Non-linear ICA Analysis of Resting-State fMRI in Mild Cognitive Impairment

Compared to linear independent component analysis (ICA), non-linear ICA is more suitable for the decomposition of mixed components. Existing studies of functional magnetic resonance imaging (fMRI) data by using linear ICA assume that the brain's mixed signals, which are caused by the activity of brain, are formed through the linear combination of source signals. But the application of the non-linear combination of source signals is more suitable for the mixed signals of brain. For this reason, we investigated statistical differences in resting state networks (RSNs) on 32 healthy controls (HC) and 38 mild cognitive impairment (MCI) patients using post-nonlinear ICA. Post-nonlinear ICA is one of the non-linear ICA methods. Firstly, the fMRI data of all subjects was preprocessed. The second step was to extract independent components (ICs) of fMRI data of all subjects. In the third step, we calculated the correlation coefficient between ICs and RSN templates, and selected ICs of the largest spatial correlation coefficient. The ICs represent the corresponding RSNs. After finding out the eight RSNs of MCI group and HC group, one sample t-tests were performed. Finally, in order to compare the differences of RSNs between MCI and HC groups, the two-sample t-tests were carried out. We found that the functional connectivity (FC) of RSNs in MCI patients was abnormal. Compared with HC, MCI patients showed the increased and decreased FC in default mode network (DMN), central executive network (CEN), dorsal attention network (DAN), somato-motor network (SMN), visual network(VN), MCI patients displayed the specifically decreased FC in auditory network (AN), self-referential network (SRN). The FC of core network (CN) did not reveal significant group difference. The results indicate that the abnormal FC in RSNs is selective in MCI patients

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

Background/Aims: The aim of our study is to investigate the molecular mechanism by which mammalian STE20-like kinase 1 (Mst1) participates in renal I/R injury through modifying mitophagy and the AMPK-YAP signalling pathway. Methods: WT mice and Mst1-knockout mice were subjected to renal ischaemia-reperfusion (I/R) in vivo. In vitro, the hypoxia-reoxygenation model was used with renal tubular epithelial cells to mimic renal I/R injury. Mitochondrial function was monitored via western blotting and immunofluorescence. Pathway blocker and siRNA knockout technology were used to establish the role of the AMPK-YAP signalling pathway in Mst1-mediated mitochondrial apoptosis in the setting of renal I/R injury. Results: Our data demonstrated that Mst1 expression was upregulated in response to renal I/R injury in vivo, and a higher Mst1 content was positively associated with renal dysfunction and more tubular epithelial cell apoptosis. However, genetic ablation of Mst1 improved renal function, alleviated reperfusion-mediated tubular epithelial cell apoptosis, and attenuated the vulnerability of kidney to I/R injury. In vitro, Mst1 upregulation induced mitochondrial damage including mitochondrial potential reduction, ROS overloading, cyt-c liberation and caspase-9 apoptotic pathway activation. At the molecular levels, I/R-mediated mitochondrial damage via repressing mitophagy and Mst1 suppressed mitophagy via inactivating AMPK signalling pathway and dowregulating OPA1 expression. Re-activation of AMPK-YAP-OPA1 signalling pathway provided a survival advantage for the tubular epithelial cell in the context of renal I/R injury by repressing mitochondrial fission. Conclusion: Overall, our results demonstrate that the pathogenesis of renal I/R injury is closely associated with an increase in Mst1 expression and the inactive AMPK-YAP-OPA1 signalling pathway. Based on this, strategies to repress Mst1 expression and activate mitophagy could serve as therapeutic targets to treat kidney ischaemia-reperfusion injury

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

Background/Aims: Hyperglycaemia stress-induced renal injury is closely associated with mitochondrial dysfunction through poorly understood mechanisms. The aim of our study is to explore the upstream trigger and the downstream effector driving diabetic nephropathy via modulating mitochondrial homeostasis. Methods: A diabetic nephropathy model was generated in wild-type (WT) mice and MAP Kinase phosphatase 1 transgenic (MKP1-TG) mice using STZ injection. Cell experiments were conducted via high-glucose treatment in the human renal mesangial cell line (HRMC). MKP1 overexpression assay was carried out via adenovirus transfection. Renal function was evaluated via ELISA, western blotting, histopathological staining, and immunofluorescence. Mitochondrial function was determined via mitochondrial potential analysis, ROS detection, ATP measurement, mitochondrial permeability transition pore (mPTP) opening evaluation, and immunofluorescence for mitochondrial pro-apoptotic factors. Loss- and gain-of-function assays for mitochondrial fragmentation were performed using a pharmacological agonist and blocker. Western blotting and the pathway blocker were used to establish the signalling pathway in response to MKP1 overexpression in the presence of hyperglycaemia stress. Results: MKP1 was downregulated in the presence of chronic high-glucose stress in vivo and in vitro. However, MKP1 overexpression improved the metabolic parameters, enhanced glucose control, sustained renal function, attenuated kidney oxidative stress, inhibited the renal inflammation response, alleviated HRMC apoptosis, and repressed tubulointerstitial fibrosis. Molecular investigation found that MKP1 overexpression enhanced the resistance of HRMC to the hyperglycaemic injury by abolishing mitochondrial fragmentation. Hyperglycaemia-triggered mitochondrial fragmentation promoted mitochondrial dysfunction, as evidenced by decreased mitochondrial potential, elevated mitochondrial ROS production, increased pro-apoptotic factor leakage, augmented mPTP opening and activated caspase-9 apoptotic pathway. Interestingly, MKP1 overexpression strongly abrogated mitochondrial fragmentation and sustained mitochondrial homeostasis via inhibiting the JNK-CaMKII-Fis1 pathway. After re-activation of the JNK-CaMKII-Fis1 pathway, the beneficial effects of MKP1 overexpression on mitochondrial protection disappeared. Conclusion: Taken together, our data identified the protective role played by MKP1 in regulating diabetic renal injury via repressing mitochondrial fragmentation and inactivating the JNK-CaMKII-Fis1 pathway, which may pave the road to new therapeutic modalities for the treatment of diabetic nephropathy

PKM2 promotes glucose metabolism and cell growth in gliomas through a mechanism involving a let-7a/c-Myc/hnRNPA1 feedback loop

AbstrAct Tumor cells metabolize more glucose to lactate in aerobic or hypoxic conditions than non-tumor cells. Pyruvate kinase isoenzyme type M2 (PKM2) is crucial for tumor cell aerobic glycolysis. We established a role for let-7a/c-Myc/hnRNPA1/PKM2 signaling in glioma cell glucose metabolism. PKM2 depletion via siRNA inhibits cell proliferation and aerobic glycolysis in glioma cells. C-Myc promotes up-regulation of hnRNPA1 expression, hnRNPA1 binding to PKM pre-mRNA, and the subsequent formation of PKM2. This pathway is downregulated by the microRNA let-7a, which functionally targets c-Myc, whereas hnRNPA1 blocks the biogenesis of let-7a to counteract its ability to downregulate the c-Myc/hnRNPA1/PKM2 signaling pathway. The down-regulation of c-Myc/ hnRNPA1/PKM2 by let-7a is verified using a glioma xenograft model. These results suggest that let-7a, c-Myc and hnRNPA1 from a feedback loop, thereby regulating PKM2 expression to modulate glucose metabolism of glioma cells. These findings elucidate a new pathway mediating aerobic glycolysis in gliomas and provide an attractive potential target for therapeutic intervention

Novel loci and pathways significantly associated with longevity

Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10(−5)). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity

Novel loci and pathways significantly associated with longevity

Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10⁻⁵). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Nature Publishing Group. The published article can be found at: http://www.nature.com/articles/srep2124

China’s Industrial Total-Factor Energy Productivity Growth at Sub-Industry Level: A Two-Step Stochastic Metafrontier Malmquist Index Approach

Under the concept of metafrontier, technology gap ratio is alternatively interpreted as potential energy efficiency. Combined with Malmquist index framework and Shephard energy distance function, we then develop a metafrontier Malmquist energy productivity index to analyze the total-factor energy productivity growth with four specific components: groupfrontier efficiency change index, groupfrontier technological change index, efficiency catch-up index and technological catch-up index. Methodologically, a newly developed two-step stochastic metafrontier analysis is applied to address the potentially biased estimation problems in the previous mixed approach. This analytical framework is used to evaluate the energy productivity growth of China’s 35 sub-industries in industrial sector from 2001 to 2015. The main empirical results show that: (1) In terms of cumulative metafrontier Malmquist energy productivity growth, China’s overall industry has witnessed a 25% growth and a U-shaped growing trend bottoming out in 2006; meanwhile, 19 sub-industries have suffered an energy productivity loss and the remaining 16 sub-industries have experienced an energy productivity gain. (2) From the technology heterogeneity perspective, light industry outperforms heavy industry in metafrontier Malmquist energy productivity growth, while the intra-group and inter-group energy productivity develops roughly in balance for overall industry. (3) The change of metafrontier Malmquist energy productivity is mainly driven by technological change components rather than efficiency change components. On average, groupfrontier technological change makes the biggest contribution to energy productivity growth, followed by technological catch-up, then efficiency catch-up, and groupfrontier efficiency change is last. (4) The metafrontier Malmquist energy productivity growth has shown a significant convergence in heavy industry and light industry, as well as overall industry

Bioinformatics Analysis of Xylanase xynMF13-GH10 Gene from Mangrove Fungi

[Objectives] The paper was to analyze and predict the structure and characteristics of xylanase xynMF13-GH10 gene and its encoded protein. [Methods] xynMF13-GH10 gene was predicted by NCBI and various information analysis tools in ExPASy website, as well as SignaIP 5.0, DNAman, TMHMM, SOPMA and SWISS-Model, and the characteristics and functions of protein structure encoded by the gene were predicted. [Results] The gene is 1 332 bp in length, the coding region is 1-1 332 bp, and the gene encodes 443 amino acids.The xynMF13-GH10 gene has high homology with xylanase in many species, and it has the highest homology with Paraphaeosphaeria sporulosa endoxylanase-like protein, with the consistency reaching 78.91% and e-value reaching 2e-159. The secondary structure consists of 48.31% random curl, 30.25% α-helix structure, 16.70% extended chain and 4.74% β-corner. [Conclusion] The results provide a reference for revealing the physiological function and expression regulation mechanism of xynMF13-GH10 gene in the future