Search

The prepared oxazolopyrimidine derivatives exhibited high anti-breast-cancer activity and ADK suppression, indicating their potential as candidates in the targeted search for new, highly effective antitumor drugs.

Adenosinergic activities are suggested to participate in SUDEP pathophysiology; this study aimed to evaluate the adenosine hypothesis of SUDEP and specifically the role of adenosine A

Dysregulated adenosine signaling pathway has been evidenced in the pathogenesis of breast cancer. However, the role of adenosine kinase (ADK) in tumorigenesis remains unclear while it crucially regulates the removal and availability of adenosine. ADK has two isoforms that localize to discrete subcellular spaces: i.e., nuclear, long-isoform (ADK-L) and cytosolic, short-isoform (ADK-S). We hypothesized that these two ADK isoforms would be differentially expressed in breast cancer and may contribute to divergent cellular actions in cancer. In this study, we examined the expression profiles of ADK isoforms in breast cancer tissues from 46 patient and followed up with an in vitro investigation by knocking down the expression of ADK-L or ADK-S using CRISPR gene editing to evaluate the role of ADK isoform in cancer progression and metastasis of cultured triple-negative breast cancer cell line MDA-MB-231. We demonstrated that (i) ADK-L expression level was significantly increased in breast cancer tissues versus paired normal tissues adjacent to tumor, whereas the ADK-S expression levels were not significantly different between cancerous and normal tissues; (ii) CRISPR/Cas9-mediated downregulation of ADK isoforms, led to suppressed cellular proliferation, division, and migration of cultured breast cancer cells; (iii) ADK-L knockdown significantly upregulated gene expression of matrix metalloproteinase (ADAM23, 9.93-fold; MMP9, 24.58-fold) and downregulated expression of cyclin D2 (CCND2, -30.76-fold), adhesive glycoprotein THBS1 (-8.28-fold), and cystatin E/M (CST6, -16.32-fold). Our findings suggest a potential role of ADK-L in mitogenesis, tumorigenesis, and tumor-associated tissue remodeling and invasion; and the manipulation of ADK-L holds promise as a therapeutic strategy for aggressive breast cancer.

Purpose: Glia and their communication via connexin 43 (Cx43) gap junctions are known to mediate neurovascular coupling, a process driven by metabolic demand. However, it is unclear whether Cx43 mediated glial communication intermediates classical autoregulation. Here we used viral transfection and a glial fibrillary acidic protein (GFAP) promoter to downregulate glial Cx43 to evaluate its role in retinal vascular autoregulation to ocular perfusion pressure (OPP) reduction. Methods: Adult rats were intravitreally injected with the viral active construct or a control. Three weeks after the injection, eyes were imaged using confocal scanning laser ophthalmoscopy before and during a period of OPP decrease induced by blood draw to lower blood pressure or by manometric IOP elevation. Vessel diameter responses to the OPP decrease were compared between Cx43-downregulated and control-injected eyes. The extent of Cx43 downregulation was evaluated by Western blot and immunohistochemistry. Results: In control eyes, the OPP decrease induced dilatation of arterioles, but not venules. In Cx43-downregulated eyes, Cx43 expression in whole retina was decreased by approximately 40%. In these eyes, the resting diameter of the venules increased significantly, but there was no effect on arterioles. In Cx43-downregulated eyes, vasoreactivity evoked by blood pressure lowering was significantly compromised in both arterioles (P = 0.005) and venules (P = 0.001). Cx43 downregulation did not affect the arteriole responses to IOP elevation, whereas the responses of the venules showed a significantly greater decrease in diameter (P < 0.001). Conclusions: The downregulation of retinal Cx43 in GFAP-expressing cells compromises vasoreactivity of both arterioles and venules in response to an OPP decrease achieved via blood pressure lowering or IOP elevation. The results also suggest that Cx43-mediated glial communication actively regulates resting venular diameter.

Epileptogenesis is a common consequence of brain insults, however, the prevention or delay of the epileptogenic process remains an important unmet medical challenge. Overexpression of glycine transporter 1 (GlyT1) is proposed as a pathological hallmark in the hippocampus of patients with temporal lobe epilepsy (TLE), and we previously demonstrated in rodent epilepsy models that augmentation of glycine suppressed chronic seizures and altered acute seizure thresholds. In the present study we evaluated the effect of the GlyT1 inhibitor, sarcosine (aka N-methylglycine), on epileptogenesis and also investigated possible mechanisms. We developed a modified rapid kindling model of epileptogenesis in rats combined with seizure score monitoring to evaluate the antiepileptogenic effect of sarcosine. We used immunohistochemistry and Western blot analysis for the evaluation of GlyT1 expression and epigenetic changes of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the epileptogenic hippocampi of rats, and further evaluated expression changes in enzymes involved in the regulation of DNA methylation, ten-eleven translocation methylcytosine dioxygenase 1 (TET1), DNA-methyltransferase 1 (DNMT1), and DNMT3a. Our results demonstrated: (i) experimental evidence that sarcosine (3 g/kg, i.p. daily) suppressed kindling epileptogenesis in rats; (ii) the sarcosine-induced antiepileptogenic effect was accompanied by a suppressed hippocampal GlyT1 expression as well as a reduction of hippocampal 5mC levels and a corresponding increase in 5hmC; and (iii) sarcosine treatment caused differential expression changes of TET1 and DNMTs. Together, these findings suggest that sarcosine has unprecedented disease-modifying properties in a kindling model of epileptogenesis in rats, which was associated with altered hippocampal DNA methylation. Thus, manipulation of the glycine system is a potential therapeutic approach to attenuate the development of epilepsy.

Background Neurofilaments (Nf) are a series of highly specific scaffolding proteins of neurons. Neurofilament light chains (Nf‐L) and the heavy one (Nf‐H) are subunits of Nf, and they are recognized as potent productions of neural damage. The concentrations of Nf aggrandized significantly in neurological disease including neuromyelitis optica, multiple sclerosis, and Alzheimer's disease. However, whether Nf in cerebrospinal fluid (CSF) elevated in anti‐N‐methyl‐d‐aspartate receptor (NMDAR) encephalitis is unclear. Here, we aimed to detect whether CSF Nf is altered in NMDAR and whether changes in CSF Nf can serve as an objective and effective biomarker to evaluate disease severity and prognosis. Methods We collected 24 anti‐NMDAR encephalitis patients, 11 viral meningoencephalitis/encephalitis (VM) patients, and 21 controls in this study. CSF Nf‐L, Nf‐H, and cytokine levels (IL‐1β, IL‐6, and IL‐17A) were determined by enzyme‐linked immunosorbent assay (ELISA) and compared between groups. We evaluated patients’ clinical outcomes or prognosis according to modified Rankin scale (mRS) score. Results Compared with controls, both CSF Nf‐L and Nf‐H levels were significantly increased in anti‐NMDAR encephalitis patients. While compared with VM patients, only Nf‐L were increased in anti‐NMDAR encephalitis patients. Moreover, CSF Nf‐L were positively correlated with concentration of cytokines (IL‐1β, IL‐17A) and mRS scores in anti‐NMDAR encephalitis patients. After treatment, both CSF Nf‐L and Nf‐H levels decreased. Furthermore, the Nf‐L during follow‐up positively correlated with 3‐month mRS scores, and ΔNf‐L positively correlated with ΔmRS. Conclusions Briefly, CSF Nf‐L levels notably increased in anti‐NMDAR encephalitis patients in acute phase and positively correlated with disease severity. It could be considered as a useful indicator for clinical outcomes and prognosis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is accepted as an autoimmune disorder of the central nervous system (CNS). NLR family pyrin domain containing 3 (NLRP3) inflammasome, a potent innate inflammatory mediator, can activate IL-1β and induce the migration of T helper cell into CNS. However, the possible role of NLRP3 inflammasome in the pathogenesis of anti-NMDAR encephalitis remains unclear. This study aims to determine the levels of NLRP3 and related cytokines (IL-1β, IL-6, and IL-17) in the cerebrospinal fluid (CSF) of anti-NMDAR encephalitis patients and to assess whether NLRP3 influences the clinical outcomes of this disease. Twenty-five patients with anti-NMDAR encephalitis, 12 viral meningoencephalitis patients and 26 controls with non-inflammatory neurological diseases were recruited. CSF NLRP3 inflammasome, IL-1β, IL-6, and IL-17 were measured by enzyme-linked immunosorbent assay. Thirteen out of 25 patients were re-examed for the concentrations of NLRP3 and cytokines 6 months later. Our results showed significant increases of CSF NLRP3 inflammasome, IL-1β, IL-6, and IL-17 in anti-NMDAR encephalitis patients. There were positive correlations between CSF NLRP3 inflammasome and cytokines in anti-NMDAR encephalitis patients. There was also a positive correlation between maximum modified Rankin Scale (mRS) scores and CSF NLRP3 inflammasome in anti-NMDAR encephalitis patients. During follow-up, the decrease of mRS was positively correlated with the decrease of CSF NLRP3 inflammasomes. These results suggested that the level of CSF NLRP3 inflammasome could represent the severity of anti-NMDAR encephalitis and the reduction of CSF NLRP3 inflammasome could act as an indicator for the prognosis of this disease.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune inflammatory brain disease that can develop a variety of neuropsychiatric presentations. However, the underlying nature of its inflammatory neuronal injury remains unclear. Mitochondrial DNA (mtDNA) is recently regarded as a damage-associated molecular pattern molecule (DAMP) that can initiate an inflammatory response. In the presenting study, we aimed to evaluate the levels of cell-free mtDNA in cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis and to determine a potential role of cell-free mtDNA in the prognosis of anti-NMDAR encephalitis. A total of 33 patients with NMDAR encephalitis and 17 patients with other non-inflammatory disorders as controls were included in this study. The CSF levels of cell-free mtDNA were measured by quantitative polymerase chain reaction (qPCR). Cytokines including interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNF-α) were measured by ELISA. The modified Rankin scale (mRS) score was evaluated for neurologic disabilities. Our data showed that the CSF levels of cell-free mtDNA and inflammation-associated cytokines were significantly higher in the patients with anti-NMDAR encephalitis compared with those in controls. Positive correlations were detected between the CSF levels of cell-free mtDNA and mRS scores of patients with anti-NMDAR encephalitis at both their admission and 6-month follow up. These findings suggest that the CSF level of cell-free mtDNA reflects the underlying neuroinflammatory process in patients with anti-NMDAR encephalitis and correlates with their clinical mRS scores. Therefore, cell-free mtDNA may be a potential prognostic biomarker for anti-NMDAR encephalitis.

Aspirin, one of the most commonly used anti-inflammatory drugs, has been recently reported to display multiple effects in the central nervous system (CNS), including neuroprotection and upregulation of ciliary neurotrophic factor (CNTF) expression in astrocytes. Although it was most recently reported that aspirin could promote the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) after white matter lesion, the underlying mechanisms remain unclear. To dissect the effects of aspirin on oligodendroglial development and explore possible mechanisms, we here demonstrated the following: (i) in vitro treatment of aspirin on OPC cultures significantly increased the number of differentiated oligodendrocytes (OLs) but had no effect on the number of proliferative OPCs, indicating that aspirin can promote OPC differentiation but not proliferation; (ii) in vivo treatment of aspirin on neonatal (P3) rats for 4 days led to a nearly twofold increase in the expression of myelin basic protein (MBP), devoid of change in OPC proliferaion, in the corpus callosum (CC); (iii) finally, aspirin treatment increased the phosphorylation level of β-catenin and counteracted Wnt signaling pathway synergist QS11-induced suppression on OPC differentiation. Together, our data show that aspirin can directly target oligodendroglial lineage cells and promote their differentiation through inhibition of Wnt/β-catenin signaling pathway. These findings suggest that aspirin may be a novel candidate for the treatment of demyelinating diseases.

The industrialization is progressing on the unparalleled scale, bringing an ever greater impetus to the growth of mining industry. China has had its unique pattern of developing its mining engineerin: firstly importing technologies, then studying and absorbing them, and finally achieving some innovation. Until now, China has been honored with some of mining theories taking the lead in the international mining world. As the disseminators of human civilization including advanced mining technologies, the Chinese professionals concerned are duty-bound to introduce abroad Chinas new progresses in mining engineering; that they are skillfully equipped with the four kinds of English abilities in reading, writing, listening and speaking, which is prerequisite for them to work well in foreign cooperation, has become an urgent matter to for them as well as for the authorities concerned.

The existence and release of fluid inclusions in bornite and its associated minerals, namely, quartz and calcite were investigated and confirmed. The structures, forms, and phases of these large quantities of fluid inclusions were also studied. A mass of fluid inclusions with various sizes, distributions, shapes, and phases exist in bornite and its associated minerals. Their sizes vary from a few micrometers to tens of micrometers, and the forms appear as negative crystals, or elongated, elliptical, and irregular. At room temperature, fluid inclusions were mainly characterized as gas-liquid twophase. However, small amounts of fluid inclusions with pure gas phase and pure liquid single-phase were also observed in quartz and calcite. These fluid inclusions initially broke during the ore crushing and grinding process and then released into the flotation pulp in the flotation process. The quantitative analysis of fluid inclusions in the solution and the comparisons of mineral dissolution show that the amount of copper and iron released by fluid inclusions in the bornite sample is higher than the amount dissolved by the mineral; fluid inclusions in the associated gangue minerals, quartz, and calcite also make contribution.

The present study aims to characterize the copper ore from east area of Yunnan province. The results indicate that the ores is a representative low grade and and ultra-fine-grained ore. As a result, a suitable flotation flow i.e. “ultrafine grinding- sulphidizing and dispersing - bulk flotation with low dosage collector” was presented for processing of eligible copper concentrate with high recovery and the main factors i.e. grinding fineness, regulators types and dosage and collector dosage affecting the indexes of roughing concentration was investigated. As a result, a close-circuit flotation test scheme was proceeded, which obtained a high quality copper concentrate with Cu grade of 25.12%, copper recovery of 87.63%. This index is successful in the aim of recovery copper for such mixed copper ore.

A technology route of Reverse flotation of acid-consuming gangue mineralsAcid leaching for copperExtractingElectrodepositing is proposed for recovery copper from a tailings with high content of calcium oxide and magnesium oxide and high content of combined copper oxide. The effect of H2SO4concentration, leaching time and stirring speed on copper leaching was investigated. The leaching solution obtained under the optimal copper leaching conditions, was used to be proceeded for extracting and electrodepositing test. The best leaching conditions are stirring speed of 30 m/min, H2SO4concentration of 150 Kg/t ore, leaching time of 30 minutes. Under the best conditions, the acid leaching test presented that the production of per ton copper consumes sulfuric acid of 17.31 t, and Cu leaching rate is 84.70%.

Adenosine A2A receptor (A2AR) plays an important regulatory role in the processes of inflammation and fibrosis. However, it is unknown whether A2AR can mediate renal interstitial fibrosis (RIF). To evaluate the effect of genetic A2AR knockout (KO) on the pathological progress of RIF, we applied a unilateral ureteral obstruction (UUO) model of RIF on A2AR KO mice and their wild-type (WT) littermates. Renal pathological assessment was performed at different post-UUO stages using hematoxylin and eosin (HE) and Masson's trichrome staining as well as quantitative morphological analysis. Our data demonstrated that: (i) the extent of RIF was determined by the development of UUO in a time-dependent manner; (ii) A2AR KO exacerbated the pathological progress of RIF in mice at the early post-UUO stage, i.e. day 3 and day 7; (iii) the profibrotic effect of A2AR KO was prominent until the late post-UUO stage, i.e. day 14, at which RIF reached a similar severity level in A2AR KO and WT mice. Our findings revealed that A2AR KO significantly exacerbated the progression of UUO-induced RIF in mice, prominently at the initial stage.

Schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile (3 weeks), young-adult (6 weeks) and middle-aged (8 months), were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated: (1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; (2) the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1-positive mature oligodendrocytes, and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

A craft of concentrated acid-heating reinforced leaching process is investigated for the treatment of a high arsenic pyrite cinder, a common by-product in vitriol industry. The pyrite cinder, containing 57.37% Fe, and 2.78% As, was conducted for the acid leaching process. The results demonstrated that iron concentrate with 60.57% Fe, 0.28% As and 96.23% of iron recovery was obtained under the optimal acid leaching conditions(Sulphuric acid concentration is a mass ratio of 20%, a leaching temperature of 60°C, a liquid-solid ratio of 2:1 and a leaching time of 120 min).This craft can be used to utilize pyrite cinder and produce qualified concentrate as iron-bearing feed for steel industry, which will help to solve the pollution of sulfuric acid residue and extend raw material sourcing for Chinese steel industry.

Improving the recovery of molybdenum is a research hotspot in the bulk flotation of Mo-copper sulphide ore. In this paper, the optimum flotation parameters for a kind of molybdenite ore obtained form Yunnan province, involving the grinding fineness, pulp concentration, dosages of kerosene and butyl xanthate, were determined in order to improve the recovery of Mo in the bulk Mo-copper flotation. In addition, a close-circuit flotation test was also conducted to simulate the practical process. A Mo-copper concentrate with Mo grade of 3.02% and recovery of 93.46% was obtained through the close-circuit flotation test, which satisfy the requirement for the bulk flotation of Mo-copper ore.

A technology of “depth cleaning- sulfuric and acid producing- residuals for ironmaking” is proposed for efficient utilization of sulphur concentration with high quality. The effect of the main factors involving grinding fineness, activators, collector type and dosage was investigated. On this regard, a close-circuit flotation test scheme was proceeded, by which a high quality sulphur concentrate was obtained with 52.39% of iron grade, 86.44% of iron recovery, 39.46% of sulphur grade and 91.52% of recovery sulphur. This concentrate can be directly used in the production of sulfuric acid and preparation of iron concentrate. This technology can be used to fully utilize sulphur and produce high quality concentrate as iron-bearing feed for steel industry, which will help to extend raw material sourcing for Chinese steel industry.

An emerging theory of schizophrenia postulates that hypofunction of adenosine signaling may contribute to its pathophysiology. This study was designed to test the "adenosine hypothesis" of schizophrenia and to evaluate focal adenosine-based strategies for therapy. We found that augmentation of adenosine by pharmacologic inhibition of adenosine kinase (ADK), the key enzyme of adenosine clearance, exerted antipsychotic-like activity in mice. Further, overexpression of ADK in transgenic mice was associated with attentional impairments linked to schizophrenia. We observed that the striatal adenosine A2A receptor links adenosine tone and psychomotor response to amphetamine, an indicator of dopaminergic signaling. Finally, intrastriatal implants of engineered adenosine-releasing cells restored the locomotor response to amphetamine in mice overexpressing ADK, whereas the same grafts placed proximal to the hippocampus of transgenic mice reversed their working memory deficit. This functional double dissociation between striatal and hippocampal adenosine demonstrated in Adk transgenic mice highlights the independent contributions of these two interconnected brain regions in the pathophysiology of schizophrenia and thus provides the rationale for developing local adenosine augmentation therapies for the treatment of schizophrenia.

Based on the analysis of the properties of the ore from Weixin area in Yunnan province, a suitable technical route was presented for the processing of sulphur concentrate with high quality. The main factors i.e. grinding fineness, pH, collector type and dosage, affecting the quality of roughing concentrate was investigated. On this basis, a close-circuit flotation test scheme was proceeded, which obtained a high quality sulphur concentrate with sulphur grade of 51.58%, sulphur recovery of 99.22%, iron grade of 45.14% and impurities content of 3.28%. In addition, a decrease of slurry concentration of cleaning further increase the quality of sulphur concentrate, which contained 52.82% sulphur, 45.29% iron and 1.89% impurities.

The valuable minerals of a copper sulfide ore in Chile, mainly consist of chalcopyrite and chalcocite as well as contain small amounts of cuprite. Gangue minerals are mainly chlorite, quartz, calcite, arsenopyrite, etc. Most are coarse-grained disseminated minerals, while some are fine-grained disseminated minerals. Flotation has been used for processing these ores. The grinding fineness, lime dosage, collector type and dosage all have influences on flotation results. In the present work, the best condition of grinding fineness, lime, and collector dosage was used to separate the copper sulfide and other minerals in the ores. The results showed that, in the grinding fineness of −74 μm accounting for 80%, the vast majority of copper minerals were to monomer dissociation. The flowsheet of one stage roughing, two stage scavenging, and two stage cleaning was adopted. The ideal results of 27.58% and 96.89% for the copper concentrate grade and copper recovery, respectively, were obtained.

This study aimed to obtain volatile copper from a high-copper pyrite cinder by optimizing the chloridizing roasting process using response surface methodology (RSM). The effect of key parameters, i.e., dosage of CaCl2 addition, roasting time and roasting temperature, on the copper volatile ratio was investigated and a quadratic model was suggested by the methodology to correlate the variables to this volatile ratio. The results indicated that the model was in good agreement with the experimental data at a correlation coefficient (R2) of 0.9782, and the most influential parameter on efficiency was identified as the dosage of CaCl2 addition. The optimum conditions for chloridizing roasting from the high copper pyrite cinder were identified as a dosage of CaCl2 addition of 4.8 wt%, a roasting time of 19.28 min and a roasting temperature of 1151.51 °C; under such conditions, a copper volatile ratio of 97.82% was achieved. The pellets obtained by this process are characterized by a high content of hematite, and the main impurity element contents are consistent with the requirements for iron concentrate, which is suitable for use in ironmaking.

In this study, factors influencing zinc oxide flotation are investigated. These factors include the dosages of sulfidizing reagent, the pH of the regulator and the activator, the use of sodium carbonate as the pH regulator and activator, the use of copper sulfate as the activator and the use of isoamyl xanthate as the collector. All of the above factors are essential to the effective recovery of zinc oxide. Flotation using mixed collectors (isoamyl xanthogenate + dithionphosphate) showed promising results. The ratio of the mixed collectors and the addition sequence of the mixed collectors were important in attaining a true mixed collector for zinc oxide flotation. In the closed circuit experiment, these agents helped to produce a zinc concentrate with 12.41% Zn, 80.03% recovery and 17.29% Zn in the tailings. The zinc concentrate with 12.41% Zn was used as a material for hydrometallurgy to collect zinc.

A technology of “arsenic removing- sulfuric acid producing- residuals for ironmaking” is proposed for comprehensive utilization of pyrite with high content of arsenic. The effect of roasting temperature and time on arsenic removing was investigated. The arsenic removed residuals obtained under the optimal arsenic removed conditions, was used to be proceeded for sulphur volatilization test. The results demonstrate that final residuals with 63.53% of Fe can be used for steel industry. This technology can be used to fully utilize sulphur and produce high quality concentrate as iron-bearing feed for steel industry, which will help to reduce the pollution of arsenic and extend raw material sourcing for Chinese steel industry.

Low-grade oxide copper ore is an important resource, reserves of which are scattered all over the world. In the present study, the characteristics of oxide copper ore are studied using multi-element analysis and X-ray diffraction. The oxide copper minerals in the ore are mainly in the form of cuprite, malachite, chrysocollite and azurite. The effects of grinding fineness and agent regulation on flotation are also investigated. Floatability was unsatisfactory because of the many kinds of oxide copper minerals present in the sample. The flotation results indicate that a concentrate grade of 18.32% at 73.46% recovery can be obtained using the closed circuit process of one-stage roughing, three-stage scavenging and two-stage cleaning flotation under the optimum parameters, with raw ore characteristics of 1.29% Cu, 92.25% copper oxidation rate, and 65.59% slime content.

For low-grade iron ore, smelting costs and resource wastage will be increased. Product quality of such ore is affected adversely by an excessive amount of sulfur. This also causes environmental pollution. In accordance with the vanadium-titanium (V-Ti) magnetite concentrate properties with low iron grade and high sulfur content, the joint process of magnetic separation and flotation was carried out. Magnetic separation was conducted to increase the iron grade, while reverse flotation was used to reduce sulfur content. Results show that the feeding mainly contains titanomagnetite, hematite, and pyrite. The sulfur was primarily found in pyrite. The separation effect was influenced by the grinding fineness, magnetic intensity, collector type and dosage, and pH value. At a grinding fineness of −45 μm accounting for 87%, most of the iron minerals exhibited monomer dissociation. An open-circuit experiment was carried out under the best conditions of magnetic intensity, as well as collector and modifier dosage. Good experimental results were obtained as follows: the iron grade increased to 57.17%, iron recovery was 89.94%, sulfur content decreased from 0.66% to 0.26%, reverse flotation of sulfur foam concentrate contained almost 15.68% sulfur, the upgrade ratio was about 23, and the cobalt in the sulfur concentrate was enriched 20-fold. A method for improving the comprehensive utilization level and effect of mineral resources is provided in this study.

The study aims to comprehensive recovery of Cu, Mo, Co and Fe from copper polymetallic sulphide ore in Sichuan province, China. In the light of the minerals characteristics, a united flow sheet, i.e., flotation-magnetic separation with new powerful flotation reagents were used to effectively recovery copper together with the associated valuable metals (Mo, Co and Fe) from the ore. The result of the closed circuit experiment shows that a copper recovery of 93.38% with a concentrate grade of 21.25%, Mo recovery of 45.72% with a concentrate grade of 45.78%, Co recovery of 46.42% with a concentrate grade of 0.46% and Fe recovery of 38.26% with a concentrate grade of 63.73% were achieved from the ore.

Pharmacotherapy of schizophrenia based on the dopamine hypothesis remains unsatisfactory for the negative and cognitive symptoms of the disease. Enhancing N-methyl-D-aspartate receptors (NMDAR) function is expected to alleviate such persistent symptoms, but successful development of novel clinically effective compounds remains challenging. Adenosine is a homeostatic bioenergetic network modulator that is able to affect complex networks synergistically at different levels (receptor-dependent pathways, biochemistry, bioenergetics, and epigenetics). By affecting brain dopamine and glutamate activities, it represents a promising candidate for reversing the functional imbalance in these neurotransmitter systems believed to underlie the genesis of schizophrenia symptoms, as well as restoring homeostasis of bioenergetics. Suggestion of an adenosine hypothesis of schizophrenia further posits that adenosinergic dysfunction might contribute to the emergence of multiple neurotransmitter dysfunctions characteristic of schizophrenia via diverse mechanisms. Given the importance of adenosine in early brain development and regulation of brain immune response, it also bears direct relevance to the aetiology of schizophrenia. Here, we provide an overview of the rationale and evidence in support of the therapeutic potential of multiple adenosinergic targets, including the high-affinity adenosine receptors (A(1)R and A(2A)R), and the regulatory enzyme adenosine kinase (ADK). Key preliminary clinical data and preclinical findings are reviewed.

Adolescence is the critical time for developing proper oligodendrocyte (OL)-neuron interaction and the peak of onset for many cognitive diseases, among which anxiety disorders display the highest prevalence. However, whether impairment of de novo OL development causes neuronal abnormalities and contributes to the early onset of anxiety phenotype in childhood still remains unexplored. In this study, we tested the hypothesis that defects in OL maturation manifests cortical neuron function and leads to anxiety-like behaviors in juvenile mice. We report here that conditional knockout of the Olig2 gene (Olig2 cKO) specifically in differentiating OLs in the mouse brain preferentially impaired OL maturation in the gray matter of cerebral cortex. Interestingly, localized proton magnetic resonance spectroscopy revealed that Olig2 cKO mice displayed abnormally elevated cortical glutamate levels. In addition, transmission electron microscopy demonstrated increased vesicle density in excitatory glutamatergic synapses in the cortex of the Olig2 cKO mice. Moreover, juvenile Olig2 cKO mice exhibited anxiety-like behaviors and impairment in behavioral inhibition. Taken together, our results suggest that impaired OL development affects glutamatergic neuron function in the cortex and causes anxiety-related behaviors in juvenile mice. These discoveries raise an intriguing possibility that OL defects may be a contributing mechanism for the onset of anxiety in childhood.

Summary Purpose—Given the high incidence of refractory epilepsy, novel therapeutic approaches and concepts are urgently needed. To date, viral mediated delivery and endogenous expression of antisense sequences as a strategy to prevent seizures has received little attention in epilepsy therapy development efforts. Here we validate adenosine kinase (ADK), the astrocyte-based key negative regulator of the brain’s endogenous anticonvulsant adenosine, as a potential therapeutic target for antisense-mediated seizure suppression. Methods—We developed adeno-associated virus 8 (AAV8)-based gene therapy vectors to selectively modulate ADK expression in astrocytes. Cell type selectivity was achieved by expressing an Adk-cDNA in sense or antisense orientation under the control of an astrocytespecific gfaABC1D promoter. Viral vectors where injected into the CA3 of wild-type mice or spontaneously epileptic Adk-tg transgenic mice that overexpress ADK in brain. After virus injection, ADK expression was assessed histologically and biochemically. In addition, intracranial EEG-recordings were performed. Key Findings—We demonstrate in wild-type mice that viral overexpression of ADK within astrocytes is sufficient to trigger spontaneous recurrent seizures in the absence of any other epileptogenic event, whereas ADK downregulation via AAV8-mediated RNA interference almost completely abolished spontaneous recurrent seizures in Adk-tg mice. Significance—Our data demonstrate that modulation of astrocytic ADK expression can trigger or prevent seizures, respectively. This is the first study to use an antisense approach to validate ADK as a rational therapeutic target for the treatment of epilepsy and suggests that gene therapies based on the knock down of ADK might be a feasible approach to control seizures in refractory epilepsy.

During brain injury, extracellular adenosine and glutamate levels increase rapidly and dramatically. We hypothesized that local glutamate levels in the brain dictates the adenosine–adenosine A2Areceptor (A2AR) effects on neuroinflammation and brain damage outcome. Here, we showed that, in the presence of low concentrations of glutamate, the A2AR agonist 3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoic acid (CGS21680) inhibited lipopolysaccharide (LPS)-induced nitric oxide synthase (NOS) activity of cultured microglial cells, an effect that was dependent on the protein kinase A (PKA) pathway. However, in high concentrations of glutamate, CGS21680 increased LPS-induced NOS activity in a protein kinase C (PKC)-dependent manner. Thus, increasing the local level of glutamate redirects A2AR signaling from the PKA to the PKC pathway, resulting in a switch in A2AR effects from antiinflammatory to proinflammatory. In a cortical impact model of traumatic brain injury (TBI) in mice, brain water contents, behavioral deficits, and expression of tumor necrosis factor-α, interleukin-1 mRNAs, and inducible NOS were attenuated by administering CGS21680 at post-TBI time when brain glutamate levels were low, or by administering the A2AR antagonist ZM241385 [4-(2-{[5-amino-2-(2-furyl)[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl]amino}ethyl)phenol] at post-TBI time when brain glutamate levels were elevated. Furthermore, pre-TBI treatment with the glutamate release inhibitor (S)-4C3HPG [(S)-4-carboxy-3-hydroxyphenylglycine] converted the debilitating effect of CGS21680 administered at post-TBI time with high glutamate level to a neuroprotective effect. This further indicates that the switch in the effect of A2AR activation in intact animals from antiinflammatory to proinflammatory is dependent on glutamate concentration. These findings identify a novel role for glutamate in modulation of neuroinflammation and brain injury via the adenosine–A2AR system.

Heat shock protein 90 (Hsp90), encoded by the murine hsp84 and hsp86 genes in mice, is a pivotal regulator of glucocorticoid receptor (GR) function in the hypothalamus-pituitary-adrenal axis and affords stress protection. To explore the underlying molecular mechanisms of strain susceptibility to traumatic stress, we investigated the alteration by Hsp90 of the function of the glucocorticoid-glucocorticoid receptor (GC-GR) pathway in attenuating stress responses in C57BL/6 and BALB/c mice using the whole-body blast injury (WBBI) model. We found that C57BL/6 mice had a lower WBBI-induced mortality, higher nuclear GR level, and higher glucocorticoid-response element (GRE) binding activity than BALB/c mice. This study is the first report identifying four genetic variations of the murine hsp84 gene: 226AC, 996GC, 1483GC, and 2000GT. These nucleotide changes occur in the functional domains associated with the nuclear/cytosolic translocation of GR, GR-Hsp90 interaction, ATP binding, and self-dimerization of Hsp90, respectively. Further, we used a specific Hsp90 inhibitor, geldanamycin (GA), to assess the role of Hsp90 in the discriminative traumatic response in C57BL/6 mice. Pretreatment with GA reduced nuclear GR levels and GRE binding activity, and enhanced WBBI-induced mortality. These findings suggest that Hsp90 may underlie the strain-selective (C57BL/6 versus BALB/c) susceptibility to WBBI by mediating the nuclear translocation of GRs and GRE binding. Thus, pharmacological manipulation of Hsp90 may represent a therapeutic strategy to modify the function of the GC-GR pathway and traumatic stress response.

The adenosine A(2A) receptor (A(2A)R) is in the center of a neuromodulatory network affecting a wide range of neuropsychiatric functions by interacting with and integrating several neurotransmitter systems, especially dopaminergic and glutamatergic neurotransmission. These interactions and integrations occur at multiple levels, including (1) direct receptor- receptor cross-talk at the cell membrane, (2) intracellular second messenger systems, (3) trans-synaptic actions via striatal collaterals or interneurons in the striatum, (4) and interactions at the network level of the basal ganglia. Consequently, A(2A)Rs constitute a novel target to modulate various psychiatric conditions. In the present review we will first summarize the molecular interaction of adenosine receptors with other neurotransmitter systems and then discuss the potential applications of A(2A)R agonists and antagonists in physiological and pathophysiological conditions, such as psychostimulant action, drug addiction, anxiety, depression, schizophrenia and learning and memory.

Histone deacetylase (HDAC) plays an important role in chromatin remodeling in response to a variety of neurochemical signalings and behavioral manipulations, and may be a therapeutic target for modulation of psychostimulant behavioral sensitization. In this study, we investigated the molecular interaction between histone deacetylase inhibitor (HDACi) and psychostimulant in vivo of mice after repeated treatment with the HDACi, butyric acid (BA) and valproic acid (VPA), alone or in combination with amphetamine. Repeated treatment with amphetamine produced HDACi-like effects: enhanced global histone H4 acetylation level by Western blot as well as specific histone H4 acetylation associated with fosB promoter by chromatin immunoprecipitation in the striatum. Conversely, repeated treatment with BA or VPA produced amphetamine-like effects: enhanced cAMP responsive element binding protein (CREB) phosphorylation at Ser(133) position and increased DeltaFosB protein levels in the striatum. Furthermore, co-administration of BA or VPA with amphetamine produced additive effects on histone H4 acetylation as well as CREB phosphorylation in the striatum. The interplay of HDAC and CREB was also supported by co-immunoprecipitation assays demonstrating that repeated treatment with VPA reduced the association of CREB and HDAC1 in the striatum. Finally, the additive effect of VPA/BA and amphetamine on histone H4 acetylation, phosphorylated CREB, and DeltaFosB was associated with potentiated amphetamine-induced locomotor activity. Thus, HDACi may interact additively with psychostimulants at both histone acetylation and CREB phosphorylation through the CREB:HDAC protein complex in the striatum to modulate DeltaFosB protein levels and psychomotor behavioral sensitization.

The function of striatal adenosine A2Areceptors (A2ARs) is well recognized because of their high expression levels and the documented antagonistic interaction between A2ARs and dopamine D2receptors in the striatum. However, the role of extrastriatal A2ARs in modulating psychomotor activity is largely unexplored because of the low level of expression and lack of tools to distinguish A2ARs in intrinsic striatal versus nonstriatal neurons. Here, we provided direct evidence for the critical role of A2ARs in extrastriatal neurons in modulating psychomotor behavior using newly developed striatum-specific A2AR knock-out (st-A2AR KO) mice in comparison with forebrain-specific A2AR KO (fb-A2AR KO) mice. In contrast to fb-A2AR KO (deleting A2ARs in the neurons of striatum as well as cerebral cortex and hippocampus), st-A2AR KO mice exhibited Cre-mediated selective deletion of the A2AR gene, mRNA, and proteins in the neurons (but not astrocytes and microglial cells) of the striatum only. Strikingly, cocaine- and phencyclidine-induced psychomotor activities were enhanced in st-A2AR KO but attenuated in fb-A2AR KO mice. Furthermore, selective inactivation of the A2ARs in extrastriatal cells by administering the A2AR antagonist KW6002 into st-A2AR KO mice attenuated cocaine effects, whereas KW6002 administration into wild-type mice enhanced cocaine effects. These results identify a critical role of A2ARs in extrastriatal neurons in providing a prominent excitatory effect on psychomotor activity. These results indicate that A2ARs in striatal and extrastriatal neurons exert an opposing modulation of psychostimulant effects and provide the first direct demonstration of a predominant facilitatory role of extrastriatal A2ARs.