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Niemann-Pick disease, type C1 (NPC1) is a fatal, neurodegenerative disorder for which there is no definitive therapy. In NPC1, a pathological cascade including neuroinflammation, oxidative stress and neuronal apoptosis likely contribute to the clinical phenotype. While the genetic cause of NPC1 is known, we sought to gain a further understanding into the pathophysiology by identifying differentially expressed proteins in Npc1 mutant mouse cerebella. Using two-dimensional gel electrophoresis and mass spectrometry, 77 differentially expressed proteins were identified in Npc1 mutant mice cerebella compared to controls. These include proteins involved in glucose metabolism, detoxification/oxidative stress and Alzheimer disease-related proteins. Furthermore, members of the fatty acid binding protein family, including FABP3, FABP5 and FABP7, were found to have altered expression in the Npc1 mutant cerebellum relative to control. Translating our findings from the murine model to patients, we confirm altered expression of glutathione s-transferase α, superoxide dismutase, and FABP3 in cerebrospinal fluid of NPC1 patients relative to pediatric controls. A subset of NPC1 patients on miglustat, a glycosphingolipid synthesis inhibitor, showed significantly decreased levels of FABP3 compared to patients not on miglustat therapy. This study provides an initial report of dysregulated proteins in NPC1 which will assist with further investigation of NPC1 pathology and facilitate implementation of therapeutic trials.

A glycolytic profile unifies a group of pheochromocytomas and paragangliomas (PHEOs/PGLs) with distinct underlying gene defects, including von Hippel-Lindau (VHL) and succinate dehydrogenase B (SDHB) mutations. Nevertheless, their tumor aggressiveness is distinct: PHEOs/PGLs metastasize rarely in VHL-, but frequently in SDHB-patients. To date, the molecular mechanisms causing the more aggressive phenotype in SDHB-PHEOs/PGLs remain largely unknown. Recently, however, an excellent model to study aggressive PHEOs (mouse tumor tissue (MTT) cells) has been developed from mouse PHEO cells (MPC). We employed this model for a proteomics based approach to identify changes characteristic for tumor aggressiveness, which we then explored in a homogeneous set of human SDHB- and VHL-PHEOs/PGLs. The increase of glucose transporter 1 in VHL, and of hexokinase 2 in VHL and SDHB, confirmed their glycolytic profile. In agreement with the cell model and in support of decoupling of glycolysis, the Krebs cycle and oxidative phosphorylation (OXPHOS), SDHB tumors showed increased lactate dehydrogenase levels. In SDHB-PGLs OXPHOS complex activity was increased at complex III and, as expected, decreased at complex II. Moreover, protein and mRNA expression of all tested OXPHOS-related genes were higher in SDHB- than in VHL-derived tumors. Although there was no direct evidence for increased reactive oxygen species production, elevated superoxide dismutase 2 expression may reflect elevated oxidative stress in SDHB-derived PHEOs/PGLs. For the first time, we show that despite dysfunction in complex II and evidence for a glycolytic phenotype, the Warburg effect does not seem to fully apply to SDHB-PHEOs/PGLs with respect to decreased OXPHOS. In addition, we present evidence for increased LDHA and SOD2 expression in SDHB-PHEOs/PGLs, proteins that have been proposed as promising therapeutic targets in other cancers. This study provides new insight into pathogenic mechanisms in aggressive human PHEOs/PGLs, which may lead to identifying new diagnostic and prognostic markers in the near future.

Carborane bisphenol novolacs (3 and 4) were synthesized in the presence of acid catalyst from carborane bisphenols (5 and 6) and formaldehyde. Further epoxidization of carborane bisphenol novolacs with epichlorohydrin gave carborane bisphenol epoxy novolacs (1 and 2). The molecular weight and epoxy value of obtained resins were determined using the molecular weight of their precursors. The epoxy values of 1 and 2 were 0.48 and 0.52 respectively, higher than the maximum theoretical epoxy value (0.45) of difunctional carborane bisphenol epoxy resins. FTIR and NMR were utilized to characterize 1 and 2. The curing behaviors were also studied by DSC and the optimized curing conditions were obtained. TGA analysis indicated that carborane moiety could shield its adjacent organic structures against initial decomposition. On the other hand, B―H on carborane cage could react with oxygen to form a three-dimensional network linked by B―O―B and B―C bonds, which further blocked the movement of formed radicals and thus the degradation process was inhibited.

The effects of osmotic pressure, temperature and stocking density on medusae survival of Craspedacusta sowerbii were examined. The medusae were shown to be sensitive to the variations of osmotic pressure. And the survival time was 〈90 h at 34 mOsm/L and it declined rapidly with rising osmotic pressure. The peak survival time of 〉200 h was recorded at 0.2 mOsm/L. Comparing with 27℃ and 32 ℃ treatments, 23 ℃ treatment yielded lower activities at a range of 8-13/min. However, there was a longer survival time. A non-linear relationship existed between survival time and stocking density. Lower density resulted in larger body size. And sexual reproduction resumed after breeding for 〉22 days. Newly-formed polyps and medusae appeared subsequently but only in the higher-density groups of 10, 14 and 18 ind./L. It suggested that the number of newly-formed polyps and medusae was highly dependent on stocking density. That is, a higher stocking density produced more organisms. However, newly-formed medusae died within one month and none grew a diameter of 〉5 mm.

The rapid progress of cloud technology has attracted a growing number of video providers to consider deploying their streaming services onto cloud platform for more cost-effective, scalable and reliable performance. In this paper, we utilize Markov decision process model to formulate the dynamic deployment of cloud-based video services over multiple geographically distributed datacenters. We focus on maximizing the average profits for the video service provider over a long run and introduce an average performance criteria which reflects the cost and user experience jointly. We develop an optimal algorithm based on the sensitivity analysis and sample-based policy iteration to obtain the optimal video placement and request dispatching strategy. We demonstrate the optimality of our algorithm with theoretical proof and specify the practical feasibility of our algorithm. We conduct simulations to evaluate the performance of our algorithm and the results show that our strategy can effectively cut down the total cost and guarantee users’ quality of experience (QoE).

In this paper, the authors consider a class of bilinear pseudo-differential operators with symbols of order 0 and type （1, 0） in the sense of HSrmander and use the atomic decompositions of local Hardy spaces to establish the boundedness of the bilinear pseudo-differential operators and the bilinear singular integral operators on the product of local Hardy spaces.

This study was carried out to explore the roles of circular RNAs (circRNAs) in nucleus pulposus (NP) tissues in intervertebral disc degeneration (IDD). Differentially expressed circRNAs in IDD and normal NP tissues were identified based on the results of microarray analysis. Bioinformatics techniques were employed to predict the direct interactions of selected circRNAs, microRNAs (miR), and mRNAs. CircRNA_104670 was selected as the target circRNA due to its large multiplier expression in IDD tissues. After luciferase reporter and EGFP/RFP reporter assays, we confirmed that circRNA_104670 directly bound to miR-17-3p, while MMP-2 was the direct target of miR-17-3p. The receiver-operating characteristic (ROC) curve showed that circRNA_104670 and miR-17-3p had good diagnostic significance for IDD (AUC circRNA_104670  = 0.96; AUC miRNA-17-3p  = 0.91). A significant correlation was detected between the Pfirrmann grade and expression of circRNA_104670 ( r  = 0.63; p  = 0.00) and miR-17-3p ( r  = −0.62; p  = 0.00). Flow-cytometric analysis and the MTT assay showed that interfering with circRNA_104670 using small interfering RNA (siRNA) inhibited NP cell apoptosis ( p  < 0.01), and this inhibition was reduced by interfering with miR-17-3p. Interfering with circRNA_104670 suppressed MMP-2 expression and increased extracellular matrix (ECM) formation, which were also reduced by interfering with miR-17-3p. Finally, an MRI evaluation showed that circRNA_104670 inhibition mice had a lower IDD grade compared with control mice ( p  < 0.01), whereas circRNA_104670 and miRNA-17-3p inhibition mice had a higher IDD grade compared with circRNA_104670 inhibition mice ( p  < 0.05). CircRNA_104670 is highly expressed in the NP tissues of IDD and acts as a ceRNA during NP degradation. Spinal disease: A roundabout route to disc degeneration ‘RNA sponges’ may provoke lower back pain by soaking up regulatory RNAs that normally protect the protein infrastructure surrounding cells in intervertebral discs. Many people suffer from lower back pain arising from disc degeneration (IDD). A team led by Fei-Zou and Jian-Yuan Jiang at Fudan University, Shanghai, China set out to identify molecular mechanisms that might contribute to IDD. They focused on circular RNAs, non-protein coding RNAs that have been linked to a variety of diseases. The researchers learned that IDD is associated with strongly elevated expression of a circular RNA that acts as an ‘RNA sponge’, binding to and thereby inactivating other RNA molecules. This inactivation ultimately results in the excessive production of an enzyme that can damage the protein matrix that supports cells within spinal discs, potentially setting up the conditions for IDD.

Regulatory T cells (Tregs) have been found to play crucial roles in immune tolerance. However, the status of Tregs in refractory rheumatoid arthritis (RA) is still unclear. Moreover, low-dose interleukin-2 (IL-2) has been reported to selectively promote the expansion of Tregs. This study investigated the status of CD4 Tregs and low-dose IL-2 therapy in patients with refractory RA. The absolute number of CD4 CD25 FOXP3 Treg (CD4 Treg), CD4 IL17 T (Th17), and other subsets in peripheral blood (PB) from 41 patients with refractory RA and 40 healthy donors was characterized by flow cytometry combined with an internal microsphere counting standard. Twenty-six patients with refractory RA were treated with daily subcutaneous injections of 0.5 million IU of human IL-2 for five consecutive days. Then, its effects on CD4 Treg and Th17 cells in PB were analyzed. A decrease in the absolute number of PB CD4 Tregs rather than the increase in the number of Th17 was found to contribute to an imbalance between Th17 and CD4 Tregs in these patients, suggesting an essential role of CD4 Tregs in sustained high disease activity. Low-dose IL-2 selectively increased the number of CD4 Tregs and rebalanced the ratio of Th17 and CD4 Tregs, leading to increased clinical symptom remission without the observed side effects. An absolute decrease of PB CD4 Tregs in patients with refractory RA was associated with continuing disease activation but not the increase of Th17 cells. Low-dose IL-2, a potential therapeutic candidate, restored decreased CD4 Tregs and promoted the rapid remission of patients with refractory RA without overtreatment and the observed side effects. http://www.chictr.org.cn/showproj.aspx?proj=13909, identifier ChiCTR-INR-16009546.

Background Difficult-to-treat Rheumatoid arthritis (D2T RA) is primarily characterised by failure of at least two different mechanism of action biologic/targeted synthetic disease-modifying antirheumatic drug (DMARDs) with evidence of active/progressive disease. While a variety of drugs have been used in previous studies to treat D2T RA, there has been no systematic summary of these drugs. This study conducted a systematic review of randomized controlled trials aimed at analyzing the efficacy and safety of individual therapeutic agents for the treatment of D2T RA and recommending the optimal therapeutic dose. Methods The English databases were searched for studies on the treatment of D2T RA published between the date of the database’s establishment and March, 2024. This study uses R 3.1.2 for data analysis, and the rjags package runs JAGS 3.4.0.20. The study fitted a stochastic effects Bayesian network meta-analysis for each outcome measure. Result A total of 42 studies were included in this study. Compared with placebo, the improvement of Disease Activity Score of 28 Joints (DAS28) score is ranked from high to low as tocilizumab, baricitinib and opinercept. The improvement of American College of Rheumatology 50 response (ACR50) score in patients with drug use was ranked from good to poor as follows: olokizumab, tocilizumab, adalimumab, baricitinib, and upadacitinib, and 8 mg/4w tocilizumab demonstrated the best efficacy. Notably, rituximab is generally the safest drug. Janus kinase (JAK) inhibitors and T cell costimulation modulators are effective in D2T RA refractory to biologic DMARDs, while JAK inhibitors and interleukin-6 (IL-6) inhibitors show effectiveness in D2T RA refractory to csDMARDs. Conclusion Tocilizumab and rituximab have better efficacy and safety in the treatment of D2T RA, and the 8 mg/4w dose of tocilizumab may be the first choice for achieving disease remission.