Overexpression of SIRT1 in Mouse Forebrain Impairs Lipid/Glucose Metabolism and Motor Function

SIRT1 plays crucial roles in glucose and lipid metabolism, and has various functions in different tissues including brain. The brain-specific SIRT1 knockout mice display defects in somatotropic signaling, memory and synaptic plasticity. And the female mice without SIRT1 in POMC neuron are more sensitive to diet-induced obesity. Here we created transgenic mice overexpressing SIRT1 in striatum and hippocampus under the control of CaMKIIα promoter. These mice, especially females, exhibited increased fat accumulation accompanied by significant upregulation of adipogenic genes in white adipose tissue. Glucose tolerance of the mice was also impaired with decreased Glut4 mRNA levels in muscle. Moreover, the SIRT1 overexpressing mice showed decreased energy expenditure, and concomitantly mitochondria-related genes were decreased in muscle. In addition, these mice showed unusual spontaneous physical activity pattern, decreased activity in open field and rotarod performance. Further studies demonstrated that SIRT1 deacetylated IRS-2, and upregulated phosphorylation level of IRS-2 and ERK1/2 in striatum. Meanwhile, the neurotransmitter signaling in striatum and the expression of endocrine hormones in hypothalamus and serum T3, T4 levels were altered. Taken together, our findings demonstrate that SIRT1 in forebrain regulates lipid/glucose metabolism and motor function

Gene Expression Profile Change and Associated Physiological and Pathological Effects in Mouse Liver Induced by Fasting and Refeeding

Food availability regulates basal metabolism and progression of many diseases, and liver plays an important role in these processes. The effects of food availability on digital gene expression profile, physiological and pathological functions in liver are yet to be further elucidated. In this study, we applied high-throughput sequencing technology to detect digital gene expression profile of mouse liver in fed, fasted and refed states. Totally 12162 genes were detected, and 2305 genes were significantly regulated by food availability. Biological process and pathway analysis showed that fasting mainly affected lipid and carboxylic acid metabolic processes in liver. Moreover, the genes regulated by fasting and refeeding in liver were mainly enriched in lipid metabolic process or fatty acid metabolism. Network analysis demonstrated that fasting mainly regulated Drug Metabolism, Small Molecule Biochemistry and Endocrine System Development and Function, and the networks including Lipid Metabolism, Small Molecule Biochemistry and Gene Expression were affected by refeeding. In addition, FunDo analysis showed that liver cancer and diabetes mellitus were most likely to be affected by food availability. This study provides the digital gene expression profile of mouse liver regulated by food availability, and demonstrates the main biological processes, pathways, gene networks and potential hepatic diseases regulated by fasting and refeeding. These results show that food availability mainly regulates hepatic lipid metabolism and is highly correlated with liver-related diseases including liver cancer and diabetes

A local mechanism mediates NAD-dependent protection of axon degeneration

Axon degeneration occurs frequently in neurodegenerative diseases and peripheral neuropathies. Important insight into the mechanisms of axon degeneration arose from findings that the degeneration of transected axons is delayed in Wallerian degeneration slow (Wlds) mice with the overexpression of a fusion protein with the nicotinamide adenine dinucleotide (NAD) synthetic enzyme, nicotinamide mononucleotide adenylyltransferase (Nmnat1). Although both Wlds and Nmnat1 themselves are functional in preventing axon degeneration in neuronal cultures, the underlying mechanism for Nmnat1- and NAD-mediated axon protection remains largely unclear. We demonstrate that NAD levels decrease in degenerating axons and that preventing this axonal NAD decline efficiently protects axons from degeneration. In support of a local protective mechanism, we show that the degeneration of axonal segments that have been separated from their soma could be prevented by the exogenous application of NAD or its precursor nicotinamide. Furthermore, we provide evidence that such Nmnat1/NAD-mediated protection is primarily mediated by their effects on local bioenergetics. Together, our results suggest a novel molecular pathway for axon degeneration

Piezo-photoelectronic coupling effect of BaTiO₃@TiO₂ nanowires for highly concentrated dye degradation

The induced built-in electric field by piezoelectric materials has proven to be one of the most effective strategies for modulating the charge-transfer pathway and inhibiting carrier recombination. In this work, a series of core-shell structured BaTiO3@TiO2 nanowires (BT@TiO2 NWs) heterojunctions were synthesized and the significant coupling effects between BaTiO3 (BT) and TiO2 resulted in surperior piezo-photocatalytic performance, which was demonstrated by three typical types of dyes with high concentrations. The degradation efficiency of 30 mg/L Rhodamine B (RhB), Methylene blue (MB) and Indigo Carmine (IC) solutions by 0.5 g/L BT@TiO2 NWs reached 99.5% in 75 min, 99.8% in 105 min and 99.7% in 45 min, respectively, which are much higher than piezo-photocatalysis systems reported before. To reveal the coupling mechanisms, photoelectrochemical measurements and band diagram analysis were carried out. The carrier concentration was increased from 2.28 × 1017 cm−3 to 4.91 × 1018 cm−3 and the lifetime of charges was improved from 50.37 ms to 60.98 ms due to the construction of a heterojunction between TiO2 and BT. It was proposed that the tilting and bending of the energy band caused by the introduction of a piezoelectric polarization can facilitate carrier separation both in the bulk phase and at the surfaces of semiconductors, resulting in outstanding piezo-photocatalytic properties for highly concentrated dye degradation. This work provides a universal catalyzer for highly concentrated dye degradation.</p

WldS Reduces Paraquat-Induced Cytotoxicity via SIRT1 in Non-Neuronal Cells by Attenuating the Depletion of NAD

WldS is a fusion protein with NAD synthesis activity, and has been reported to protect axonal and synaptic compartments of neurons from various mechanical, genetic and chemical insults. However, whether WldS can protect non-neuronal cells against toxic chemicals is largely unknown. Here we found that WldS significantly reduced the cytotoxicity of bipyridylium herbicides paraquat and diquat in mouse embryonic fibroblasts, but had no effect on the cytotoxicity induced by chromium (VI), hydrogen peroxide, etoposide, tunicamycin or brefeldin A. WldS also slowed down the death of mice induced by intraperitoneal injection of paraquat. Further studies demonstrated that WldS markedly attenuated mitochondrial injury including disruption of mitochondrial membrane potential, structural damage and decline of ATP induced by paraquat. Disruption of the NAD synthesis activity of WldS by an H112A or F116S point mutation resulted in loss of its protective function against paraquat-induced cell death. Furthermore, WldS delayed the decrease of intracellular NAD levels induced by paraquat. Similarly, treatment with NAD or its precursor nicotinamide mononucleotide attenuated paraquat-induced cytotoxicity and decline of ATP and NAD levels. In addition, we showed that SIRT1 was required for both exogenous NAD and WldS-mediated cellular protection against paraquat. These findings suggest that NAD and SIRT1 mediate the protective function of WldS against the cytotoxicity induced by paraquat, which provides new clues for the mechanisms underlying the protective function of WldS in both neuronal and non-neuronal cells, and implies that attenuation of NAD depletion may be effective to alleviate paraquat poisoning

PANDORA-seq expands the repertoire of regulatory small RNAs by overcoming RNA modifications

Although high-throughput RNA sequencing (RNA-seq) has greatly advanced small non-coding RNA (sncRNA) discovery, the currently widely used complementary DNA library construction protocol generates biased sequencing results. This is partially due to RNA modifications that interfere with adapter ligation and reverse transcription processes, which prevent the detection of sncRNAs bearing these modifications. Here, we present PANDORA-seq (panoramic RNA display by overcoming RNA modification aborted sequencing), employing a combinatorial enzymatic treatment to remove key RNA modifications that block adapter ligation and reverse transcription. PANDORA-seq identified abundant modified sncRNAs—mostly transfer RNA-derived small RNAs (tsRNAs) and ribosomal RNA-derived small RNAs (rsRNAs)—that were previously undetected, exhibiting tissue-specific expression across mouse brain, liver, spleen and sperm, as well as cell-specific expression across embryonic stem cells (ESCs) and HeLa cells. Using PANDORA-seq, we revealed unprecedented landscapes of microRNA, tsRNA and rsRNA dynamics during the generation of induced pluripotent stem cells. Importantly, tsRNAs and rsRNAs that are downregulated during somatic cell reprogramming impact cellular translation in ESCs, suggesting a role in lineage differentiation

Discovery of the major 15–30 nt mammalian small RNAs, their biogenesis and function

Abstract Small RNAs (sRNAs) within 15-30 nt such as miRNA, tsRNA, srRNA with 3’-OH have been identified. However, whether these sRNAs are the major 15-30 nt sRNAs is still unknown. Here we show about 90% mammalian sRNAs within 15-30 nt end with 2’,3’-cyclic phosphate (3’-cP). TANT-seq was developed to simultaneously profile sRNAs with 3’-cP (sRNA-cPs) and sRNA-OHs, and huge amount of sRNA-cPs were detected. Surprisingly, sRNA-cPs and sRNA-OHs usually have distinct sequences. The data from TANT-seq were validated by a novel method termed TE-qPCR, and Northern blot. Furthermore, we found that Angiogenin and RNase 4 contribute to the biogenesis of sRNA-cPs. Moreover, much more sRNA-cPs than sRNA-OHs bind to Ago2, and can regulate gene expression. Particularly, snR-2-cP regulates Bcl2 by targeting to its 3’UTR dependent on Ago2, and subsequently regulates apoptosis. In addition, sRNA-cPs can guide the cleavage of target RNAs in Ago2 complex as miRNAs without the requirement of 3’-cP. Our discovery greatly expands the repertoire of mammalian sRNAs, and provides strategies and powerful tools towards further investigation of sRNA-cPs

Modelling of energy storage system in the Australian electricity market

With the increasing integration of variable renewable energy, the electricity market supply and demand dynamics is expected to shift accordingly. Consequently, the renewable share in the global total energy mix is predicted to grow substantially over the next decade. This will boost the required capacity for the frequency regulation ancillary services and lead to an increase in variable renewable energy curtailment level if no action is taken. On the other hand, with the advance in the Energy Storage System (ESS) technologies, ESS is expected to play an important role in the electricity market in a high renewable energy penetration future. However, the economic viability of the ESS depends on both the revenue streams of the market applications and its operation cost profile (i.e. calendar life cost and cycle life cost). In this thesis, we firstly propose a dynamic ESS revenue estimation method and investigate and quantity the ESS’s revenue opportunities in the electricity spot market (price arbitrage) and frequency regulation ancillary service markets while the ESS is assumed to have a quick charge and discharge capability.While electric vehicle (EV) is gaining more popularity, a collection of retired EV battery packs provides an economic option for meeting the additional frequency regulation needs. We then propose a ESS market operation model that takes into account of both the revenue streams of the spot market and the frequency regulation ancillary service markets, and the ESS operation cost profile (a battery operation cost estimator is built to evaluate the potential impacts of market operations on battery lifespan). Specifically, the model is designed for retired EV lithium batteries under the Australian national electricity market framework.Finally, a hybrid ESS sizing framework is proposed for the combined wind-storage system. The operation is fully driven by the revenue opportunities including price arbitrage and storing curtailed wind energy and the ESS cost profile. The hybrid ESS sizing framework scales two distinctive types of ESSs (collectively a hybrid ESS) simultaneously and is analysed under different market frameworks and generation mixes

The Consistency of Subjective and Objective Factors Influencing Walking Path Choice around Rail Transit Stations

The station–city integration development strategy, guided by the Transit-Oriented Development (TOD) model, has enhanced the coupling relationship between rail transit stations and urban areas. Walking, as a core mode of low-carbon urban transport, plays a significant role in the connectivity between stations and urban areas and in the rate of passenger flow dispersal. During peak periods, large volumes of passengers flood the streets, forming complex and diverse walking paths that penetrate urban neighborhoods. Route choice is a complex decision-making process influenced by both subjective and objective factors. Previous studies on pathfinding activities have often focused on either subjective or objective factors in isolation, with limited research on their interaction. This paper establishes a comparative analysis framework based on the translation of subjective and objective information and behavioral feedback mechanisms. Using Lvcuo Station, a transit station on Xiamen’s Metro Line 1 in Fujian Province, China, as a case study, we collected walking data from 410 passengers through field surveys. We used the Kappa consistency coefficient test method to analyze the performance of the interaction between the objective environment and subjective environmental cognitive factors when pedestrians exit the rail transit station and walk to their destinations. We also used multinomial logistic regression (MLR) to analyze the correlation between subjective perception variables and objective built environment variables and to consider the influence of individual pedestrian characteristics and attributes on path selection. The results revealed the following: (1) Overall, there is a significant deviation effect of subjective and objective factors on passengers’ pathfinding behavior, with some spatial correlation with the built environment of the streets. (2) The consistency of influences on walking activities varies significantly across different travel periods, distances, and purposes. (3) Visual elements, urban life with a bustling atmosphere, street permeability, and route connectivity positively correlate with subjective perception while “supporting walking facilities” and “meeting consumption needs along the way” negatively correlate with subjective perception. These findings underscore the need to enhance the understanding of the built environment in the street spaces within rail transit station areas from the perspectives of pedestrians to improve the walkability of these streets