Autophagy-Lysosome Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two devastating neurodegenerative diseases. Several lines of evidence suggest that these diseases are part of a continuum with common genetic factors. As researchers uncover more genes associated with ALS/FTLD, studies have shown that majority of these genes regulate lysosome‐related processes. Lysosomes play important roles in clearing damaged organelles and proteins through the autophagy‐lysosome pathway and clearing extracellular debris by the endolysosomal pathway. Disruption of both the autophagy and endolysosomal pathways has been implicated in ALS/FTLD pathogenesis

Let-7b expression determines response to chemotherapy through the regulation of Cyclin D1 in Glioblastoma

BACKGROUND: Glioblastoma is the most common type of primary brain tumors. Cisplatin is a commonly used chemotherapeutic agent for Glioblastoma patients. Despite a consistent rate of initial responses, cisplatin treatment often develops chemoresistance, leading to therapeutic failure. Cellular resistance to cisplatin is of great concern and understanding the molecular mechanisms is an utter need. METHODS: Glioblastoma cell line U251 cells were exposed to increasing doses of cisplatin for 6 months to establish cisplatin-resistant cell line U251R. The differential miRNA expression profiles in U251 and U251R cell lines were identified by microarray analysis and confirmed by Q-PCR. MiRNA mimics were transfected into U251R cells, and cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. RESULTS: U251R cells showed 3.1-fold increase in cisplatin resistance compared to its parental U251 cells. Microarray analysis identified Let-7b and other miRNAs significantly down-regulated in U251R cells compared to U251 cells. Transfection of Let-7b mimics greatly re-sensitized U251R cells to cisplatin, while transfection of other miRNAs has no effect or slightly effect. Cyclin D1 is predicted as a target of Let-7b through bioinformatics analysis. Over-expression of Let-7b mimics suppressed cyclin D1 protein expression and inhibited cyclin D1-3’-UTR luciferase activity. Knockdown of cyclin D1 expression significantly increased cisplatin-induced G1 arrest and apoptosis. CONCLUSIONS: Collectively, our results indicated that cisplatin treatment leads to Let-7b suppression, which in turn up-regulates cyclin D1 expression. Let-7b may serve as a marker of cisplatin resistance, and can enhance the therapeutic benefit of cisplatin in glioblastoma cells

Using noble gases to trace groundwater evolution and assess helium accumulation in Weihe Basin, central China

The severe shortage of helium resources is an impending global problem. However, the helium accumulation processes and conditions favorable for helium enrichment in reservoirs remain poorly understood, which makes helium exploration challenging. Noble gases are good tracers of subsurface fluids provenance, migration and storage, as well as indicators of the nature and quantity of associated phases. In this study the variation of major gases and noble gases data in Weihe Basin provide us with an excellent opportunity to understand the groundwater evolution and helium accumulation processes. Twelve gas samples collected from wellheads of geothermal wells can be classified into three groups, in which Group A has high concentrations of N2 (58.57% - 91.66%) and He (0.32% - 2.94%); Group B has high contents of CH4 (52.94% and 69.50%) and low concentrations of He (0.057% and 0.062%); Group C has a high content of CH4 (71.70%) and He (2.11%). Helium isotopic ratios are predominantly radiogenic in origin and therefore crustally derived. Measured elemental ratios of noble gases are compared with multiple fractionation models for Group A and B samples, implying that open system heavy oil-water fractionation with excess heavy noble gases has occurred in the basin with Voil/Vwater ratios of 0.06-0.18. The amount of helium in Group A and B samples requires the release of all 4He produced in the crust since 0.30Ma-1.98Ma into the groundwater. The Group C sample requires an additional He flux from adjacent granitic bodies. The accumulation of helium and hydrocarbon in the Weihe Basin can be explained by a 4-stage process. Accumulation of commercially viable helium requires high He flux from source rocks, the existence of a free gas phase of major gas components (CH4 in most cases, N2 or CO2) and minimal major gas addition after formation of the free gas phase

Acute toxicity study of tilmicosin-loaded hydrogenated castor oil-solid lipid nanoparticles

<p>Abstract</p> <p>Background</p> <p>Our previous studies demonstrated that tilmicosin-loaded hydrogenated castor oil solid lipid nanoparticles (Til-HCO-SLN) are a promising formulation for enhanced pharmacological activity and therapeutic efficacy in veterinary use. The purpose of this work was to evaluate the acute toxicity of Til-HCO-SLN.</p> <p>Methods</p> <p>Two nanoparticle doses were used for the study in ICR mice. The low dose (766 mg/kg.bw) with tilmicosin 7.5 times of the clinic dosage and below the median lethal dose (LD₅₀) was subcutaneously administered twice on the first and 7th day. The single high dose (5 g/kg.bw) was the practical upper limit in an acute toxicity study and was administered subcutaneously on the first day. Blank HCO-SLN, native tilmicosin, and saline solution were included as controls. After medication, animals were monitored over 14 days, and then necropsied. Signs of toxicity were evaluated via mortality, symptoms of treatment effect, gross and microscopic pathology, and hematologic and biochemical parameters.</p> <p>Results</p> <p>After administration of native tilmicosin, all mice died within 2 h in the high dose group, in the low dose group 3 died after the first and 2 died after the second injections. The surviving mice in the tilmicosin low dose group showed hypoactivity, accelerated breath, gloomy spirit and lethargy. In contrast, all mice in Til-HCO-SLN and blank HCO-SLN groups survived at both low and high doses. The high nanoparticle dose induced transient clinical symptoms of treatment effect such as transient reversible action retardation, anorexy and gloomy spirit, increased spleen and liver coefficients and decreased heart coefficients, microscopic pathological changes of liver, spleen and heart, and minor changes in hematologic and biochemical parameters, but no adverse effects were observed in the nanoparticle low dose group.</p> <p>Conclusions</p> <p>The results revealed that the LD₅₀of Til-HCO-SLN and blank HCO-SLN exceeded 5 g/kg.bw and thus the nanoparticles are considered low toxic according to the toxicity categories of chemicals. Moreover, HCO-SLN significantly decreased the toxicity of tilmicosin. Normal clinic dosage of Til-HCO-SLN is safe as evaluated by acute toxicity.</p

MicroRNA-181a Functions as an Oncogene in Gastric Cancer by Targeting Caprin-1

MicroRNA-181a (miRNA-181a) is a multifaceted miRNA implicated in various cellular processes, particularly in cell fate determination and cellular invasion. It is frequently expressed aberrantly in human tumors and shows opposing functions in different types of cancers. In this study, we found that miRNA-181a is overexpressed in Gastric cancer (GC) tissues. Clinical and pathological analyses revealed that the expression of miRNA-181a is correlated with tumor size, lymph node metastasis, distant metastasis, and TNM stage. Kaplan-Meier analysis indicated that overexpression of miRNA-181a is associated with poor overall survival of patients with GC. Moreover, miRNA-181a is overexpressed in GC cells, and downregulation of miRNA-181a induced cell apoptosis and suppressed the proliferation, invasion, and metastasis of GC cells both in vitro and in vivo. Target prediction and luciferase reporter assay showed that caprin-1 was a direct target of miRNA-181a. Downregulation of caprin-1 expression resulted in a converse change with miRNA-181a in GC. Spearman’s correlation test confirmed that the expression of miRNA-181a expression was inversely correlated with that of caprin-1 in GC cells. Furthermore, the expression of caprin-1 increased after downregulation of miRNA-181a in the GC cells. Caprin-1 siRNA can rescue the oncogenic effect of miRNA-181a on GC cell proliferation, apoptosis, migration, and invasion. These findings suggest that miRNA-181a directly inhibits caprin-1 and promotes GC development. miRNA-181a could be a target for anticancer drug development

Lingguizhugan decoction improves non-alcoholic steatohepatitis partially by modulating gut microbiota and correlated metabolites

BackgroundLingguizhugan decoction is a traditional Chinese medicine prescription that has been used to improve non-alcoholic fatty liver disease and its progressive form, non-alcoholic steatohepatitis (NASH). However, the anti-NASH effects and underlying mechanisms of Lingguizhugan decoction remain unclear.MethodsMale Sprague-Dawley rats were fed a methionine- and choline-deficient (MCD) diet to induce NASH, and then given Lingguizhugan decoction orally for four weeks. NASH indexes were evaluated by histopathological analysis and biochemical parameters including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver triglycerides (TG), etc. Fecal samples of rats were subjected to profile the changes of gut microbiota and metabolites using 16S rRNA sequencing and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS). Bioinformatics was used to identify Lingguizhugan decoction reversed candidates, and Spearman’s correlation analysis was performed to uncover the relationship among gut microbiota, fecal metabolites, and NASH indexes.ResultsFour-week Lingguizhugan decoction treatment ameliorated MCD diet-induced NASH features, as evidenced by improved hepatic steatosis and inflammation, as well as decreased serum AST and ALT levels. Besides, Lingguizhugan decoction partially restored the changes in gut microbial community composition in NASH rats. Meanwhile, the relative abundance of 26 genera was significantly changed in NASH rats, and 11 genera (such as odoribacter, Ruminococcus_1, Ruminococcaceae_UCG-004, etc.) were identified as significantly reversed by Lingguizhugan decoction. Additionally, a total of 99 metabolites were significantly altered in NASH rats, and 57 metabolites (such as TDCA, Glutamic acid, Isocaproic acid, etc.) enriched in different pathways were reversed by Lingguizhugan decoction. Furthermore, Spearman’s correlation analyses revealed that most of the 57 metabolites were significantly correlated with 11 genera and NASH indexes.ConclusionLingguizhugan decoction may exert protective effects on NASH partially by modulating gut microbiota and correlated metabolites

A smart community energy management scheme considering user dominated demand side response and P2P trading

This paper proposed a Peer-to-Peer (P2P) local community energy pool and a User Dominated Demand Side Response (UDDSR) that can help energy sharing and reduce energy bills of smart community. The proposed UDDSR allows energy users within the community to submit flexible Demand Response (DR) bids to Community Energy Management Scheme (EMS) with flexible start time, stop time and response durations with regarding to users' comfort zones for electric heating systems, electric vehicles and other home appliances, which gives maximum freedom to the DR participants. The scheduling of the DR bids, originally a multi-objective optimization problem (maximize the total flexible demand and the flexible demand in every interval during the whole DR duration), is transferred to a single objective optimization problem (maximize the total demand with penalty for demand imbalance during the whole DR duration) that can significantly decrease the computational complexity. Furthermore, to facilitate efficient energy usage among neighbourhoods, a local energy pool is also proposed to enable the energy trading among users aiming to facilitate the usage of surplus energy within the community. The electricity price of energy pool is determined by the real-time demand/supply ratio, and upper/lower limit for the price is configured to ensure the profitability for all the participants within the pool. To evaluate the performance of proposed UDDSR and local energy pool, comprehensive numerical analysis is conducted. It is found that the energy pool participants without PV can get at least 6.16% savings on electricity bill (when PV penetration level equals to 20%). The energy pool participants with PV can get much better return (at least 13.4% profit increase) on the PV generation compared to the conventional Feed-in-Tariff. If energy users join the UDDSR scheme, the participants can get further return, and the proposed UDDSR can provide a constant load reduction/increase during the every time interval of the whole DR event. If Battery Energy Storage System (BESS) is included in the DR operation, the usage efficiency of customers' flexible loads can achieve more than 85%

Identification of KANSARL as the First Cancer Predisposition Fusion Gene Specific to the Population of European Ancestry Origin

Gene fusion is one of the hallmarks of cancer. Recent advances in RNA-seq of cancer transcriptomes have facilitated the discovery of fusion transcripts. In this study, we report identification of a surprisingly large number of fusion transcripts, including six KANSARL (KANSL1-ARL17A) transcripts that resulted from the fusion between the KANSL1 and ARL17A genes using a RNA splicingcode model. Five of these six KANSARL fusion transcripts are novel. By systematic analysis of RNA-seq data of glioblastoma, prostate cancer, lung cancer, breast cancer, and lymphoma from different regions of the World, we have found that KANSARL fusion transcripts were rarely detected in the tumors of individuals from Asia or Africa. In contrast, they exist in 30 - 52% of the tumors from North Americans cancer patients. Analysis of CEPH/Utah Pedigree 1463 has revealed that KANSARL is a familially-inherited fusion gene. Further analysis of RNA-seq datasets of the 1000 Genome Project has indicated that KANSARL fusion gene is specific to 28.9% of the population of European ancestry origin. In summary, we demonstrated that KANSARL is the first cancer predisposition fusion gene associated with genetic backgrounds of European ancestry origin