Analysis of endoplasmic reticulum stress-related gene signature for the prognosis and pattern in diffuse large B cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. This study aimed to determine the prognostic significance of endoplasmic reticulum (ER) stress-related genes in DLBCL. ER stress-related genes were obtained from the molecular signatures database. Gene expression data and clinical outcomes from the gene expression omnibus and TCGA datasets were collected, and differentially expressed genes (DEGs) were screened out. Gene ontology enrichment analysis, the kyoto encyclopaedia of genes and genomes pathway analysis, and geneset enrichment analysis were used to analyse the possible biological function of ER stress-related DEGs in DLBCL. Protein-protein interaction network construction using the STRING online and hub genes were identified by cytoHubba on Cytoscape software. The significant prognosis-related genes were screened, and the differential expression was validated. The immune microenvironment assessment of significant genes were evaluated. Next, the nomogram was built using univariate and multivariate Cox regression analysis. 26 ER stress-related DEGs were screened. Functional enrichment analysis showed them to be involved in the regulation of the endoplasmic reticulum mainly. NUPR1 and TRIB3 were identified as the most significant prognostic-related genes by comparison with the GSE10846, GSE11318, and TCGA datasets. NUPR1 was correlated with a good prognosis and immune infiltration in DLBCL; on the other hand, high expression of TRIB3 significantly correlated with a poor prognosis, which was an independent prognostic factor for DLBCL. In summary, we identified NUPR1 and TRIB3 as critical ER stress-related genes in DLBCL. NUPR1 might be involved in immune infiltration in DLBCL, and TRIB3 might serve as a potential therapeutic target and prognostic factor in DLBCL.

Partial Replacement of Oat Hay with Whole-Plant Hydroponic Barley Seedlings Modulates Ruminal Microbiota and Affects Growth Performance of Holstein Heifers.

The dairy industry is facing challenges in balancing forage supply and crop production. Therefore, forage supply based on a farm land-saving approach should be developed to overcome the human−livestock competition on farmland. The objective of this study was to learn the potential impact of partially replacing oat hay with whole-plant hydroponic barley seedlings (HBS) produced via a land-saving hydroponic method on growth performance, digestibility, and rumen microbiota in Holstein dairy heifers. In total, 39 Holstein heifers were randomly divided into 13 blocks based on age and body weight for an 8-week experimental period. The heifers within each block were randomly allocated to one of three diets group: (1) 0% HBS and 16% oat hay (CON); (2) 4% HBS and 12% oat hay (25% HBS); and (3) 8% HBS and 8% oat hay (50% HBS). Compared to CON, feed intake, growth performance, and body N retention were similar to those in cows fed 25% HBS but lower in 50% HBS-fed animals (p < 0.05). Reduced digestibility (crude protein (CP) and organic matter (OM)) was observed in 50% HBS animals (p < 0.05). Compared to the control, the levels of Lachnospiraceae_XPB1014_group, Bacillus, and Colidextribacter were higher, but the levels of Sphaerochaeta and Ruminiclostridium were lower in 50% HBS animals (p < 0.05). Additionally, the digestibility of CP (p < 0.01, r = −0.61) and ether extract (EE) (p < 0.01, r = −0.58) was negatively correlated with Lachnospiraceae_XPB1014_group. The digestibility of OM (p = 0.01, r = −0.55), neutral detergent fiber (NDF) (p = 0.01, r = −0.56), acid detergent fiber (ADF) (p = 0.02, r = −0.52), and CP (p < 0.01, r = −0.61) was negatively correlated with Bacillus. The digestibility of NDF (p = 0.02, r = −0.52) and ADF (p = 0.03, r = −0.50) was negatively correlated with Colidextribacter. The digestibility of OM (p = 0.03, r = 0.50), NDF (p = 0.03, r = 0.50), and ADF (p = 0.03, r = 0.49) was positively correlated with Ruminiclostridium. The digestibility of OM (p = 0.04, r = 0.47), CP (p < 0.01, r = 0.58), and EE (p = 0.03, r = 0.49) was positively correlated with unclassified_f_Rikenellaceae. The digestibility of CP was positively correlated with Sphaerochaeta (p = 0.02, r = 0.53). In conclusion, the current study suggests that HBS could replace oat hay in a ratio-dependent manner. The reduced growth performance could be caused by lower feed intake and digestibility, which may be attributed to the alteration in the rumen's microbial population. Further exploration of the inhibiting factors of HBS would broaden the application of hydroponic feed in the future.

The Deletion of US3 Gene of Pseudorabies Virus (PRV) ΔgE/TK Strain Induces Increased Immunogenicity in Mice.

Re-emerging pseudorabies (PR) caused by pseudorabies virus (PRV) variant has been prevailing among immunized herds in China since 2011, indicating that commercially available PR vaccine strains couldn't provide complete protection against novel, epidemic PRV variant. Before this study, a gE/TK-gene-deleted virus (PRV ΔgE/TK) was constructed from PRV QYY2012 variant through homologous recombination and Cre/LoxP system. Here, PRV ΔgE/TK/US3 strain was generated by deleting US3 gene based on PRV ΔgE/TK strain using the same method. The growth characteristics of PRV ΔgE/TK/US3 were analogous to that of PRV ΔgE/TK. Moreover, the deletion of US3 gene could promote apoptosis, upregulate the level of swine leukocyte antigen class I molecule (SLA-I) in vitro, and relieve inflammatory response in inoculated BALB/c mice. Subsequently, the safety and immunogenicity of PRV ΔgE/TK/US3 was evaluated as a vaccine candidate in mice. The results revealed that PRV ΔgE/TK/US3 was safe for mice, and mice vaccinated with PRV ΔgE/TK/US3 could induce a higher level of PRV-specific neutralizing antibodies and cytokines, including IFN-γ, IL-2 and IL-4, also higher level of CD8+ CD69+ Tissue-Resident Memory T cells (TRM). The results show that the deletion of US3 gene of PRV ΔgE/TK strain could induce increased immunogenicity, indicating that the PRV ΔgE/TK/US3 strain is a promising vaccine candidate for preventing and controlling of the epidemic PR in China.

PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response.

Programmed death ligand 1 (PD-L1) has been recently shown to be a major obstacle to antiviral immunity by binding to its receptor programmed death 1 (PD-1) on specific IFN-γ producing T cells in chronic hepatitis B. Currently, IFN-α is widely used to treat hepatitis B virus (HBV) infection, but its antiviral effect vary greatly and the mechanism is not totally clear. We found that IFN-α/γ induced a marked increase of PD-L1 expression in hepatocytes. Signal and activators of transcription (Stat1) was then identified as a major transcription factor involved in IFN-α/γ-mediated PD-L1 elevation both in vitro and in mice. Blockage of the PD-L1/PD-1 interaction by a specific mAb greatly enhanced HBV-specific T cell activity by the gp96 adjuvanted therapeutic vaccine, and promoted HBV clearance in HBV transgenic mice. Our results demonstrate the IFN-α/γ-Stat1-PD-L1 axis plays an important role in mediating T cell hyporesponsiveness and inactivating liver-infiltrating T cells in the hepatic microenvironment. These data raise further potential interest in enhancing the anti-HBV efficacy of IFN-α and therapeutic vaccines.

Spacer-Assisted Amine-Coiled Carbon Nanotubes for CO2 Capture.

Architecture of a DNA-wrapped carbon nanotube (CNT) inspires rational design of a polymer-wrapped CNT effective for CO2 capture. Polyethyleneimine (PEI) selected as a spiral wrapper of CNT is modified by insertion of spacer molecules loaded with amino groups such as siloxanes and purine to enhance the CO2 capture performance. A porous adsorbent made by packing these functional nanowires (e.g., PEI-purine-CNT) reveals CO2 uptake as large as 3.875 mmol/g. Adsorbent materials from this biomolecule-inspired design drop the adsorption heat to 29.00 kJ/mol if secondary and tertiary amines are adopted, besides the primary one, a value that is one-third of the absorption heat of an industrially deployed, liquid absorbent of CO2. The corresponding adsorption and desorption kinetics agree with an Avrami model, indicating that both processes involve multiple sorption pathways. Furthermore, PEI-purine-CNT maintains its adsorption capacity after 50 adsorption-desorption cycles, implying a great potential for carbon capture from smokestacks and air in a stable and cyclic manner.

CD8+ T-Cell Response-Associated Evolution of Hepatitis B Virus Core Protein and Disease Progress.

Under the immune pressure of cytotoxic T cells (CTLs), hepatitis B virus (HBV) evolves to accumulate mutations more likely within epitopes to evade immune detection. However, little is known about the specific patterns of the immune pressure-associated HBV mutation of T-cell epitopes and their link to disease progression. Here, we observed a correlation of the accumulated variants on HBV core protein (HBc) with the disease severity of HBV infection. Further analysis indicated that these substitutions were mostly located within CD8+ T-cell epitopes of HBc protein, which were systematically screened and identified in an unbiased manner in our study. From individual peptide level to the human leukocyte antigen I (HLA-I)-restricted population level, we elucidated that the mutations in these well-defined HLA-I-restricted T-cell epitopes significantly decreased antiviral activity-specific CTLs and were positively associated with clinical parameters and disease progression in HBV-infected patients. The molecular pattern for viral epitope variations based on the sequencing of 105 HBV virus genomes indicated that the C-terminal portion (Pc), especially the Pc-1 and Pc-2 positions, have the highest mutation rates. Further structural analysis of HLA-A*02 complexed to diverse CD8+ T-cell epitopes revealed that the highly variable C-terminal bulged peak of M-shaped HBc-derived epitopes are solvent exposed, and most of the CDR3ßs of the T-cell receptor hover over them. These data shed light on the molecular and immunological mechanisms of T-cell immunity-associated viral evolution in hepatitis B progression, which is beneficial for designing immunotherapies and vaccines.IMPORTANCE The specific patterns of sequence polymorphisms of T-cell epitopes and the immune mechanisms of the HBV epitope mutation-linked disease progression are largely unclear. In this study, we systematically evaluated the contribution of CD8+ T cells to the disease progress-associated evolution of HBV. By evaluation of patient T-cell responses based on the peptide repertoire, we comprehensively characterized the association of clinical parameters in chronic hepatitis B with the antiviral T-cell response-associated mutations of the viruses from the single-epitope level to the overall HLA-I-restricted peptide levels. Furthermore, we investigated the molecular basis of the HLA-A2-restricted peptide immune escape and found that the solvent-exposed C-terminal portion of the epitopes is highly variable under CDR3ß recognition. Our work may provide a comprehensive evaluation of viral mutations impacted by the host CTL response in HBV disease progression in the context of the full repertoire of HBc-derived epitopes.

A comparison of the main outcomes from BP-BES and DP-DES at five years of follow-up: A systematic review and meta-analysis.

Biodegradable polymer biolimus-eluting stents (BP-BES) are third-generation drug-eluting stents (DES) composed of biodegradable polymers that may improve prognosis after percutaneous coronary intervention (PCI). After five years of follow-up, BP-BES showed conflicting results compared to durable polymer drug-eluting stents (DP-DES). We performed a meta-analysis of the outcomes of studies on BP-BES and DP-DES after percutaneous coronary intervention (PCI) at five years of follow-up. Eligible studies were retrieved from PubMed, Embase and the Cochrane Library and reported the results of all-cause mortality, myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR) and stent thrombosis (ST) at five years of follow-up. Five studies of a total of 4687 patients were included in the meta-analysis. At five years of follow-up, BP-BES was associated with lower rates of major adverse cardiac events (MACE) (OR = 0.83, 95%CI = [0.71, 0.97]), TLR (OR = 0.77, 95%CI = [0.62, 0.96]) and ST (OR = 0.60, 95%CI = [0.43 to 0.84]), whereas no significant differences in mortality, MI, or TVR rates were detected. Our results demonstrated that at five years of follow-up, BP-BES can significantly reduce the risk of MACE, TLR and ST, which indicate that safety and efficacy were increased after PCI.

Stability, Molecular Sieving, and Ion Diffusion Selectivity of a Lamellar Membrane from Two-Dimensional Molybdenum Disulfide.

Two-dimensional (2D) subnanometer channels allow unique mass transport promising for molecular sieving. New 2D channels of MoS2 nanosheets allow one to understand molecular transmission and separation, unlike the graphene oxide counterpart containing various defects and cationic metal contaminants. Membranes from layered MoS2 platelets show extraordinary stability in an aqueous environment and compatibility with polymer filters, both beneficial to efficient manufacturing. Sharing gas-tightness and unimpeded water vapor permeation with a graphene oxide membrane, our lamellar MoS2 membrane demonstrates a molecular sieving property for organic vapor for the first time. The MoS2 membrane also reveals diffusion selectivity of aqueous ions, attributable to the energy penalty in bulk-to-2D dimensional transition. These newly revealed properties of the lamellar membrane full of angstrom-sized 2D channels point to membrane technology applications for energy and environment.

Hepatitis B virus mRNAs functionally sequester let-7a and enhance hepatocellular carcinoma.

Hepatitis B virus (HBV) infection induces hepatocarcinogenesis and malignant progression, yet global effects of the redundant viral mRNAs produced during infection are unexplored. Here, microRNA (miRNA) target prediction and whole genome expression analysis revealed that HBV pre-C/C mRNA leads to upregulation of multiple let-7a targeted genes. A let-7a complementary region from nt 86 to 108 in the HBV genome was then identified in HBV pre-C/C, pre-S, and S mRNAs. The let-7a sequestration effect by HBV mRNAs was observed under transfection and virus infection, which is dependent on the let-7a response sequence. Moreover, we found reduced AGO2 binding, as well as functional mRNA and protein de-repression of let-7a targets (e.g., c-myc, K-RAS, and CCR7), upon viral mRNA expression. Let-7a levels in the liver were significantly decreased in hepatocellular carcinoma (HCC) patients with HBV infection and were negatively correlated with intrahepatic pre-S2 mRNA levels. Finally, both in vitro and in vivo studies demonstrated that let-7a inhibition by HBV mRNAs resulted in enhanced HCC cell colony formation and tumor growth, providing evidence of the oncogenic potential of HBV mRNAs.

Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels.

Persistent inflammation in chronic hepatitis plays a major role in the development of hepatocellular carcinoma (HCC). In this study, the major inflammatory cytokines expressed in chronic hepatitis, IL-6 and TNF-α, induced a marked decrease in microRNA-122 (miR-122) levels, and miR-122 expression was downregulated in the livers of chronic hepatitis B (CHB) patients. The decrease of miR-122 caused upregulation of the proinflammatory chemokine CCL2. IL-6 and TNF-α suppressed miR-122 both by directly downregulating the transcription factor C/EBPα and indirectly upregulating c-myc, which blocks C/EBPα-mediated miR-122 transcription. In addition, IL-6 and TNF-α levels were elevated and miR-122 levels were decreased in mouse and rat models of diethylnitrosamine (DEN)-induced HCC. Restoration of miR-122 levels through delivery of agomir-122 suppressed DEN-induced hepatocarcinogenesis in mice. Our results show that inflammation-induced miR-122 downregulation in hepatitis contributes to carcinogenesis and suggest that increasing miR-122 may be an effective strategy for preventing HCC development in CHB patients.

Chaperone gp96 mediates ER-α36 cell membrane expression.

ER (estrogen receptor)-α36, a variant of human ERα, activates non-genomic cell signaling pathways. ER-α36 on the cell membrane plays a role in breast cancer growth and development, and contributes to tamoxifen resistance. However, it is not understood how cell membrane expression of ER-α36 is regulated. In this study, we investigated the role of cell membrane glycoprotein 96 (mgp96) in the regulation of ER-α36 expression and signaling. We found that the C-terminal domain of mgp96 directly interacts with ER-α36 on the cell membrane of breast tumor cells. This interaction stabilizes the ER-α36 protein, thereby increasing its signaling, which, in turn, increases tumor cell growth and invasion. Moreover, targeting mgp96 with siRNA or monoclonal antibody (mAb) blocks the mgp96-ER-α36 interaction and inhibits breast cancer growth and invasion both in vitro and in vivo. These results provide insights into the modulation of cell membrane ER-α36 expression and suggest that mgp96 could be a potential therapeutic target for ER-α36-overexpressing breast cancer.

Highly reproducible SERS arrays directly written by inkjet printing.

SERS arrays with uniform gold nanoparticle distribution were fabricated by direct-writing with an inkjet printing method. Quantitative analysis based on Raman detection was achieved with a small standard statistical deviation of less than 4% for the reproducibility and less than 5% for the long-term stability for 12 weeks.

A gold nanoparticle ink suitable for the fabrication of electrochemical electrode by inkjet printing.

Inkjet printing is a non-contact and low-cost method for high resolution deposition of nanomaterials and mass production of electro-devices. In this study, an environmentally friendly gold nanoparticles (AuNPs) ink was prepared and electrochemical electrodes were fabricated through inkjet printing technology. Electrochemical behaviors of the printed electrodes with different printing layers and laser sintering intensities were studied by cyclic voltammetry. Electrode sintered at 0.6 A with double layers showed a good reproducibility and well linear relation in voltammetric measurement of potassium ferricyanide. Moreover, the prepared electrode was found to be effective for formaldehyde electro-oxidation in alkaline medium. The above results indicated that this AuNPs ink, which can be facilely prepared, may have great potential applications for the preparation of flexible and low-cost electrochemical sensing devices and biosensors by inkjet printing.

A new unconventional HLA-A2-restricted epitope from HBV core protein elicits antiviral cytotoxic T lymphocytes.

Cytotoxic T cells (CTLs) play a key role in the control of Hepatitis B virus (HBV) infection and viral clearance. However, most of identified CTL epitopes are derived from HBV of genotypes A and D, and few have been defined in virus of genotypes B and C which are more prevalent in Asia. As HBV core protein (HBc) is the most conservative and immunogenic component, in this study we used an overlapping 9-mer peptide pool covering HBc to screen and identify specific CTL epitopes. An unconventional HLA-A2-restricted epitope HBc141-149 was discovered and structurally characterized by crystallization analysis. The immunogenicity and anti-HBV activity were further determined in HBV and HLA-A2 transgenic mice. Finally, we show that mutations in HBc141-149 epitope are associated with viral parameters and disease progression in HBV infected patients. Our data therefore provide insights into the structure characteristics of this unconventional epitope binding to MHC-I molecules, as well as epitope specific CTL activity that orchestrate T cell response and immune evasion in HBV infected patients.

Controlled inkjetting of a conductive pattern of silver nanoparticles based on the coffee-ring effect.

Conductive patterns with line widths of 5-10 µm are successfully fabricated by utilizing the coffee-ring effect in inkjet printing, resulting in transmittance values of up to 91.2% in the visible to near-infrared region. This non-lithographic approach broadens the range of fabrication procedures that can be used to create various nanoparticle-based microstructures and electronic devices.

Continuous microwire patterns dominated by controllable rupture of liquid films.

Controllable microwire patterns are prepared by dominating the rupture of liquid films. Regular rhombic-shaped micropillar arrays serve as wetting defects to pin or depin liquids, yielding continuous, herringbone, bead-shaped polystyrene microwire patterns or bead arrays. The results provide a deeper understanding of the controllable rupture of liquid films and offer a general strategy for the organization of polymers into structures needed for wiring, interconnects, and functional devices for future microfabrication.

Synthesis of monodisperse silver nanoparticles for ink-jet printed flexible electronics.

In this study, monodisperse silver nanoparticles were synthesized with a new reduction system consisting of adipoyl hydrazide and dextrose at ambient temperature. By this facile and rapid approach, high concentration monodisperse silver nanoparticles were obtained on a large scale at low protectant/AgNO(3) mass ratio which was highly beneficial to low cost and high conductivity. Based on the synthesized monodisperse silver nanoparticles, conductive inks were prepared with water, ethanol and ethylene glycol as solvents, and were expected to be more environmentally friendly. A series of electrocircuits were fabricated by ink-jet printing silver nanoparticle ink on paper substrate with a commercial printer, and they had low resistivity in the range of 9.18 × 10( - 8)-8.76 × 10( - 8) Ω m after thermal treatment at 160 °C for 30 min, which was about five times that of bulk silver (1.586 × 10( - 8) Ω m). Moreover, a radio frequency identification (RFID) antenna was fabricated by ink-jet printing, and 6 m wireless identification was realized after an Alien higgs-3 chip was mounted on the printed antenna by the flip-chip method. These flexible electrocircuits produced by ink-jet printing would have enormous potential for low cost electrodes and sensor devices.