Transcriptome of Small Regulatory RNAs in the Development of the Zoonotic Parasite Trichinella spiralis

BACKGROUND: Trichinella spiralis is a parasite with unique features. It is a multicellular organism but with an intracellular parasitization and development stage. T. spiralis is the helminthic pathogen that causes zoonotic trichinellosis and afflicts more than 10 million people worldwide, whereas the parasite's biology, especially the developmental regulation is largely unknown. In other organisms, small non-coding RNAs, such as microRNAs (miRNA) and small interfering RNAs (siRNA) execute post-transcriptional regulation by translational repression or mRNA degradation, and a large number of miRNAs have been identified in diverse species. In T. spiralis, the profile of small non-coding RNAs and their function remains poorly understood. METHODOLOGY AND PRINCIPAL FINDINGS: Here, the transcriptional profiles of miRNA and siRNA in three developmental stages of T. spiralis in the rat host were investigated, and compared by high-throughput cDNA sequencing technique ("RNA-seq"). 5,443,641 unique sequence tags were obtained. Of these, 21 represented conserved miRNAs related to 13 previously identified metazoan miRNA families and 213 were novel miRNAs so far unique to T. spiralis. Some of these miRNAs exhibited stage-specific expression. Expression of miRNAs was confirmed in three stages of the life cycle by qRT-PCR and northern blot analysis. In addition, endogenous siRNAs (endo-siRNAs) were found mainly derived from natural antisense transcripts (NAT) and transposable elements (TE) in the parasite. CONCLUSIONS AND SIGNIFICANCE: We provide evidence for the presence of miRNAs and endo-siRNAs in T. spiralis. The miRNAs accounted for the major proportion of the small regulatory RNA population of T. spiralis, while fewer endogenous siRNAs were found. The finding of stage-specific expression patterns of the miRNAs in different developmental stages of T. spiralis suggests that miRNAs may play important roles in parasite development. Our data provide a basis for further understanding of the molecular regulation and functional evolution of miRNAs in parasitic nematodes

Engineering PtRu bimetallic nanoparticles with adjustable alloying degree for methanol electrooxidation: enhanced catalytic performance

Abstract(#br)PtRu bimetal is of particularly attractive in various electrocatalytic reactions owing to its synergistic effect, ligand effect and strain effect. Here, PtRu nanoalloy supported on porous graphitic carbon (PC) has been successfully prepared via a very facile method involving co-reduction the precursors of Pt and Ru at 300 °C by H 2 (PtRu/PCL) followed by thermal treatment at high temperature (700 °C, PtRu/PC–H). Specifically, the electrocatalytic performance of PtRu/PC nanoalloy could be dramatically enhanced through high-temperature annealing. This strategy has synthesized smaller Pt and PtRu nanoparticles (ca. L and Pt/PC nanocatalysts. The mass activity and specific activity on PtRu/PC–H nanoalloy can be increased to 1674.2 mA mg −1 Pt and 4.4 mA cm −2 for MOR, it is 4.08 and 8.80 times higher than that of the Pt/PC nanocatalyst, respectively. From in-situ FTIR spectra, we can discover PtRu/PC–H nanoalloy generates CO 2 at a lower potential of −150 mV than those on PtRu/PC–L (0 mV) and Pt/PC (50 mV) nanocatalysts, dramatically improves the ability of cleavage C–H bond and alleviates the CO ads poisoning on active sites. The PtRu/PCH nanocatalyst exhibits maximum power density of 83.7 mW cm −2 in single methanol fuel cell test, which more than threefold than that of commercial Pt/C as the anode catalyst. Those experimental results open an effective and clean avenue in the development and preparation of high-performance Pt-based nanocatalysts for direct methanol fuel cells

Glycyrrhizin arginine salt protects against cisplation-induced acute liver injury by repressing BECN1-mediated ferroptosis

The study aimed to investigate the protective effects and biological mechanisms of glycyrrhizin arginine salt (Gly-Arg) against cisplatin (Cis)-induced liver injury. Our data showed that Gly-Arg improved Cis-induced liver injury. Further study showed that BECN1 (beclin1) and LC3-II/LC3-I protein expression was significantly increased in primary hepatocytes and mouse liver tissues after Cis treatment, but Gly-Arg reduced the protein levels of BECN1 and LC3-II/LC3-I in primary hepatocytes and mouse liver tissues. Also, Gly-Arg improved indicators related to Cis-induced ferroptosis. Furthermore, Cis increased colocalization of lysosomal membrane-associated protein 1A (LAMP1) with ferritin heavy chain 1 (FTH1) in primary mouse hepatocytes, while Gly-Arg intervention attenuated this colocalization in primary hepatocytes. More improtantly, Cis enhanced the formation of the BECN1-xCT complex, thus inhibiting solute carrier family 7 member 11 (SLC7A11, xCT) and glutathione peroxidase-4 (GPX4) activity. In contrast, Gly-Arg intervention disrupted the formation of this complex. However, Gly-Arg alleviated Cis-induced liver injury in mice by preventing autophagic death and ferroptosis through the inhibition of BECN1-xCT complex formation

Preparation and Evaluation of Poly(Ethylene Glycol)–Poly(Lactide) Micelles as Nanocarriers for Oral Delivery of Cyclosporine A

A series of monomethoxy poly(ethylene glycol)–poly(lactide) (mPEG–PLA) diblock copolymers were designed according to polymer–drug compatibility and synthesized, and mPEG–PLA micelle was fabricated and used as a nanocarrier for solubilization and oral delivery of Cyclosporine A (CyA). CyA was efficiently encapsulated into the micelles with nanoscaled diameter ranged from 60 to 96 nm with a narrow size distribution. The favorable stabilities of CyA-loaded polymeric micelles were observed in simulated gastric and intestinal fluids. The in vitro drug release investigation demonstrated that drug release was retarded by polymeric micelles. The enhanced intestinal absorption of CyA-loaded polymeric micelles, which was comparable to the commercial formulation of CyA (Sandimmun Neoral®), was found. These suggested that polymeric micelles might be an effective nanocarrier for solubilization of poorly soluble CyA and further improving oral absorption of the drug

Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Adaptive Decentralized Output Feedback Tracking Control for Large-Scale Interconnected Systems with Time-Varying Output Constraints

This paper investigates a novel adaptive output feedback decentralized control scheme for nonstrict feedback large-scale interconnected systems with time-varying constraints. A decentralized linear state observer is designed to estimate the unmeasurable states of subsystems. Time-varying barrier Lyapunov functions are designed to ensure outputs are not violating constraints. A variable separation approach is applied to deal with the nonstrict feedback problem. Moreover, dynamic surface control and minimal parameter learning technologies are adopted to reduce the computation burden, and there are only two parameters for every subsystem to be updated online. The proof of stability is obtained by the Lyapunov method. Finally, simulation results are given to show the effectiveness of the proposed control scheme

Evaluating Trends of Land Productivity Change and Their Causes in the Han River Basin, China: In Support of SDG Indicator 15.3.1

The Han River Basin is a main agricultural production area and a water source for the middle route of the South-to-North Water Diversion Project in China. Over the past 20 years, human exploitation and ecological construction have disturbed the sustainability of land productivity in the Han River Basin. Theil&ndash;Sen trend analysis, Mann&ndash;Kendall statistical test, and Hurst index methods were applied to examine spatial&ndash;temporal trends and sustainability characteristics of land net primary productivity (NPP) change in the Han River Basin from 2001 to 2019 using MOD17A3 NPP product, natural, and socio-economic data obtained from Google Earth Engine (GEE). The findings demonstrated that the interannual variation of land NPP exhibited a fluctuating upward trend, with a more pronounced growth rate from 2001 to 2010 than from 2011 to 2019. The spatial heterogeneity of land NPP was evident, with high values in the west and low values in the east. Of the basin area, 57.82% presented a significant increase in land NPP, while only 0.96% showed a significant decrease. In the future, land NPP in the Han River Basin will present sustained growth. The results were also compared with Trends.Earth&rsquo;s calculations for the SDG 15.3.1 sub-indicator of land productivity. In addition, the spatial heterogeneity of factors influencing land NPP change was explored using a multiscale geographically weighted regression (MGWR) model. Precipitation and population count were the dominant factors in most regions. Besides, precipitation, population count, and human modification all exhibited inhibitory effects on the increase in land NPP except for elevation. The research can provide a scientific basis for tracking land degradation neutrality (LDN) progress and achieving sustainable socio-ecological development of the Han River Basin

Evaluating Trends of Land Productivity Change and Their Causes in the Han River Basin, China: In Support of SDG Indicator 15.3.1

The Han River Basin is a main agricultural production area and a water source for the middle route of the South-to-North Water Diversion Project in China. Over the past 20 years, human exploitation and ecological construction have disturbed the sustainability of land productivity in the Han River Basin. Theil–Sen trend analysis, Mann–Kendall statistical test, and Hurst index methods were applied to examine spatial–temporal trends and sustainability characteristics of land net primary productivity (NPP) change in the Han River Basin from 2001 to 2019 using MOD17A3 NPP product, natural, and socio-economic data obtained from Google Earth Engine (GEE). The findings demonstrated that the interannual variation of land NPP exhibited a fluctuating upward trend, with a more pronounced growth rate from 2001 to 2010 than from 2011 to 2019. The spatial heterogeneity of land NPP was evident, with high values in the west and low values in the east. Of the basin area, 57.82% presented a significant increase in land NPP, while only 0.96% showed a significant decrease. In the future, land NPP in the Han River Basin will present sustained growth. The results were also compared with Trends.Earth’s calculations for the SDG 15.3.1 sub-indicator of land productivity. In addition, the spatial heterogeneity of factors influencing land NPP change was explored using a multiscale geographically weighted regression (MGWR) model. Precipitation and population count were the dominant factors in most regions. Besides, precipitation, population count, and human modification all exhibited inhibitory effects on the increase in land NPP except for elevation. The research can provide a scientific basis for tracking land degradation neutrality (LDN) progress and achieving sustainable socio-ecological development of the Han River Basin