Temporal gene expression profiling reveals CEBPD as a candidate regulator of brain disease in prosaposin deficient mice

<p>Abstract</p> <p>Background</p> <p>Prosaposin encodes, in tandem, four small acidic activator proteins (saposins) with specificities for glycosphingolipid (GSL) hydrolases in lysosomes. Extensive GSL storage occurs in various central nervous system regions in mammalian prosaposin deficiencies.</p> <p>Results</p> <p>Our hypomorphic prosaposin deficient mouse, PS-NA, exhibited 45% WT levels of brain saposins and showed neuropathology that included neuronal GSL storage and Purkinje cell loss. Impairment of neuronal function was observed as early as 6 wks as demonstrated by the narrow bridges tests. Temporal transcriptome microarray analyses of brain tissues were conducted with mRNA from three prosaposin deficient mouse models: PS-NA, prosaposin null (PS-/-) and a V394L/V394L glucocerebrosidase mutation combined with PS-NA (4L/PS-NA). Gene expression alterations in cerebrum and cerebellum were detectable at birth preceding the neuronal deficits. Differentially expressed genes encompassed a broad spectrum of cellular functions. The number of down-regulated genes was constant, but up-regulated gene numbers increased with age. CCAAT/enhancer-binding protein delta (CEBPD) was the only up-regulated transcription factor in these two brain regions of all three models. Network analyses revealed that CEBPD has functional relationships with genes in transcription, pro-inflammation, cell death, binding, myelin and transport.</p> <p>Conclusion</p> <p>These results show that: 1) Regionally specific gene expression abnormalities precede the brain histological and neuronal function changes, 2) Temporal gene expression profiles provide insights into the molecular mechanism during the GSL storage disease course, and 3) CEBPD is a candidate regulator of brain disease in prosaposin deficiency to participate in modulating disease acceleration or progression.</p

Perioperative cerebral blood flow measured by arterial spin labeling with different postlabeling delay in patients undergoing carotid endarterectomy: a comparison study with CT perfusion

BackgroundArterial spin labeling (ASL) is a non-invasive technique for measuring cerebral perfusion. Its accuracy is affected by the arterial transit time. This study aimed to (1) evaluate the accuracy of ASL in measuring the cerebral perfusion of patients who underwent carotid endarterectomy (CEA) and (2) determine a better postlabeling delay (PLD) for pre- and postoperative perfusion imaging between 1.5 and 2.0 s.MethodsA total of 24 patients scheduled for CEA due to severe carotid stenosis were included in this study. All patients underwent ASL with two PLDs (1.5 and 2.0 s) and computed tomography perfusion (CTP) before and after surgery. Cerebral blood flow (CBF) values were measured on the registered CBF images of ASL and CTP. The correlation in measuring perioperative relative CBF (rCBF) and difference ratio of CBF (DRCBF) between ASL with PLD of 1.5 s (ASL1.5) or 2.0 s (ASL2.0) and CTP were also determined.ResultsThere were no significant statistical differences in preoperative rCBF measurements between ASL1.5 and CTP (p = 0.17) and between ASL2.0 and CTP (p = 0.42). Similarly, no significant differences were found in rCBF between ASL1.5 and CTP (p = 0.59) and between ASL2.0 and CTP (p = 0.93) after CEA. The DRCBF measured by CTP was found to be marginally lower than that measured by ASL2.0_1.5 (p = 0.06) and significantly lower than that measured by ASL1.5_1.5 (p = 0.01), ASL2.0_2.0 (p = 0.03), and ASL1.5_2.0 (p = 0.007). There was a strong correlation in measuring perioperative rCBF and DRCBF between ASL and CTP (r = 0.67–0.85, p &lt; 0.001). Using CTP as the reference standard, smaller bias can be achieved in measuring rCBF by ASL2.0 (−0.02) than ASL1.5 (−0.07) before CEA. In addition, the same bias (0.03) was obtained by ASL2.0 and ASL1.5 after CEA. The bias of ASL2.0_2.0 (0.31) and ASL2.0_1.5 (0.32) on DRCBF measurement was similar, and both were smaller than that of ASL1.5_1.5 (0.60) and ASL1.5_2.0 (0.60).ConclusionStrong correlation can be found in assessing perioperative cerebral perfusion between ASL and CTP. During perioperative ASL imaging, the PLD of 2.0 s is better than 1.5 s for preoperative scan, and both 1.5 and 2.0 s are suitable for postoperative scan

Characterization of Anti-bacterial Compounds from the Seed Coat of Chinese Windmill Palm Tree (Trachycarpus fortunei)

The increasing of multidrug resistance in bacterial associated infections has impaired the current antimicrobial therapy and it forces the search for other alternatives. In this study, we aimed to find the in vitro antibacterial activity of seed coat of Trachycarpus fortunei against a panel of clinically important bacterial species. Ethanolic extracts of target tissues were fractionated through macro porous resin by column chromatography, using ethanol as an organic solvent with a concentration gradient of 0–100%, each along with 20% concentration increment. The minimum inhibitory (MIC) concentrations of all fractions were measured. It is found that 20% ethanolic fraction showed the most significant inhibition against tested bacterial species. All fractions were analyzed by Ultra-Performance Liquid Chromatography/mass spectrometry (UPLC/MS) and compounds were identified by comparing mass spectra with standard libraries. By pairing the identified compounds from different fractions with the antibacterial activity of each fraction, it was shown that compounds stearamide (7), 1-(4-Fluorophenyl)-2-(methylthio)-1H-imidazole-5-carboxylic acid (9) and 2,4,5 triacetoxybiphenyl (10) topped in the list for anti-bacterial activity. Further experiment with pure chemicals verified that compounds 9 and 10 have antibacterial activity against Gram-negative bacteria. Whereas, the lowest MIC value (39.06 μg/mL) was obtained by compound 10 against Staphylococcus epidermidis. Hence, the seed coat of T. fortunei with its antimicrobial spectrum could be a good candidate for further bactericidal research

In Vivo and Ex Vivo Evaluation of L-Type Calcium Channel Blockers on Acid β-Glucosidase in Gaucher Disease Mouse Models

Gaucher disease is a lysosomal storage disease caused by mutations in acid β-glucosidase (GCase) leading to defective hydrolysis and accumulation of its substrates. Two L-type calcium channel (LTCC) blockers—verapamil and diltiazem—have been reported to modulate endoplasmic reticulum (ER) folding, trafficking, and activity of GCase in human Gaucher disease fibroblasts. Similarly, these LTCC blockers were tested with cultured skin fibroblasts from homozygous point-mutated GCase mice (V394L, D409H, D409V, and N370S) with the effect of enhancing of GCase activity. Correspondingly, diltiazem increased GCase protein and facilitated GCase trafficking to the lysosomes of these cells. The in vivo effects of diltiazem on GCase were evaluated in mice homozygous wild-type (WT), V394L and D409H. In D409H homozygotes diltiazem (10 mg/kg/d via drinking water or 50–200 mg/kg/d intraperitoneally) had minor effects on increasing GCase activity in brain and liver (1.2-fold). Diltiazem treatment (10 mg/kg/d) had essentially no effect on WT and V394L GCase protein or activity levels (<1.2-fold) in liver. These results show that LTCC blockers had the ex vivo effects of increasing GCase activity and protein in the mouse fibroblasts, but these effects did not translate into similar changes in vivo even at very high drug doses

Isofagomine In Vivo Effects in a Neuronopathic Gaucher Disease Mouse

The pharmacological chaperone, isofagomine (IFG), enhances acid β-glucosidase (GCase) function by altering folding, trafficking, and activity in wild-type and Gaucher disease fibroblasts. The in vivo effects of IFG on GCase activity, its substrate levels, and phenotype were evaluated using a neuronopathic Gaucher disease mouse model, 4L;C* (V394L/V394L + saposin C-/-) that has CNS accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) as well as progressive neurological deterioration. IFG administration to 4L;C* mice at 20 or 600 mg/kg/day resulted in life span extensions of 10 or 20 days, respectively, and increases in GCase activity and protein levels in the brain and visceral tissues. Cerebral cortical GC and GS levels showed no significant reductions with IFG treatment. Increases of GC or GS levels were detected in the visceral tissues of IFG treated (600 mg/kg/day) mice. The attenuations of brain proinflammatory responses in the treated mice were evidenced by reductions in astrogliosis and microglial cell activation, and decreased p38 phosphorylation and TNFα levels. Terminally, axonal degeneration was present in the brain and spinal cord from untreated and treated 4L;C* mice. These data demonstrate that IFG exerts in vivo effects by enhancing V394L GCase protein and activity levels, and in mediating suppression of proinflammation, which led to delayed onset of neurological disease and extension of the life span of 4L;C* mice. However, this was not correlated with a reduction in the accumulation of lipid substrates

Corrigendum to: The TianQin project: current progress on science and technology

In the originally published version, this manuscript included an error related to indicating the corresponding author within the author list. This has now been corrected online to reflect the fact that author Jun Luo is the corresponding author of the article

Spatio-Temporal Coupling Coordination Analysis between Urbanization and Water Resource Carrying Capacity of the Provinces in the Yellow River Basin, China

With the rapid expansion of the Chinese economy in recent years, the urbanization process of the provinces in the Yellow River Basin (YRB) has put serious pressure on the sustainability of the water resources carrying capacity (WRCC). It is necessary to analyze and diagnose the coordination state between urbanization and the WRCC. In this study, based on the Population-Economic-Social-Spatial (PESS) framework and Pressure-State-Response (PSR) model, we developed two index systems for the urbanization and WRCC, respectively. At the basis of the two index systems, the coupling coordination degree (CCD) of the two systems is calculated by applying the improved CCD model. Based on the calculated CCD for each province, the spatio-temporal analysis was performed to analyze the characteristics of CCD in the YRB. The obstacle factor model is utilized to obtain the main obstacle factors. The results show that: (1) the coordination state between the urbanization and WRCC systems was improved to some extent in 2017, compared to 2008, but there are differences in the coordination state of the different provinces in the YRB. (2) In terms of the level of urbanization, the gap between the seven provinces’ performance levels widened because urbanization grew at different rates. The WRCC system’s performance presented a fluctuating downward trend from 2008 to 2017 in the YRB. (3) The pressure subsystem had a significant impact on the two systems’ coordination state in the YRB, while the social urbanization and response subsystem had a less significant impact on the urbanization system and the WRCC system, respectively. Due to the growth of urbanization, the imbalanced development of the WRCC and urbanization has become the principal contradiction that must be solved in order to achieve sustainability in the YRB. The analysis of the coupling relationship between urbanization and WRCC may guide the policy makers in planning for realistic goals. The results provide a guide for high-quality development in the YRB

Spatio-Temporal Coupling Coordination Analysis between Urbanization and Water Resource Carrying Capacity of the Provinces in the Yellow River Basin, China

With the rapid expansion of the Chinese economy in recent years, the urbanization process of the provinces in the Yellow River Basin (YRB) has put serious pressure on the sustainability of the water resources carrying capacity (WRCC). It is necessary to analyze and diagnose the coordination state between urbanization and the WRCC. In this study, based on the Population-Economic-Social-Spatial (PESS) framework and Pressure-State-Response (PSR) model, we developed two index systems for the urbanization and WRCC, respectively. At the basis of the two index systems, the coupling coordination degree (CCD) of the two systems is calculated by applying the improved CCD model. Based on the calculated CCD for each province, the spatio-temporal analysis was performed to analyze the characteristics of CCD in the YRB. The obstacle factor model is utilized to obtain the main obstacle factors. The results show that: (1) the coordination state between the urbanization and WRCC systems was improved to some extent in 2017, compared to 2008, but there are differences in the coordination state of the different provinces in the YRB. (2) In terms of the level of urbanization, the gap between the seven provinces’ performance levels widened because urbanization grew at different rates. The WRCC system’s performance presented a fluctuating downward trend from 2008 to 2017 in the YRB. (3) The pressure subsystem had a significant impact on the two systems’ coordination state in the YRB, while the social urbanization and response subsystem had a less significant impact on the urbanization system and the WRCC system, respectively. Due to the growth of urbanization, the imbalanced development of the WRCC and urbanization has become the principal contradiction that must be solved in order to achieve sustainability in the YRB. The analysis of the coupling relationship between urbanization and WRCC may guide the policy makers in planning for realistic goals. The results provide a guide for high-quality development in the YRB

Recent Advances in Nanostructured Inorganic Hole-Transporting Materials for Perovskite Solar Cells

Organic-inorganic halide perovskite solar cells (PSCs) have received particular attention in the last decade because of the high-power conversion efficiencies (PCEs), facile fabrication route and low cost. However, one of the most crucial obstacles to hindering the commercialization of PSCs is the instability issue, which is mainly caused by the inferior quality of the perovskite films and the poor tolerance of organic hole-transporting layer (HTL) against heat and moisture. Inorganic HTL materials are regarded as promising alternatives to replace organic counterparts for stable PSCs due to the high chemical stability, wide band gap, high light transmittance and low cost. In particular, nanostructure construction is reported to be an effective strategy to boost the hole transfer capability of inorganic HTLs and then enhance the PCEs of PSCs. Herein, the recent advances in the design and fabrication of nanostructured inorganic materials as HTLs for PSCs are reviewed by highlighting the superiority of nanostructured inorganic HTLs over organic counterparts in terms of moisture and heat tolerance, hole transfer capability and light transmittance. Furthermore, several strategies to boost the performance of inorganic HTLs are proposed, including fabrication route design, functional/selectively doping, morphology control, nanocomposite construction, etc. Finally, the challenges and future research directions about nanostructured inorganic HTL-based PSCs are provided and discussed. This review presents helpful guidelines for the design and fabrication of high-efficiency and durable inorganic HTL-based PSCs

Life Cycle Assessment of Environmental Impact of Steelmaking Process

The steel industry is facing problems such as serious environmental pollution and high resource consumption. At the same time, it lacks effective methods to quantify potential environmental impacts. The purpose of this work is to conduct a specific environmental analysis of steelmaking production in steel plants. The ultimate goal is to discover the main pollution of steelmaking and identify potential options for improving the environment. This paper uses life cycle assessment method to carry out inventory and quantitative analysis on the environmental impact of steelmaking system. Through analysis, the hazards are divided into four major categories, which are human health, climate change, ecosystem quality, and resources. The results show that molten iron has the greatest impact on human health, followed by the greatest impact on resources. The impact of scrap steel on human health ranks third. Molten iron is a key process that affects human health, climate change, ecosystems quality, and resources. In addition, processes such as fuels, working fluids, and auxiliary materials also cause certain environmental damage, accounting for a relatively small proportion. Optimizing the utilization of scrap steel and molten iron resources and improving the utilization efficiency of resources and energy are helpful to reduce the environmental hazards of steelmaking system