Loss-of-function mutations in Parkin are the most common causes of autosomal recessive Parkinson's disease (PD). Many putative substrates of parkin have been reported; their pathogenic roles, ...however, remain obscure due to poor characterization, particularly in vivo. Here, we show that synaptotagmin-11, encoded by a PD-risk gene SYT11, is a physiological substrate of parkin and plays critical roles in mediating parkin-linked neurotoxicity. Unilateral overexpression of full-length, but not C2B-truncated, synaptotagmin-11 in the substantia nigra pars compacta (SNpc) impairs ipsilateral striatal dopamine release, causes late-onset degeneration of dopaminergic neurons, and induces progressive contralateral motor abnormalities. Mechanistically, synaptotagmin-11 impairs vesicle pool replenishment and thus dopamine release by inhibiting endocytosis. Furthermore, parkin deficiency induces synaptotagmin-11 accumulation and PD-like neurotoxicity in mouse models, which is reversed by SYT11 knockdown in the SNpc or knockout of SYT11 restricted to dopaminergic neurons. Thus, PD-like neurotoxicity induced by parkin dysfunction requires synaptotagmin-11 accumulation in SNpc dopaminergic neurons.
...unlike the mechanism of neurotransmission via quantal exocytosis (Katz, 1959, 1969; Augustine and Neher, 1992; Neher, 1998; Sudhof, 2004; Pankratov et al., 2006, 2007; Sudhof and Rothman, 2009), ...the mechanisms by which ATP is released remain controversial. Because ATP is easily hydrolyzed, monitoring its real-time release is a challenge. In the Ca2+-independent pathway, ATP is released through channels expressed on the astrocyte plasma membrane, such as the swelling-induced anion channel, connexin hemichannels activated by lower Ca2+ concentrations, and ionotropic purinergic receptor channels. Since P2X7 itself is not mechanosensor, we hypothesize that a mechanosensor such as piezo 1 protein (Zhao et al., 2018) binds P2X7 and “transactivates” mechanical force to activate P2X7 One recent example of protein-transactivation is that a voltage-sensor channel activates another binding protein of vesicle fusion-pore (Chai et al., 2017). ...the large ATP release via MARA would recruit microglia, leading to protective or pathological pathways (Dou et al., 2012). ...we propose that MARA could be a mechanism underlying brain diseases such as those associated with hypoxia/ischemia and trauma, as well as other neurological disorders (Parkinson's disease, Alzheimer's disease, and epilepsy) (Figure 1D).
As a central part of the mammalian brain, the prefrontal cortex (PFC) has been implicated in regulating cocaine-induced behaviors including compulsive seeking and reinstatement. Although dysfunction ...of the PFC has been reported in animal and human users with chronic cocaine abuse, less is known about how the PFC is involved in cocaine-induced behaviors. By using two-photon Ca
imaging to simultaneously record tens of intact individual networking neurons in the frontal association cortex (FrA) in awake male mice, here we report that a systematic acute cocaine exposure decreased the FrA neural activity in mice, while the chemogenetic intervention blocked the cocaine-induced locomotor sensitization. The hypoactivity of FrA neurons was critically dependent on both dopamine transporters and dopamine transmission in the ventromedial PFC (vmPFC). Both dopamine D1R and D2R neurons in the vmPFC projected to and innervated FrA neurons, the manipulation of which changed the cocaine-induced hypoactivity of the FrA and locomotor sensitization. Together, this work demonstrates acute cocaine-induced hypoactivity of FrA neurons in awake mice, which defines a cortico-cortical projection bridging dopamine transmission and cocaine sensitization.
Co-release of multiple neurotransmitters from secretory vesicles is common in neurons and neuroendocrine cells. However, whether and how the transmitters co-released from a single vesicle are ...differentially regulated remains unknown. In matrix-containing dense-core vesicles (DCVs) in chromaffin cells, there are two modes of catecholamine (CA) release from a single DCV: quantal and sub-quantal. By combining two microelectrodes to simultaneously record co-release of the native CA and ATP from a DCV, we report that (1) CA and ATP were co-released during a DCV fusion; (2) during kiss-and-run (KAR) fusion, the co-released CA was sub-quantal, whereas the co-released ATP was quantal; and (3) knockdown and knockout of the DCV matrix led to quantal co-release of both CA and ATP even in KAR mode. These findings strongly imply that, in contrast to sub-quantal CA release in chromaffin cells, fast synaptic transmission without transmitter-matrix binding is mediated exclusively via quantal release in neurons.
•One vesicle releases two native transmitters via two modes (quantal versus sub-quantal)•Sub-quantal is produced jointly by fusion pore and intravesicular matrix•Co-release of catecholamine and ATP from a 100-nm vesicle recorded by two electrodes
Zhang et al. uncover the mystery of sub-quanta and quanta during vesicular release of multi-neurotransmitters. Catecholamine sub-quanta are jointly produced by fusion pores and the vesicular matrix, whereas the co-released ATP quanta are fully released during transient fusion events.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Ni–CsxH3−xPW12O40/SiO2 catalysts for hydrocracking were prepared by direct synthesis.•The addition of Cs enhances the resistance to the sulfur and nitrogen compounds.•The direct synthesized catalyst ...had better dispersion than impregnated catalyst.•The catalysts achieve the good balance between acidity and hydrogenation function.
A series of Ni–CsxH3−xPW12O40/SiO2 catalysts were prepared by direct synthesis method and characterized by BET, XRD, in situ XRD, FT-IR, NH3-TPD, H2-TPR, and H2-TPD. The catalytic performance of the catalysts for the hydrocracking of n-decane with various concentrations of thiophene and pyridine was studied. The best result was obtained on direct synthesized 8%Ni–50%Cs1.5H1.5PW/SiO2 catalyst which has shown the highest activity for the hydrocracking of n-decane and excellent tolerance to the sulfur and nitrogen compounds in the feedstock, superior to the impregnated catalyst and the industrial catalyst. The highest catalytic performance of the catalyst may be due to that the direct synthesized catalysts had better dispersion, higher numbers of acid sites and stronger hydrogenation-dehydrogenation function than that of the impregnated catalyst.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The effect of Cs content in CsxH3-xPW12O40 on the catalytic performance of the reduced Ni-CsxH3-xPW12O40/Al2O3 catalysts for hydrocracking of n-decane with the presence of thiophene and pyridine is ...studied. The catalysts were characterized by BET, XRD, in situ XRD, Raman, H2-TPR, H2-TPD, NH3-TPD and FT-IR of pyridine adsorption. The best result was obtained on 8%Ni-50%CsH2PW12O40/Al2O3 catalyst which shows the highest catalytic activity and with tolerance to 525ppm of thiophene and 170ppm of pyridine (the reaction conditions: 2.0MPa, LHSV=2.92h−1, H2/n-decane 1500 vol/vol at 300°C). The high catalytic performance of the catalyst may be due to the proper balance between metal and acid functions by adding a certain proportion of Cs to the system.
►Effect of Cs in Ni-CsxH3-xPW12O40/Al2O3 for hydrocracking of n-decane is studied. ►Proper balance between metal and acid functions is established by adding Cs. ►The highest catalytic activity is obtained on 8% Ni-50% CsH2PW12O40/Al2O3.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The study focused on the diagnostic value of deep learning-based ultrasound combined with gastroscope examination for upper gastrointestinal submucous lesions and nursing. A total of 104 patients ...with upper gastrointestinal submucous lesions diagnosed in hospital were selected as the research subjects. In this study, the feed forward denoising convulsive neural network (DnCNN) was improved, and the n-DnCNN model was designed and applied to ultrasonic image processing. The peak signal-to-noise ratio (PSNR) and structural similarity (SSIM) of Gaussian filtering, NL-means, and DnCNN were then compared with n-DnCNN. Subsequently, the distribution and types of submucosal lesions in different parts of the upper digestive tract were analyzed by ultrasound combined with gastroscope and gastroscope examination alone, and the diagnostic performance of this method was evaluated. The results showed that the average PSNR and SSIM of the n-DnCNN model were 33.01 dB and 0.87, respectively, which were significantly higher than GF, NL-means, and DnCNN algorithms, and the difference was statistically significant (P<0.05). Of the 116 lesions detected, 49 were located in the esophagus (42.24%), 52 in the stomach (44.83%), and 15 in the duodenum (12.93%). Of the 49 esophageal submucosal lesions, 6.12% were located in the upper esophagus, 55.1% in the middle esophagus, and 38.79% in the lower esophagus, and the difference was statistically significant (P<0.05). Of the gastric submucosal lesions, the lesions in the gastric cardia were significantly less than in other parts, and the difference was statistically significant (P<0.05). The accuracy of ultrasound combined with gastroscope in the diagnosis of upper gastrointestinal submucous episodes was 82.32%, higher than that of gastroscope examination, and the difference was statistically significant (P<0.05). In conclusion, the n-DnCNN model has a good noise reduction effect, and the obtained image is of high quality. Ultrasound combined with gastroscope examination can effectively improve the accuracy of diagnosis of upper gastrointestinal submucous lesions.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Previous studies showed that down-regulation of GAS5 was involved in the development of gastric cancer (GC). However, the regulatory mechanism of down-expressed GAS5 in GC remains obscure. We aimed ...to investigate the role of rs145204276 of GAS5 in the development and metastasis process of GC.
853 GC patients and 954 healthy controls were recruited. The variant rs145204276 was genotyped and the Chi
test was used to compare the frequency of the genotype and the allele between the patients and the controls. Odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated to estimate the association of rs145204276 with the risk of development and metastasis of GC.
Patients were found to have significantly lower rate of genotype del/del than the controls (7.2% vs. 8.9%, P=0.016). The allele del was significantly associated with a decreased risk of GC (26.4% vs. 30.7%, P=0.005) with an OR of 0.81 (95% CI=0.70-0.94). Patients with allele del were less likely to develop lymph node metastasis (P=0.01), with an OR of 0.75 (95% CI=0.60-0.93). Comparably, rs145204276 was also significantly associated with a decreased risk of distant metastasis of GC (P=0.007; OR=0.55).
We confirmed that rs145204276 of GAS5 is a functional variant associated with the susceptibility and metastasis of GC. It plays a protective role in the development of GC possibly through the regulation of GAS5.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Acidic zeolites beta with wider Si/Al ratios were desilicated and dealuminated using the alkali–acid treatment approach involving hydrothermal alkali pre–etching. Zeolites beta subjected to mesopore ...modification were characterized by the techniques of XRD, N2 physisorption, SEM, TEM, EDX, ICP–AES, NH3–TPD, pyridine FTIR adsorption, and immersion porosimetry to examine changes of structural/textural and acidic properties with initial Si/Al ratio. Benzene alkylation with 1-dodecene was used as a model reaction to elucidate the influence of mediated acidity and texturally mesoporous structure on bulky hydrocarbon transformations. The resulting zeolites beta were shown to have hierarchical porous structures and regular mesoporous size distributions. Initial Si/Al ratios appeared to dominate significant mesoporosity development though no clear threshold of initial Si/Al ratio was identified to be more instrumental in forming mesopores. A volumetric fraction of intraparticle to total BJH mesopores proved to reduce with increasing initial Si/Al ratio. The modified zeolites showed more than 95% desilication selectivity whereas less than 5.0% dealumination selectivity upon overall treating processes. T-atoms removal efficiencies relative to areal, volumetric and diametrical factors revealed the coherent characteristics to T-atoms removal selectivities. Moreover, the dependency of benzene alkylation activity on mesopore size distribution was observed from changes of 1-dodecene conversion and LAB selectivity, both of which were promoted by the hierarchical zeolites. Despite both with comparable acidic properties, the typical sample subjected to the combined alkali–acid treatments was shown to have narrowing mesopore size distribution and hence to exhibit the enhanced catalytic performance for selective production of linear alkylbenzenes compared with the purely desilicated sample with broadening mesopore size distribution.
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•Surface modification of BEA zeolites upon alkali–acid treatments.•Hierarchical materials featuring regularly mesoporous size distribution.•Whether T-atoms removal behavior depends on initial Si/Al ratios.•Alkylation performance promoted by textural mesopores and mild acidity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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