano-induced El Niño and the associated stronger than non-volcanic El Niño warm pool air-sea interaction intensify EASM precipitation, overwhelming volcanic-induced moisture deficiency. This work sheds light on the intertwined relationship between external forcing and internal climate variability and potential flood disasters resulting from tropical volcanic eruptions.

Peroxisome proliferator-activated receptor-γ ameliorates neuronal ferroptosis after traumatic brain injury in mice by inhibiting cyclooxygenase-2.

Among the multiple kinds of neuronal cell death triggered by traumatic brain injury (TBI), ferroptosis, an iron-dependent lipid peroxidative regulatory cell death, has a critical role. Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear transcription factor that regulates lipid metabolism and suppresses neuronal inflammation. However, the role of PPARγ in neuronal ferroptosis induced by TBI remains unclear. Here, we investigated the regulatory effect of PPARγ on neuronal ferroptosis in a weight-drop TBI model in vivo and an RAS-selective lethal 3 (RSL3)-activated ferroptotic neuronal model in vitro. PPARγ was mainly localized in the nucleus of neurons and was decreased in both the in vivo TBI model and the in vitro ferroptotic neuronal model. The addition of a specific agonist, pioglitazone, activated PPARγ, which protected neuronal function post-TBI in vivo and increased the viability of ferroptotic neurons in vitro. Further investigation suggested that PPARγ probably attenuates neuronal ferroptosis by downregulating cyclooxygenase-2 (COX2) protein expression levels in vivo and in vitro. This study revealed the relationship among PPARγ, ferroptosis and TBI and identified a potential target for comprehensive TBI treatment.

Dobutamine promotes the clearance of erythrocytes from the brain to cervical lymph nodes after subarachnoid hemorrhage in mice.

Background: Erythrocytes and their breakdown products in the subarachnoid space (SAS) are the main contributors to the pathogenesis of subarachnoid hemorrhage (SAH). Dobutamine is a potent ß1-adrenoreceptor agonist that can increase cardiac output, thus improving blood perfusion and arterial pulsation in the brain. In this study, we investigated whether the administration of dobutamine promoted the clearance of red blood cells (RBCs) and their degraded products via meningeal lymphatic vessels (mLVs), thus alleviating neurological deficits in the early stage post-SAH. Materials and methods: Experimental SAH was induced by injecting autologous arterial blood into the prechiasmatic cistern in male C57BL/6 mice. Evans blue was injected into the cisterna magna, and dobutamine was administered by inserting a femoral venous catheter. RBCs in the deep cervical lymphatic nodes (dCLNs) were evaluated by hematoxylin-eosin staining, and the hemoglobin content in dCLNs was detected by Drabkin's reagent. The accumulation of RBCs in the dura mater was examined by immunofluorescence staining, neuronal death was evaluated by Nissl staining, and apoptotic cell death was evaluated by TUNEL staining. The Morris water maze test was used to examine the cognitive function of mice after SAH. Results: RBCs appeared in dCLNs as early as 3 h post-SAH, and the hemoglobin in dCLNs peaked at 12 h after SAH. Dobutamine significantly promoted cerebrospinal fluid (CSF) drainage from the SAS to dCLNs and obviously reduced the RBC residue in mLVs, leading to a decrease in neuronal death and an improvement in cognitive function after SAH. Conclusion: Dobutamine administration significantly promoted RBC drainage from cerebrospinal fluid in the SAS via mLVs into dCLNs, ultimately relieving neuronal death and improving cognitive function.

Restoration of Brain Angiotensin-Converting Enzyme 2 Alleviates Neurological Deficits after Severe Traumatic Brain Injury via Mitigation of Pyroptosis and Apoptosis.

Clinically, the renin-angiotensin-aldosterone system is activated intensely in patients with moderate to severe traumatic brain injury (TBI). Increased angiotensin II in circulatory blood after TBI can enter the brain through the disrupted blood-brain barrier. Angiotensin-converting enzyme 2 (ACE2) is an enzyme that metabolizes angiotensin II into angiotensin (1-7), which has been shown to have neuroprotective results. The expression and role of ACE2 in the brain after TBI remains elusive, however. We found that ACE2 protein abundance was downregulated around the contusional area in the brains of both humans and mice. Endogenous ACE2 was expressed in neurons, astrocytes, and microglia in the cortex of the mouse brain. Administration of recombinant human ACE2 intracerebroventricularly alleviated neurological defects after TBI in mice. Treatment of recombinant human ACE2 suppressed TBI-induced increase of angiotensin II and the decrease of angiotensin (1-7) in the brain, mitigated neural cell death, reduced the activation of NLRP3 and caspase3, decreased phosphorylation of mitogen-activated protein kinases, and nuclear factor kappa B, and reduced inflammatory cytokines tumor necrosis factor alpha and interleukin-1ß. Administration of ACE2 enzyme activator diminazene aceturate intraperitoneally rescued downregulation of ACE2 enzymatic activity and protein abundance in the brain. Diminazene aceturate treatment once per day in the acute stage after TBI alleviated long-term cognitive defects and neuronal loss in mice. Collectively, these results indicated that restoration of ACE2 alleviated neurological deficits after TBI by mitigation of pyroptosis and apoptosis.

Expression of FOXO transcription factors in the brain following traumatic brain injury.

Traumatic brain injury (TBI) is a substantial clinical and social problem worldwide, causing high morbidity and mortality along with significant economic and medical costs. Forkhead box O transcription factors (FOXOs) have been found to play a critical role in the regulation of cell functions, such as nutrient metabolism, programmed cell death, and tumor suppression. In the central nervous system, FOXOs are reported to be pivotal regulators of learning and memory, neurite outgrowth, and axonal degeneration. However, the role of FOXOs in TBI is still unknown. Here, we investigate changes in the expression of FOXOs in the acute stage following TBI. First, we evaluated the expression of FOXO proteins in the brains of humans after TBI. A TBI model was then established in mice, and the ipsilateral cerebral cortex was collected at 3 h, 6 h, 9 h, 12 h, 24 h, and 72 h post-TBI. The dynamic expression of Foxo proteins was observed. Neuron-specific localization of Foxos was detected by double immunofluorescence staining. Following TBI, FOXO proteins in the brains of humans were significantly increased. In mice, Foxo protein levels generally peaked at 24 h. By examining co-localization with neurons, the proportion of Foxo(+) neurons was found to increase following TBI and peak at 24 h. This study reveals the time-dependent and neuron-specific expression of Foxos following TBI in mice, providing insight to enhance understanding of the role of Foxos in TBI.

Effects of biochar aging in the soil on its mechanical property and performance for soil CO2 and N2O emissions.

Biochar application into the soils has been reported to have huge carbon sequestration potential, although it remains unclear that how the biochar aging in the soil affects its mechanical properties and soil CO2 and N2O emissions. This work assessed the impact of soil biochar aging on its physicochemical properties, microbiota community in the biochar, and soil CO2 and N2O emissions. Various characterizations (e.g., SEM-EDS, XRD, and FTIR) of fresh and aged biochar indicated that soil minerals accumulated on the biochar during the field aging process, forming organo-mineral complexes and blocking the cracks and channels on the biochar. The measured hardness and compressive strength of aged biochar were significantly higher than those of fresh biochar, consistent with the presence of soil minerals on the aged biochar. The soil CO2 and N2O emissions were significantly decreased after the addition of aged biochar particles, as compared to fresh biochar particles. This was probably because that the improved mechanical properties could inhibit the fragmentation of biochar particles, reducing the release of labile fractions from the biochar and the subsequent CO2 and N2O emissions. Moreover, the presence of CO2-fixing bacteria (e.g., Chloroflexi) and inhibited nitrification and ammonia oxidation in aged biochar particles might also reduce CO2 and N2O emissions. These findings suggest aged biochar particles with improved physical stability to the soil could enhance soil carbon sequestration and greenhouse gas emission reduction.

Deferoxamine reduces amyloid-beta peptides genesis and alleviates neural apoptosis after traumatic brain injury.

Traumatic brain injury (TBI) is recognized as the most influential risk factor for neurodegenerative diseases later in life, including Alzheimer's disease. The aberrant genesis of amyloid-ß peptides, which is triggered by TBI, is associated with the development of Alzheimer's disease. Evidence suggests that iron plays a role in both the production of amyloid-ß and its neurotoxicity, and iron overload has been noted in the brain after TBI. We therefore investigated the effects of an iron-chelating treatment on amyloid-ß genesis in a weight-drop model of TBI in mice. Human brain samples were obtained from patients undergoing surgery for severe brain trauma. The Institute of Cancer Research mice were treated with deferoxamine by intraperitoneal injection after TBI induction. Changes in amyloid-ß(1-42) were assessed using western blot and immunohistochemical staining. Ferritin was also detected using western blot to investigate iron deposition in the mice brain. Immunofluorescent terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was also performed to evaluate neural apoptosis. The amyloid-ß(1-42) was markedly elevated after TBI in both humans and mice. Deferoxamine treatment in mice significantly decreased the levels of both amyloid-ß(1-42) and ferritin in the brain, and reduced TBI-induced neural cell apoptosis. The iron chelator deferoxamine can alleviate the increase of amyloid-ß(1-42) in the brain after TBI, and may therefore be a potential therapeutic strategy to prevent TBI patients from undergoing neurodegenerative processes.

FTY720 Reduces Endothelial Cell Apoptosis and Remodels Neurovascular Unit after Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. A sequence of pathological processes occurred when there is TBI. Previous studies showed that sphingosine-1-phosphate receptor 1 (S1PR1) played a critical role in inflammatory response in the brain after TBI. Thus, the present study was designed to evaluate the effects of the S1PR1 modulator FTY720 on neurovascular unit (NVU) after experimental TBI in mice. The weight-drop TBI method was used to induce TBI. Western blot (WB) was performed to determine the levels of SIPR1, claudin-5 and occludin at different time points. FTY720 was intraperitoneally administered to mice after TBI was induced. The terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL) assay was used to assess endothelial cell apoptosis. Immunofluorescence and WB were performed to measure the expression of tight junction proteins: claudin-5 and occludin. Evans blue (EB) permeability assay and brain water content were applied to evaluate the blood-brain barrier (BBB) permeability and brain edema. Immunohistochemistry was performed to assess the activation of astrocytes and microglia. The results showed that FTY720 administration reduced endothelial cell apoptosis and improved BBB permeability. FTY720 also attenuated astrocytes and microglia activation. Furthermore, treatment with FTY720 not only improved neurological function, but also increased the survival rate of mice significantly. These findings suggest that FTY720 administration restored the structure of the NVU after experimental TBI by decreasing endothelial cell apoptosis and attenuating the activation of astrocytes. Moreover, FTY720 might reduce inflammation in the brain by reducing the activation of microglia in TBI mice.

Effect and mechanism of biochar on CO2 and N2O emissions under different nitrogen fertilization gradient from an acidic soil.

"Nature based solutions" has been proposed at COP25 as an important venture for combating anthropogenic climate change, and soil biochar amendment have been proposed to have vast carbon sequestration potential. On the other hand, biochar carbon storage in soils is confronted with both biochar and soil carbon and nitrogen loss. The superposition of these two influences leads to complex variation in net greenhouse gas emissions from biochar-amended-soils. Nitrogen fertilization is a common agriculture practice in China and worldwide. To study the effects and mechanisms of biochar on soil net greenhouse gas emissions (CO2, N2O) under different nitrogen fertilization gradient in a ferrallitic soil, a soil column experiment was conducted. Maize straw derived biochar (pyrolysed at 500 °C) and nitrogen fertilizer (ammonium sulfate) were investigated at varying application rates. It was found that biochar amendment increased CO2 emissions by 51.1%-57.1% and N2O emissions by 50.0%-73.7%, respectively, when soil was incubated with 50 mg N/kg nitrogen fertilization. The N2O emission in soil was dominated by nitrification, and the labile fraction of biochar played the dominant role in increasing soil CO2 and N2O emissions. Therefore, water or acid washing of biochar before its application would significantly reduce the net GHG emissions. When the nitrogen fertilization was applied at the unusually high level of 450 mg N/kg, the N2O emissions mainly came from denitrification. Biochar amendment introduced less soil CO2 emission increment, and suppressed N2O emissions by inhibition of denitrification via adsorption protection mechanism (towards nitrogen) and aeration effect. A chain mechanism has been illustrated and results from this study suggest that biochar is best applied to an environment or the circumstance that maximizes adsorption protection mechanism and aeration effect to achieve total greenhouse gas emission reduction. This study therefore provides basis for the scientific sound application and regulation of biochar amendment in soils.

Activation of the Nrf2-ARE signal pathway after blast induced traumatic brain injury in mice.

Background: Treatment of blast-induced traumatic brain injury (bTBI) has been hindered. Previous studies have demonstrated that oxidative stress may contribute to the pathophysiological process. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway exhibits a protective effect after traumatic brain injury (TBI). This study explored whether the Nrf2-ARE pathway was activated in a modified bTBI mouse model. Method: Mice were randomly divided into six groups: the 6 h, 1 d, 3 d, 7 d and 14 d after bTBI groups and a sham group. The protein levels of nuclear Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1) were detected using western blot, and HO-1 and NQO1 mRNA levels were determined by real-time quantitative polymerase chain reaction. Moreover, HO-1 and Nrf2 were localized using histological staining. Results: The protein level of the Nrf2-ARE pathway in the frontal lobe increased significantly in the 3 d after bTBI. The HO-1 and NQO1 mRNA levels also reached a peak in the frontal lobe 3 d after bTBI. The histological staining demonstrated higher expression of HO-1 in the frontal lobe and hippocampus 3 d after bTBI, when nuclear import of Nrf2 reached a peak in the frontal lobe. Conclusions: bTBI activated the Nrf2-ARE signaling pathway in the brain. The peak activation time in the frontal lobe may be 3 d after injury, and activating the Nrf2 pathway could be a new direction for treatment.

Role of eruption season in reconciling model and proxy responses to tropical volcanism.

The response of the El Niño/Southern Oscillation (ENSO) to tropical volcanic eruptions has important worldwide implications, but remains poorly constrained. Paleoclimate records suggest an "El Niño-like" warming 1 year following major eruptions [Adams JB, Mann ME, Ammann CM (2003) Nature 426:274-278] and "La Niña-like" cooling within the eruption year [Li J, et al. (2013) Nat Clim Chang 3:822-826]. However, climate models currently cannot capture all these responses. Many eruption characteristics are poorly constrained, which may contribute to uncertainties in model solutions-for example, the season of eruption occurrence is often unknown and assigned arbitrarily. Here we isolate the effect of eruption season using experiments with the Community Earth System Model (CESM), varying the starting month of two large tropical eruptions. The eruption-year atmospheric circulation response is strongly seasonally dependent, with effects on European winter warming, the Intertropical Convergence Zone, and the southeast Asian monsoon. This creates substantial variations in eruption-year hydroclimate patterns, which do sometimes exhibit La Niña-like features as in the proxy record. However, eruption-year equatorial Pacific cooling is not driven by La Niña dynamics, but strictly by transient radiative cooling. In contrast, equatorial warming the following year occurs for all starting months and operates dynamically like El Niño. Proxy reconstructions confirm these results: eruption-year cooling is insignificant, whereas warming in the following year is more robust. This implies that accounting for the event season may be necessary to describe the initial response to volcanic eruptions and that climate models may be more accurately simulating volcanic influences than previously thought.

Correlation of Nrf2 and HIF-1α in glioblastoma and their relationships to clinicopathologic features and survival.

OBJECTIVES: Glioblastoma (GB) is the most common, aggressive, and proliferative among all brain tumors. The prognosis of GB is still far from satisfactory currently, thus demanding great modification and enhancement, which may be acquired by the help of the molecular target therapy. Nuclear factor E2-related factor 2 (Nrf2), a pivotal transcriptional factor of cellular responses to oxidative stress, was observed to function remarkably in cancer pathobiology. In the current study, we analyzed the correlation between Nrf2 and Hypoxia-inducible factor-1alpha (HIF-1alpha) in GB, together with their association to the features and survival of clinicopathology. METHODS: We examined the expression of Nrf2 and HIF-1alpha in 68 specimens of GB by tissue microarray and immunohistochemistry, and correlated this investigation to the outcome of GB patients. RESULTS: Nrf2 and HIF-1alpha were overexpressed in GB tissues. There was significant correlation between the high level of Nrf2 and tumor necrosis on MRI and 1-year survival. There was significant correlation between HIF-1alpha level and Nrf2 status (r = 0·294, P = 0·015). Kaplan-Meier analysis showed that high Nrf2 expression was significantly associated with shorter overall survival (OS) (log-rank test, P = 0·006), and was identified as an independent prognostic factor in multivariate analysis (P = 0·034). HIF-1alpha was another independent factor for both OS and progression-free survival by Cox regression analysis (P = 0·048 and P = 0·032, respectively). DISCUSSION: Mutual association between Nrf2 and HIF-1alpha was found in GB: higher Nrf2 expression and poorer outcome of GB patients. Nrf2 would therefore be a new molecular marker for the targeted treatment of GB.

Knockdown of NF-E2-related factor 2 inhibits the proliferation and growth of U251MG human glioma cells in a mouse xenograft model.

NF-E2-related factor 2 (Nrf2) is a pivotal transcription factor of cellular responses to oxidative stress and recent evidence suggests that Nrf2 plays an important role in cancer pathobiology. However, the underlying mechanism has yet to be elucidated, particularly in glioma. In the present study, we investigated the role of Nrf2 in the clinical prognosis, cell proliferation and tumor growth of human glioblastoma multiforme (GBM). We detected overexpression of Nrf2 protein levels in GBM compared to normal brain tissues. Notably, higher protein levels of Nrf2 were significantly associated with poorer overall survival and 1-year survival for GBM patients. Furthermore, we constructed the plasmid Si-Nrf2 and transduced it into U251MG cells to downregulate the expression of Nrf2 and established stable Nrf2 knockdown cells. The downregulation of Nrf2 suppressed cell proliferation in vitro and tumor growth in mouse xenograft models. We performed immunohistochemistry staining to detect the protein levels of Nrf2, Ki-67, caspase-3 and CD31 in the xenograft tumors and found that the expression levels of Nrf2 and Ki-67 were much lower in the Si-Nrf2 group compared to the Si-control group. In addition, the number of caspase-3-positive cells was significantly increased in the Si-Nrf2 group. By analysis of microvessel density (MVD) assessed by CD31, the MVD value in the Si-Nrf2 group decreased significantly compared to the Si-control group. These findings indicate that the knockdown of Nrf2 may suppress tumor growth by inhibiting cell proliferation, increasing cell apoptosis and inhibiting angiogenesis. These results highlight the potential of Nrf2 as a candidate molecular target to control GBM cell proliferation and tumor growth.